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A linkage study of Emery-Dreifuss muscular dystrophy
Shirley Hodgson; Ernst Boswinkel; Charlotte Cole; Alison Walker; V. Dubowitz; Claudia Granata; L. Merlini; M. Bobrow
We have searched for linkage between polymorphic loci defined by DNA markers on the X chromosome and X-linked Emery-Dreifuss muscular dystrophy (EDMD). There are high recombination rates between EDMD and the Xp loci known to be linked to Becker and Duchenne muscular dystrophy. There is a suggestion of linkage between EDMD and the loci DXS52 and DXS15, defined by probes
Increased resting energy expenditure in subjects with Emery-Dreifuss muscular dystrophy.
Vaisman, N; Katzenellenbogen, S; Nevo, Y
We have studied changes in energy expenditure and body composition in adult males with Emery-Dreifuss muscular dystrophy, age-matched males with hyperCKemia and age-matched healthy controls. All participants were studied twice, 2-3 years apart. Resting energy expenditure was studied by indirect calorimetry, lean body mass and body fat by dual X-ray absorptiometry, and muscle mass was estimated based on 24-h urinary creatinine excretion. At baseline and 2-3 years later, body fat was significantly higher (P < 0.011 and P < 0.003, respectively) and lean body mass significantly lower (P < 0.024 and P < 0.012, respectively) in patients with Emery-Dreifuss muscular dystrophy as compared to subjects with hyperCKemia and healthy controls. Resting energy expenditure, over the study period, increased significantly in patients with Emery-Dreifuss muscular dystrophy (P < 0.031), but not in patients with hyperCKemia nor in healthy controls. Our study suggests that patients with Emery-Dreifuss muscular dystrophy may have increased energy expenditure relative to healthy subjects. If not met by increased caloric intake, this greater energy expenditure may partially contribute to a further deterioration in their muscle performance. PMID:14733961
Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy
Luca Cartegni; Marina Raffaele; Rita Barresi; Stefano Squarzoni; Patrizia Sabatelli; Nadir Maraldi; Marina Mora; Claudia Di Blasi; Ferdinando Cornelio; Luciano Merlini; Antonello Villa; Fabio Cobianchi; Daniela Toniolo
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD gene encodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell
Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant EmeryľDreifuss muscular dystrophy
Maggie C. Walter; Thomas N. Witt; Beate Schlotter Weigel; Peter Reilich; Pascale Richard; Dieter Pongratz; GisŔle Bonne; Manfred S. Wehnert; Hanns LochmŘller
Mutations in the LMNA gene encoding the nuclear envelope protein, lamins A and C, have been associated with at least nine distinct disorders now called laminopathies, including EmeryľDreifuss muscular dystrophy and CharcotľMarieľTooth type 2 disease. We identified a novel mutation in the 5? region of the LMNA gene ?3del15, resulting in the loss of 15 nucleotides from ?3 to +12,
Identification of lamin A\\/C ( LMNA ) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B
Chang-Seok Ki; Jong Seo Hong; Gyu-Young Jeong; Kyoung Ju Ahn; Kwang-Mo Choi; Duk-Kyung Kim; Jong-Won Kim
Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders:\\u000a autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B;\\u000a MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently,\\u000a we have studied
Expression and localization of nuclear proteins in autosomal-dominant Emery-Dreifuss muscular dystrophy with LMNA R377H mutation
Beate Reichart; Ruth Klafke; Christine Dreger; Eleonora KrŘger; Isabell Motsch; Andrea Ewald; Jochen Schńfer; Heinz Reichmann; Clemens R MŘller; Marie-Christine Dabauvalle
BACKGROUND: The autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) is caused by mutations in the gene encoding for the lamins A and C (LMNA). Lamins are intermediate filament proteins which form the nuclear lamina underlying the inner nuclear membrane. We have studied the expression and the localization of nuclear envelope proteins in three different cell types and muscle tissue
Pathology and nuclear abnormalities in hearts of transgenic mice expressing M371K lamin A encoded by an LMNA mutation causing Emery-Dreifuss muscular dystrophy
Yuexia Wang; Alan J. Herron; Howard J. Worman
Mutations in LMNA, which encodes nuclear lamins A and C, cause a broad range of diseases, including autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) and related disorders with a predominant cardiomyopathy. Homozygous Lmna model 'knock-in' and null mice develop cardiomyopathy, whereas het- erozygous mice do not. Overexpression of lamin A mutants that cause cardiomyopathy in cultured cells induces morphological abnormalities in
Genetics Home Reference: Emery-Dreifuss muscular dystrophy
... causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), ... traits to their sons. In females (who have two X chromosomes), a mutation typically must be present in both ...
Rare Muscular Dystrophies: Congenital, Distal, Emery-Dreifuss and Oculopharyngeal Muscular Dystrophies
... understood how the loss of emerin from the nuclear membrane in X-linked EDMD leads to the ... of emerin interferes with the reorganization of the nuclear membrane after a cell has divided, leading to ...
Pseudohypertrophic muscular dystrophy; Muscular dystrophy - Duchenne type ... Duchenne muscular dystrophy is a form of muscular dystrophy . It worsens quickly. Other muscular dystrophies (including Becker's muscular dystrophy ) get ...
Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies
Takuro Arimura; Anne Helbling-Leclerc; Catherine Massart; Shaida Varnous; Florence Niel; Emmanuelle Lacene; Yves Fromes; Marcel Toussaint; Anne-Marie Mura; Dagmar I. Keller; Helge Amthor; Richard Isnard; Marie Malissen; Ketty Schwartz; Gisele Bonne
Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and\\/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated
Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...
Muscular dystrophy is a group of inherited disorders that cause muscle weakness and loss of muscle tissue, which ... Muscular dystrophies, or MD, are a group of inherited conditions. This means they are passed down through families. ...
... time), cataracts, and heart problems. Congenital muscular dystrophy (CMD) is the term for all types of MD ... diagnosed right away. Like other forms of MD, CMD involves muscle weakness and poor muscle tone. Occurring ...
Muscular dystrophy - resources
Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association - www.mdausa.org National Institute of Neurological Disorders and Stroke - www.ninds.nih. ...
... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ... to become weak. How Does a Kid Get Muscular Dystrophy? MD is not contagious (say: con-TAY-juss), ...
NINDS Muscular Dystrophy Information Page Clinical Trials Finding the Optimum Regimen for Duchenne Muscular Dystrophy (FOR-DMD) This study will ... Trials Organizations Additional resources from MedlinePlus What is Muscular Dystrophy? The muscular dystrophies (MD) are a group of ...
Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.
Tan, Dandan; Yang, Haipo; Yuan, Yun; Bonnemann, Carsten; Chang, Xingzhi; Wang, Shuang; Wu, Yuchen; Wu, Xiru; Xiong, Hui
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD. PMID:26098624
PhenotypeľGenotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy
Tan, Dandan; Yang, Haipo; Yuan, Yun; Bonnemann, Carsten; Chang, Xingzhi; Wang, Shuang; Wu, Yuchen; Wu, Xiru; Xiong, Hui
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotypeľgenotype analysis determines that some mutations are well correlated with LMNA-related MD. PMID:26098624
Muscular Dystrophy Association
MDA | Muscular Dystrophy Association About MDA Advocacy Publications Media Give Now. Give online Give by mail Give by phone Main ... Get Involved Publications Site Map Connect with MDA Muscular Dystrophy Association Ś USA National Office 222 S. Riverside Plaza, Suite ...
Muscular Dystrophy Coordinating Committee
Muscular Dystrophy Coordinating Committee (MDCC) WE ARE NO LONGER ACCEPTING COMMENTS AND EDITS THROUGH THIS SITE. THIS COPY ... on the Draft 2015 Action Plan for the Muscular Dystrophies Draft 2015 Action Plan (PDF, 1.06MB) Request ...
Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies.
Li, Ping; Meinke, Peter; Huong, Le Thi Thanh; Wehnert, Manfred; Noegel, Angelika A
Mutations in several genes encoding nuclear envelope (NE) associated proteins cause Emery-Dreifuss muscular dystrophy (EDMD). We analyzed fibroblasts from a patient who had a mutation in the EMD gene (p.L84Pfs*6) leading to loss of Emerin and a heterozygous mutation in SUN1 (p.A203V). The second patient harbored a heterozygous mutation in LAP2alpha (p.P426L) and a further mutation in SUN1 (p.A614V). p.A203V is located in the N-terminal domain of SUN1 facing the nucleoplasm and situated in the vicinity of the Nesprin-2 and Emerin binding site. p.A614V precedes the SUN domain, which interacts with the KASH domain of Nesprins in the periplasmic space and forms the center of the LINC complex. At the cellular level, we observed alterations in the amounts for several components of the NE in patient fibroblasts and further phenotypic characteristics generally attributed to laminopathies such as increased sensitivity to heat stress. The defects were more severe than observed in EDMD cells with mutations in a single gene. In particular, in patient fibroblasts carrying the p.A203V mutation in SUN1, the alterations were aggravated. Moreover, SUN1 of both patient fibroblasts exhibited reduced interaction with Lamin A/C and when expressed ectopically in wild-type fibroblasts, the SUN1 mutant proteins exhibited reduced interactions with Emerin as well. PMID:24375709
Lamina-associated Polypeptide-1 Interacts with the Muscular Dystrophy Protein Emerin and is Essential for Skeletal Muscle Maintenance
Shin, Ji-Yeon; MÚndez-Lˇpez, Ivßn; Wang, Yuexia; Hays, Arthur P.; Tanji, Kurenai; Lefkowitch, Jay H.; Schulze, P. Christian; Worman, Howard J.; Dauer, William T.
SUMMARY X-linked Emery-Dreifuss muscular dystrophy is caused by loss-of-function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy and this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from wild type controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms. PMID:24055652
Facioscapulohumeral muscular dystrophy
There is no known cure for facioscapulohumeral muscular dystrophy. Treatments are given to control symptoms and improve quality of life. Activity is encouraged. Inactivity such as bedrest can make the muscle disease worse. ...
There is no known cure for Becker muscular dystrophy. The goal of treatment is to control symptoms to maximize the person's quality of life. Some doctors prescribe steroids to help keep a patient walking for as ...
Evaluation of Limb-Girdle Muscular Dystrophy
Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)
Genetics Home Reference: Ullrich congenital muscular dystrophy
... understanding Ullrich congenital muscular dystrophy? autosomal ; autosomal dominant ; autosomal recessive ; cell ; collagen ; congenital ; deficiency ; extracellular ; extracellular matrix ; gene ; hypermobility ; inherited ; joint ; muscle cell ; muscle cells ; muscular dystrophy ; ...
Ultrastructure of Muscular Dystrophy
Sweeny, Phillip R.; Buchanan-Smith, J. G.; deMille, F.; Pettit, J. R.; Moran, E. T.
The ultrastructure of the semitendonosus muscle of lambs and the pectoralis major muscles of chickens suffering from nutritional muscular dystrophy were studied. Samples of tissue from histologically normal and mildly degenerate areas were examined. Ultrastructural examination of areas that appeared apparently normal histologically, revealed lesions in the small vessels, connective tissue elements and neuromuscular elements. The possible relationship of these findings to the etiology of this disease are discussed. ImagesFig 7Fig 8Fig 9Figs 10-11Fig 12Fig 13Fig 1Fig 2Fig 3Fig 14Fig 15Fig 16Fig 4Fig 5Fig 6 PMID:5054255
Orocaecal transit time in Duchenne muscular dystrophy.
Korman, S H; Bar-Oz, B; Granot, E; Meyer, S
Smooth muscle degeneration may occur in Duchenne muscular dystrophy. We measured fasting orocaecal transit time in patients with advanced Duchenne muscular dystrophy and other muscular dystrophies and in healthy controls. No significant differences were found. In contrast to reports of gastric hypomotility in Duchenne muscular dystrophy, we found no evidence of impaired small intestinal motility. PMID:1994843
Porcine models of muscular dystrophy
Technology Transfer Automated Retrieval System (TEKTRAN)
Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...
Duchenne and Becker muscular dystrophies.
Flanigan, Kevin M
The dystrophinopathies Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most common inherited disorders of muscle. Improvements in cardiac care, attention to respiratory function, and judicious use of spinal correction surgery have led to increased survival in the DMD population. Meanwhile, advances in molecular therapeutics have led to promising therapies that are in or are entering clinical trials. An understanding of the dystrophinopathies, and recent advances in their molecular diagnosis and treatment, is of benefit to practicing neurologists. PMID:25037084
Caveolin-3 in muscular dystrophy
Elizabeth M. McNally; Eloisa de Sß Moreira; David J. Duggan; Carsten G. B÷nnemann; Michael P. Lisanti; Hart G. W. Lidov; Mariz Vainzof; M. Rita Passos-Bueno; Eric P. Hoffman; Mayana Zatz; Louis M. Kunkel
DDBJ\\/EMBL\\/GenBank accession nos AF036365-AF036367 The dystrophin-glycoprotein complex (DGC) serves as a link between cytoplasmic actin, the membrane and the extracellular matrix of striated muscle. Genetic defects in genes encoding a subset of DGC proteins result in muscular dystrophy and a secondary decrease in other DGC proteins. Caveolae are dynamic structures that have been implicated in a number of functions including
Sleep disordered breathing in facioscapulohumeral muscular dystrophy
Giacomo Della Marca; Roberto Frusciante; Serena Dittoni; Catello Vollono; Cristina Buccarella; Elisabetta Iannaccone; Monica Rossi; Emanuele Scarano; Tommaso Pirronti; Alessandro Cianfoni; Salvatore Mazza; Pietro A. Tonali; Enzo Ricci
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were
Genetics and Pathogenesis of Distal Muscular Dystrophies
Bjarne Udd
\\u000a Distal myopathies are distal muscular dystrophies because they are genetic disorders with progressive loss of muscle tissue.\\u000a The true distal dystrophies not only show a distal onset; they also remain more distal than proximal throughout the course\\u000a of the disease. Currently almost 20 different entities of distal muscular dystrophies have been genetically determined, compared\\u000a to just five entities delineated on
The Muscular Dystrophies: From Genes to Therapies
Porter, Neil C; Bloch, Robert J
The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275
Duchenne muscular dystrophy: current cell therapies
Sienkiewicz, Dorota; Okurowska-Zawada, Bo?ena; Paszko-Patej, Gra?yna; Kawnik, Katarzyna
Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844
Duchenne muscular dystrophy: current cell therapies.
Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bo?ena; Paszko-Patej, Gra?yna; Kawnik, Katarzyna
Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844
Targeting Latent TGF? release in muscular dystrophy
Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U.; Hadhazy, Michele; Smith, Lucas R.; Barton, Elisabeth R.; Molkentin, Jeffery D.; McNally, Elizabeth M.
Latent TGF? binding proteins (LTBPs) bind to inactive TGF? in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGF? release. We have found that the hinge region of human LTBP4 was also readily proteolyzed, and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGF? signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGF? release and activity and decrease inflammation and muscle damage in muscular dystrophy. PMID:25338755
Symptoms of FSHD (Facioscapulohumeral Muscular Dystrophy)
... facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2005 Mar; 76(3):375-86. Review. Click to read ... Angeles FSHD CONNECTS Meeting Saturday, July 18, 2015 Mar Vista Denver FSHers meeting Tuesday, July 21, 2015 ...
Genetics Home Reference: Tibial muscular dystrophy
... skeletal muscles) and in heart (cardiac) muscle. Within muscle cells, titin is an essential component of structures called ... cardiac ; cell ; contraction ; distal ; foot drop ; gene ; inherited ; muscle cells ; muscular dystrophy ; myosin ; protein ; sign ; wasting You may ...
Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy
Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn
Acquired noncompaction in Duchenne muscular dystrophy.
Finsterer, Josef; St÷llberger, Claudia; Gaismayer, Kurt; Janssen, Bart
Acquired left ventricular hypertrabeculation/noncompaction (LVHT) is rare and has been described in patients with mitochondriopathy, Barth syndrome, and Becker muscular dystrophy. Here we report acquired LVHT in a 28-year-old man with Duchenne muscular dystrophy who required non-invasive, positive-pressure ventilation for muscular respiratory failure since age 16 years. Transthoracic echocardiography at age 22 years revealed enlarged left atrium and ventricle and reduced fractional shortening, but no LVHT. Transthoracic echocardiography at age 27 years revealed enlarged left atrium and ventricle, systolic dysfunction, mitral insufficiency, and, surprisingly, LVHT. The cause and pathomechanism of acquired LVHT in this patient remained speculative. PMID:16337060
Altered biomechanical properties of large arteries in muscular dystrophyá
Dye, Wendy Watson
Muscular dystrophy is a disease characterized by skeletal muscle weakness and wasting, but little is known of alterations in the vascular system that occur with this disease. The culprit in many muscular dystrophies is a defective dystrophin...
Genetics Home Reference: Limb-girdle muscular dystrophy
... or the removal of potentially toxic wastes from muscle cells. Limb-girdle muscular dystrophy is classified based on ... gene ; hypertrophy ; inheritance ; inheritance pattern ; inherited ; joint ; lordosis ; muscle cells ; muscular dystrophy ; mutation ; population ; prevalence ; protein ; proximal ; recessive ; ...
Lung function in Duchenne muscular dystrophy
C. S. B. Galasko; J. B. Williamson; C. M. Delaney
Over 90% of patients with Duchenne muscular dystrophy develop a scoliosis when they become wheelchair bound. The scoliosis is progressive and is associated with deteriorating lung function. The purpose of this study was firstly to assess whether a standing regimen, in patients who had gone off their feet, protected against the development of scoliosis and affected their lung function, and
Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy
ERIC Educational Resources Information Center
De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack
Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was toů
Congenital Muscular Dystrophy with Central Nervous System Involvement: Case Report
P. Martinelli; A. S. Gabellini; G. Ciucci; E. Govoni; S. Vitali; M. R. Gullý
A case of a mediterranean boy with congenital muscular dystrophy (CMD) and central nervous system (CNS) involvement with mild intellectual impairment and seizures is reported. Muscular dystrophy involved both skeletal and mimic muscles, and histological findings were consistent with a congenital dystrophy. EEG recordings showed generalized and localized paroxysmal activities. CT scan demonstrated low-density periventricular areas. Ophthalmoplegia was also observed.
Caveolae and caveolin-3 in muscular dystrophy.
Galbiati, F; Razani, B; Lisanti, M P
Caveolae are vesicular invaginations of the plasma membrane, and function as 'message centers' for regulating signal transduction events. Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolar membrane domains in skeletal muscle and in the heart. Several mutations within the coding sequence of the human caveolin-3 gene (located at 3p25) have been identified. Mutations that lead to a loss of approximately 95% of caveolin-3 protein expression are responsible for a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans. By contrast, upregulation of the caveolin-3 protein is associated with Duchenne muscular dystrophy (DMD). Thus, tight regulation of caveolin-3 appears essential for maintaining normal muscle health and homeostasis. PMID:11597517
von der Heydt, RŘdiger
The Fiscal Year 2013 (FY13) Defense Appropriations Act provides for $3.2 million (M) to the DepartmentDEPARTMENT OF DEFENSE DUCHENNE MUSCULAR DYSTROPHY RESEARCH PROGRAM FISCAL YEAR 2013 STRATEGIC PLAN of Defense Duchenne Muscular Dystrophy Research Program (DMDRP) to support innovative, high-impact Duchenne
Oculopharyngeal muscular dystrophy, other ocular myopathies, and progressive external ophthalmoplegia
Lewis P. Rowland; Michio Hirano; Salvatore DiMauro; Eric A. Schon
Progressive external ophthalmoplegia comprises many different disorders. Those of childhood onset can be separated from juvenile or adult onset. Among those of later onset the most common causes are oculopharyngeal muscular dystrophy, oculopharyngodistal muscular dystrophy and the several mitochondrial disorders, especially those with large deletions of mitochondrial DNA (mtDNA) (sporadic), those with maternal inheritance (point mutations), or the autosomal dominant
Peter Vestergaard; Henning Glerup; Birgit F. Steffensen; Lars Rejnmark; Jes Rahbek; Leif Mosekilde
We aimed at studying fracture risk in patients with Duchenne' s muscular dystrophy (DMD), Becker' s muscular dystrophy (BEMD), and spinal muscular atrophy type II and III (SMA II and III). A self-administered questionnaire was mailed to 293 patients with DMD, BEMD, SMA II or SMA III of which 229 returned the questionnaire. Each respondent was compared with an age-
Genetic counselling in facioscapulohumeral muscular dystrophy.
Lunt, P W; Harper, P S
Clinical data are presented from a survey of 41 families with dominantly inherited facioscapulohumeral muscular dystrophy (FSHD) in which over 500 family members were examined, including 168 affected subjects. New mutation could account for six isolated cases. Results suggest that 33% of heterozygotes over 40 years are mildly affected and a majority develop significant lower limb weakness; 19% over 40 years require wheelchairs. Presymptomatic testing of serum creatine kinase level (CK) is limited as a raised level occurs in only 80% of affected males under 40 years and 48% of affected women. Distribution of weakness, severity, age at onset, and CK varied between subjects, but provided no clinical evidence for genetic heterogeneity in a comparison between the 11 largest families. The conclusion of genetic homogeneity in FSHD, including subjects previously diagnosed as FSH type spinal muscular atrophy, is strongly supported by recent genetic linkage data. PMID:1941962
Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy.
Santos, Dante Brasil; Boussaid, Ghilas; Stojkovic, Tanya; Orlikowski, David; Letilly, Nadege; Behin, Anthony; Butel, Sandrine; Lofaso, FrÚdÚric; Prigent, HÚlŔne
Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P?=?0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2)?=?0.503; P?=?0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1?▒?1.9 vs. 3.2?▒?1.2; P?<0.0001) and body mass index (26.9?▒?6.0 vs. 22.9?▒?4.0ákg/m(2); P?=?0.003) and a smaller number of D4Z4 allele repeats (4.8?▒?1.6 vs. 5.7?▒?1.8; P?=?0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index. PMID:26023000
Utrophin upregulation in Duchenne muscular dystrophy.
Hirst, R C; McCullagh, K J A; Davies, K E
Duchenne Muscular Dystrophy (DMD) is a devastating, progressive muscle wasting disease for which there is currently no effective treatment. DMD is caused by mutations in the dystrophin gene many of which result in the absence of the large cytoskeletal protein dystrophin at the sarcolemma. Over-expression of utrophin, the autosomal paralogue of dystrophin, as a transgene in the mdx mouse (the mouse model of DMD) has demonstrated that utrophin can prevent the muscle pathology. Thus, up-regulation of utrophin in DMD muscle is a potential therapy for DMD. In this review we discuss recent advances in our understanding of the regulatory pathways controlling utrophin expression and the various approaches that have been applied to increasing the level of utrophin in the mdx mouse. These results are very encouraging and suggest that pharmacological up-regulation of utrophin may well be a feasible approach to therapy for DMD. PMID:16629055
Congenital Muscular Dystrophies: A Brief Review
Bertini, Enrico; D'Amico, Adele; Gualandi, Francesca; Petrini, Stefania
Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments. PMID:22172424
Porcine models of muscular dystrophy1.
Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin
Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease. PMID:25991703
Genetics Home Reference: Duchenne and Becker muscular dystrophy
... of this protein become damaged as muscles repeatedly contract and relax with use. The damaged fibers weaken and die over time, leading to the muscle weakness and heart problems characteristic of Duchenne and Becker muscular dystrophies. Mutations ...
Ocular muscular dystrophy. A cause of curare sensitivity.
Robertson, J A
A case is described of a child with ocular muscular dystrophy, who demonstrated the extreme sensitivity to non-depolarising muscle relaxants, with lack of reversal by anticholinesterases, characteristic of this condition. PMID:6703294
Genetics Home Reference: LAMA2-related muscular dystrophy
... the extracellular matrix and in the membrane of muscle cells, which helps maintain the stability of muscle fibers. ... to thrive ; gene ; hypotonia ; inherited ; joint ; lordosis ; motor ; muscle cells ; muscle tone ; muscular dystrophy ; prevalence ; protein ; proximal ; recessive ; ...
An Outbreak of Nutritional Muscular Dystrophy in Dromedary Camels
J. A. Corbera; M. Morales; M. Pulido; J. A. Montoya; C. Gutierrez
Corbera, J.A., Morales, M., Pulido, M., Montoya, J.A. and Gutierrez, C. 2002. An outbreak of nutritional muscular dystrophy in dromedary camels. J. Appl. Anim. Res., 23: 117ľ122.An outbreak of nutritional muscular dystrophy (NMD) due to vitamin E\\/selenium deficiency in an intensive dromedary camel herd causing a mortality of 25 animals (22 calves and 3 adults) is described. From a total
The Neuropsychological Profile of Infantile Duchenne Muscular Dystrophy
Giovanni Mento; Vincenza Tarantino; Patrizia S. Bisiacchi
It has been shown that children with Duchenne muscular dystrophy (DMD) exhibit specific cognitive deficits. However, the neuropsychological profile has not yet been fully characterized. In order to control for the contribution of motor impairments as a confounding variable that is usually present when assessing children with muscular pathologies, we compared children with DMD to a group of children with
Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire
ERIC Educational Resources Information Center
Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon
Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms ofů
A comparison of gait in spinal muscular atrophy, type II and Duchenne muscular dystrophy
StÚphane Armand; Eric Watelain; Karine Patte; Jacques Pelissier; Franšois Rivier
This study investigated and compared the gait of two patients with spinal muscular atrophy, type II (SMA II) and two patients with Duchenne muscular dystrophy (DMD). These diseases cause a progressive and proximal to distal muscular weakness resulting in the loss of ambulation. The DMD cases had comparable muscle weakness with the SMA II cases on manual muscle testing and
Optimizing Bone Health in Duchenne Muscular Dystrophy
Buckner, Jason L.; Bowden, Sasigarn A.; Mahan, John D.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID:26124831
Lung function in Duchenne muscular dystrophy.
Galasko, C S; Williamson, J B; Delaney, C M
Over 90% of patients with Duchenne muscular dystrophy develop a scoliosis when they become wheelchair bound. The scoliosis is progressive and is associated with deteriorating lung function. The purpose of this study was firstly to assess whether a standing regimen, in patients who had gone off their feet, protected against the development of scoliosis and affected their lung function, and secondly to evaluate the effect of spinal stabilisation in patients who had developed a progressive scoliosis. The results of the first part of this study showed that a standing regimen significantly delayed the progression of scoliosis and that patients who complied with the standing regimen had a significantly better lung function, as measured by vital capacity and peak expiratory flow rate, than those patients who did not stand. Spinal stabilisation prevented deterioration in the scoliosis, whereas the deformity continued to progress relentlessly in patients who did not undergo surgery. The patients who underwent spinal stabilisation maintained a significantly better lung function and had an improved survival compared with the patients who refused surgery. PMID:8581525
Gene therapy for muscular dystrophy: moving the field forward.
Al-Zaidy, Samiah; Rodino-Klapac, Louise; Mendell, Jerry R
Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field. PMID:25439576
The burden of Duchenne muscular dystrophy
Landfeldt, Erik; Lindgren, Peter; Bell, Christopher F.; Schmitt, Claude; Guglieri, Michela; Straub, Volker; LochmŘller, Hanns
Objective: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Methods: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in EuropeľAssessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. Results: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. Conclusions: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies. PMID:24991029
in hereditary muscular dystrophy and vitamin E deficiency1
Robert Eugene Olson
Although the myopathy of vitamin E deficiency imitates many features of hereditary muscular dystrophy, the molecular basis of these similarities remains unexplained. Unlike the water-soluble vitamins that act as coenzyme precursors in mammalian tissues, the fat-soluble vitamins appear to regulate the synthesis of specific proteins required by highly differentiated organisms. To test the hypothesis that vitamin E does regulate the
Social Behavior Problems in Boys with Duchenne Muscular Dystrophy
Social Behavior Problems in Boys with Duchenne Muscular Dystrophy VERONICA J. HINTON, PH with DMD. Parental ratings of boys with DMD (n = 181) on the Child Behavior Checklist behavior scales were of boys with DMD (n = 86), and children with cerebral palsy (CP) (n = 42). Increased ratings of general
Therapies in Muscular Dystrophy: Current Concepts and Future Prospects
J. Andoni Urtizberea
In the fast moving field of muscular dystrophy, therapeutic matters are now high on the agenda. Despite little progress made in the understanding of the exact pathogenesis, hopes have been raised with the advent of molecular medicine applied to such disorders. A constellation of techniques or therapeutic solutions are now available, but very few have reached the clinical stage. Gene
Nocturnal Oxygenation and Prognosis in Duchenne Muscular Dystrophy
REM-related oxygen desaturation occurs in advanced Duchenne muscular dystrophy (DMD) and might be an independent predictor of disease progression. We have followed 18 patients for 10 yr af- ter an initial respiratory sleep study or until death or onset of nasal ventilation. We measured base- line spirometry, blood gas tensions, maximal respiratory pressures, and body mass index. In 11 cases,
Importance of lower limb surgery in Duchenne muscular dystrophy
R. Forst; J. Forst
A total of 123 patients with Duchenne muscular dystrophy (DMD) was surgically treated during two different periods of their course by hip and knee release, aponeurectomy of the iliotibial band and z-shaped Achilles' tendon lenghtening. In 57 patients (group 1) this was carried out prophylactically as retractions of the lower limb joints were just beginning at the age of 6.4
Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy
ERIC Educational Resources Information Center
Waring, Phoebe; Woodyatt, Gail
Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the resultsů
Occupational Potential in a Population with Duchenne Muscular Dystrophy.
ERIC Educational Resources Information Center
Schkade, Janette K.; And Others
Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skillů
The Child with Muscular Dystrophy in School. Revised.
ERIC Educational Resources Information Center
Schock, Nancy C.
Practical information on children with muscular dystrophy is intended to help parents and teachers facilitate their inclusion in mainstreamed classrooms. Major topics addressed include the following: transportation arrangements; providing full information to the teacher regarding the child's specific abilities and physical limitations;ů
The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.
ERIC Educational Resources Information Center
Mearig, Judith S.
Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).ů
Stem cell transplantation for treating Duchenne muscular dystrophy
Yang, Xiaofeng
OBJECTIVE: To identify global research trends in stem cell transplantation for treating Duchenne muscular dystrophy using a bibliometric analysis of Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of studies on stem cell transplantation for treating Duchenne muscular dystrophy from 2002 to 2011 retrieved from Web of Science. SELECTION CRITERIA: Inclusion criteria: (a) peer-reviewed published articles on stem cell transplantation for treating Duchenne muscular dystrophy indexed in Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and (c) publication between 2002 and 2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) corrected papers. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to subject areas; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) distribution according to institution in China; (7) distribution according to institution that cooperated with Chinese institutions; (8) top-cited articles from 2002 to 2006; (9) top-cited articles from 2007 to 2011. RESULTS: A total of 318 publications on stem cell transplantation for treating Duchenne muscular dystrophy were retrieved from Web of Science from 2002 to 2011, of which almost half derived from American authors and institutes. The number of publications has gradually increased over the past 10 years. Most papers appeared in journals with a focus on gene and molecular research, such as Molecular Therapy, Neuromuscular Disorders, and PLoS One. The 10 most-cited papers from 2002 to 2006 were mostly about different kinds of stem cell transplantation for muscle regeneration, while the 10 most-cited papers from 2007 to 2011 were mostly about new techniques of stem cell transplantation for treating Duchenne muscular dystrophy. CONCLUSION: The publications on stem cell transplantation for treating Duchenne muscular dystrophy were relatively few. It also needs more research to confirm that stem cell therapy is a reliable treatment for Duchenne muscular dystrophy. PMID:25624797
The role of fibrosis in Duchenne muscular dystrophy.
Klingler, Werner; Jurkat-Rott, Karin; Lehmann-Horn, Frank; Schleip, Robert
Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical, humoral and cellular factors. Originating from vulnerable myofibres, muscle cell necrosis and inflammatory processes are present in DMD. Muscular recovery is limited due to the limited number and capacity of satellite cells. Hence, a proactive and multimodal approach is necessary in order to activate protective mechanisms and to hinder catabolic and tissue degrading pathways. Several avenues are discussed in terms of potential antifibrotic therapy approaches. These include pharmaceutical, nutritional, exercise-based and other mechanostimulatory modalities (such as massage or yoga-like stretching) with the intention of exerting an anti-inflammatory and antifibrotic effect on the affected muscular tissues. A preventive intervention at an early age is crucial, based on the early and seemingly non-reversible nature of the fibrotic tissue changes. Since consistent assessment is essential, different measurement technologies are discussed. PMID:23620650
Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S.
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, the most recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and non-viral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene. PMID:23553671
Autosomal recessive Duchenne-like muscular dystrophy: molecular and histochemical results.
McGuire, S A; Fischbeck, K H
An autosomal recessive disorder which mimics Duchenne muscular dystrophy has long been suspected as a cause of muscular dystrophy in karyotypically normal girls and in both boys and girls with consanguineous parents. Analysis of dystrophin now allows confirmation of the existence of this disorder. We report the results of this analysis in a brother and sister who have the typical clinical features of Duchenne muscular dystrophy, but no demonstrable abnormality in dystrophin or its gene. PMID:1766451
A phase I\\/IItrial of MYO029 in adult subjects with muscular dystrophy
Kathryn R. Wagner; James L. Fleckenstein; Anthony A. Amato; Richard J. Barohn; Katharine Bushby; Diana M. Escolar; Kevin M. Flanigan; Alan Pestronk; Rabi Tawil; Gil I. Wolfe; Michelle Eagle; Julaine M. Florence; Wendy M. King; Shree Pandya; Volker Straub; Paul Juneau; Kathleen Meyers; Cristina Csimma; Tracey Araujo; Robert Allen; Stephanie A. Parsons; John M. Wozney; Edward R. LaVallie; Jerry R. Mendell
Objective: Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We con- ducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dys- trophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy). Methods: This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each
ported our findings, in agreement with those of Mattill (ÔÇś40), demonstrating the ineffectiveness of dl-a-tocopheryl acetate for curing nutritional muscular dystrophy of rabbits when administered parenterally. The question was raised, whether this failure was due to the lack of an esterase within the body to liberate the free tocopherol, as suggested by Mattill (ÔÇś38),or whether it was due to the
Atypical facet of M÷bius syndrome: association with facioscapulohumeral muscular dystrophy.
Kolski, Hanna K; Leonard, Norma J; Lemmers, Richard J L F; Bamforth, John S
We describe a patient with facioscapulohumeral muscular dystrophy (FSHD) associated with M÷bius syndrome and congenital ophthalmoplegia. This 7-year-old girl had profound limitation of extraocular movements since birth, congenital facial diplegia, neonatal hypotonia, and progressive limb-girdle weakness. FSHD genetic testing revealed a pathogenic haplotype with a D4Z4 repeat of 30 kb. The father carries the same allele, although is minimally affected. This unusual case expands the genotypic-phenotypic spectrum of FSHD. PMID:18059038
Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy
Samira Makri; Nigel F. Clarke; Pascale Richard; Svetlana Maugenre; Laurence Demay; GisŔle Bonne; Pascale Guicheney
Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A\\/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation
DeVanna, Justin C.; Kornegay, Joe N.; Bogan, Daniel J.; Bogan, Janet R.; Dow, Jennifer L.; Hawkins, Eleanor C.
Golden retriever muscular dystrophy (GRMD) is a well-established model of Duchenne muscular dystrophy. The value of this model would be greatly enhanced with practical tools to monitor progression of respiratory dysfunction during treatment trials. Arterial blood gas analysis, tidal breathing spirometry, and respiratory inductance plethysmography (RIP) were performed to determine if quantifiable abnormalities could be identified in unsedated, untrained, GRMD dogs. Results from 11 dogs with a mild phenotype of GRMD and 11 age-matched carriers were compared. Arterial blood gas analysis was successfully performed in all dogs, spirometry in 21 of 22 (95%) dogs, and RIP in 18 of 20 (90%) dogs. Partial pressure of carbon dioxide and bicarbonate concentration were higher in GRMD dogs. Tidal breathing peak expiratory flows were markedly higher in GRMD dogs. Abnormal abdominal motion was present in 7 of 10 (70%) GRMD dogs. Each technique provided objective, quantifiable measures that will be useful for monitoring respiratory function in GRMD dogs during clinical trials while avoiding the influence of sedation on results. Increased expiratory flows and the pattern of abdominal breathing are novel findings, not reported in people with Duchenne muscular dystrophy, and might be a consequence of hyperinflation. PMID:24295812
Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD
Th Voit; E Parano; V Straub; J. M Schr÷der; J Schaper; P Pavone; R Falsaperla; L Pavone; R Herrmann
At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal
What causes muscular dystrophy?, 2D animationSite: DNA Interactive (www.dnai.org)
NSDL National Science Digital Library
The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.
What is muscular dystrophy?, 2D animationSite: DNA Interactive (www.dnai.org)
NSDL National Science Digital Library
The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.
Duchenne muscular dystrophy, 2D animationSite: DNA Interactive (www.dnai.org)
NSDL National Science Digital Library
The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.
Clinicopathological study on eyes from cases of Fukuyama type congenital muscular dystrophy
Naomi Hino; Makio Kobayashi; Noriyuki Shibata; Tomoko Yamamoto; Kayoko Saito; Makiko Osawa
Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by progressive muscular dystrophy and dysgenesis of the central nervous system and eyes. To clarify the pathomechanism of the ocular involvement in FCMD, we performed postmortem pathological analyses of eyes from three postnatal FCMD cases, two fetal FCMD cases, and three control cases by macroscopic, histopathological, immunohistochemical and
The congenital muscular dystrophies in 2004: a century of exciting progress
Francesco Muntoni; Thomas Voit
The congenital muscular dystrophies are a heterogeneous group of inherited disorders. The clinical features range from severe and often early fatal disorders to relatively mild conditions compatible with survival into adult life. The recent advances in the genetic basis of congenital muscular dystrophies have allowed to significantly improve our understanding of their pathogenesis and clinical diversity. These advances have also
Expression Profiling in the Muscular Dystrophies: Identification of Novel Aspects of Molecular Pathophysiology
Yi-Wen Chen; Po Zhao; Rehannah Borup; Eric P. Hoffman
We used expression profiling to define the pathophysiological cascades involved in the progres- sion of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and a -sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative com- parisons of duplicate datasets. We
Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration
Paolo Grumati; Luisa Coletto; Patrizia Sabatelli; Matilde Cescon; Alessia Angelin; Enrico Bertaggia; Bert Blaauw; Anna Urciuolo; Tania Tiepolo; Luciano Merlini; Nadir M Maraldi; Paolo Bernardi; Marco Sandri; Paolo Bonaldo
Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous
The molecular basis of activity-induced muscle injury in Duchenne muscular dystrophy
Basil J. Petrof
Duchenne muscular dystrophy (DMD) is the most common of the human muscular dystrophies, affecting approximately 1 in 3500 boys. Most DMD patients die in their late teens or early twenties due to involvement of the diaphragm and other respiratory muscles by the disease. The primary abnormality in DMD is an absence of dystrophin, a 427 kd protein normally found at
Meeting the Assistive Technology Needs of Students with Duchenne Muscular Dystrophy
ERIC Educational Resources Information Center
Heller, Kathryn Wolff; Mezei, Peter J.; Avant, Mary Jane Thompson
Students with Duchenne muscular dystrophy (DMD) have a degenerative disease that requires ongoing changes in assistive technology (AT). The AT team needs to be knowledgeable about the disease and its progression in order to meet these students' changing needs in a timely manner. The unique needs of students with Duchenne muscular dystrophy inů
Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)
ERIC Educational Resources Information Center
Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker
A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophyů
NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy
Goody, Michelle F.; Kelly, Meghan W.; Reynolds, Christine J.; Khalil, Andre; Crawford, Bryan D.; Henry, Clarissa A.
Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complexľ or integrin alpha7ľdeficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies. PMID:23109907
New aspects on patients affected by dysferlin deficient muscular dystrophy
Klinge, Lars; Aboumousa, Ahmed; Eagle, Michelle; Hudson, Judith; Sarkozy, Anna; Vita, Gianluca; Charlton, Richard; Roberts, Mark; Straub, Volker; Barresi, Rita; LochmŘller, Hanns
Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene. Seventeen mutations were novel; the majority of mutations were small deletions/insertions, and no mutational hotspots were identified. Sixty-one per cent of patients (22 patients) initially presented with limb girdle muscular dystrophy 2B, 31% (11 patients) with a Miyoshi phenotype, one patient with proximodistal mode of onset, one patient with muscle stiffness after exercise and one patient as a symptomatic carrier. A wider range of age of onset was noted than previously reported, with 25% of patients having first symptoms before the age of 13?years. Independent of the initial mode of presentation, in our cohort of patients the gastrocnemius muscle was the most severely affected muscle leading to an inability to stand on tiptoes, and lower limbs were affected more severely than upper limbs. As previous anecdotal evidence on patients affected by dysferlinopathy suggests good muscle prowess before onset of symptoms, we also investigated pre-symptomatic fitness levels of the patients. Fifty-three per cent of the patients were very active and sporty before the onset of symptoms which makes the clinical course of dysferlinopathy unusual within the different forms of muscular dystrophy and provides a challenge to understanding the underlying pathomechanisms in this disease. PMID:19528035
Caveolin proteins in signaling, oncogenic transformation and muscular dystrophy.
Razani, B; Schlegel, A; Lisanti, M P
In adult animals and humans, signal transduction maintains homeostasis. When homeostatic mechanisms are interrupted, an illness or disease may ensue. Caveolae are plasma membrane specializations that contain the structural proteins caveolins, and appear to be important for normal signal transduction. The caveolin scaffolding domain interacts with several signaling molecules, sequestering them in the absence of activating signals, and thereby reducing the signal-to-noise ratio. Deletion and mutation of genes that encode caveolins is implicated in the pathogenesis of several human diseases. Down-regulation of caveolin-1 protein expression leads to deregulated signaling and consequently tumorigenesis, whereas naturally occurring dominant-negative caveolin-3 mutations cause muscular dystrophy. PMID:10825283
Aging with muscular dystrophy: pathophysiology and clinical management.
Carter, Gregory T; Weiss, Michael D; Chamberlain, Joel R; Han, Jay J; Abresch, Richard T; Mirˇ, Jordi; Jensen, Mark P
Major advances in the fields of medical science and physiology, molecular genetics, biomedical engineering, and computer science have provided individuals with muscular dystrophy (MD) with more functional equipment, allowing better strategies for improvement of quality of life. These advances have also allowed a significant number of these patients to live much longer. As progress continues to change management, it also changes patients' expectations. A comprehensive medical and rehabilitative approach to management of aging MD patients can often fulfill expectations and help them enjoy an enhanced quality of life. PMID:20494287
The Molecular Biology of Mutations and Muscular Dystrophy
NSDL National Science Digital Library
Ingrid Waldron
In this mind-on analysis and discussion activity students explore the effects of different types of point mutations and deletion mutations and analyze the reasons why deletion mutations generally have more severe effects than point mutations. Students use their understanding of the molecular biology of mutations to analyze the genetic basis for the differences in severity of two types of muscular dystrophy. To maximize student participation and learning, I recommend that you have your students complete the questions individually or in pairs and then have a whole class discussion.
Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy
Pessina, Patrizia; Kharraz, Yacine; JardÝ, MercŔ; Fukada, So-ichiro; Serrano, AntonioáL.; Perdiguero, Eusebio; Mu˝oz-Cßnoves, Pura
Summary Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGF?-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. PMID:25981413
Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy.
Pessina, Patrizia; Kharraz, Yacine; JardÝ, MercŔ; Fukada, So-Ichiro; Serrano, Antonio L; Perdiguero, Eusebio; Mu˝oz-Cßnoves, Pura
Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGF?-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. PMID:25981413
Investigation of a female manifesting Becker muscular dystrophy.
Glass, I A; Nicholson, L V; Watkiss, E; Johnson, M A; Roberts, R G; Abbs, S; Brittain-Jones, S; Boddie, H G
Females manifesting Becker muscular dystrophy (BMD) are even more rarely observed than for the allelic condition Duchenne muscular dystrophy. The male proband has typical BMD with greatly raised CK activity and a myopathic muscle biopsy. His mother experienced walking difficulties from 35 years of age and has a myopathy with marked calf hypertrophy, a raised CK, and a myopathic muscle biopsy. Dystrophin analysis was undertaken on both the proband and his mother. Immunoblotting showed a protein of normal size but of reduced abundance in both. Immunocytochemical analysis in the proband indicated that the majority of the fibres showed weak dystrophin labelling and in his mother both dystrophin positive and dystrophin negative fibres were present. Non-random X inactivation at locus DXS255, was observed in DNA isolated from peripheral lymphocytes of the mother. Neither extended multiplex PCR performed on DNA from the proband nor analysis of lymphocyte derived mRNA showed a structural alteration in the dystrophin gene suggesting that an unusual mutation was responsible for BMD in this family. Images PMID:1518025
A comparison of gait in spinal muscular atrophy, type II and Duchenne muscular dystrophy.
Armand, StÚphane; Mercier, Mo´se; Watelain, Eric; Patte, Karine; Pelissier, Jacques; Rivier, Franšois
This study investigated and compared the gait of two patients with spinal muscular atrophy, type II (SMA II) and two patients with Duchenne muscular dystrophy (DMD). These diseases cause a progressive and proximal to distal muscular weakness resulting in the loss of ambulation. The DMD cases had comparable muscle weakness with the SMA II cases on manual muscle testing and patients were assessed using kinematics, kinetics, electromyography and video analysis. SMA II and DMD patients employed different gait strategies for forward movement. SMA II patients used pelvic rotation initiated by the upper body to propel the leg forward and produce the necessary step-length whereas the DMD patients tended to use hip flexion and plantar flexion. Management of SMA II patients would include preservation of hip abductor and flexor strength to maintain mobility. PMID:15886126
Fracture risk in patients with muscular dystrophy and spinal muscular atrophy.
Vestergaard, P; Glerup, H; Steffensen, B F; Rejnmark, L; Rahbek, J; Moseklide, L
We aimed at studying fracture risk in patients with Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy (BEMD), and spinal muscular atrophy type II and III (SMA II and III). A self-administered questionnaire was mailed to 293 patients with DMD, BEMD, SMA II or SMA III of which 229 returned the questionnaire. Each respondent was compared with an age- and gender-matched control subject. The mean age was 23.9 +/- 15.9 years for the patients and 23.3 +/- 16.5 years for the controls. There were significantly more fractures among patients than controls after the diagnosis was made (RR = 1.9), but not before. The patients had more fractures of the femurs, lower legs, and upper arms than the controls. Low energy fractures were more frequent in patients than controls (9% vs 0%). Many fractures in the femurs (40%), lower legs (35%), and feet and toes (44%) led to a permanent loss of function. Loss of ambulation was the major risk factor for fractures. In conclusion, fracture risk is increased in neuromuscular disease. PMID:11506212
Characterization of Adiposity and Metabolism in Lmna-Deficient Mice
Dedra A. Cutler; Teresa Sullivan; Bernice Marcus-Samuels; Colin L. Stewart; Marc L. Reitman
Dunnigan's Familial Partial Lipodystrophy (FPLD) is an autosomal dominant disease characterized by regional fat loss and insulin resistance. FPLD is caused by mutations in the LMNA gene, which encodes intermediate filaments of the nuclear lamina. Different LMNA mutations cause EmeryľDreifuss muscular dystrophy and\\/or a dilated cardiomyopathy. It is not known how LMNA mutations cause any of the disease phenotypes. Here
Biochemistry of muscle membranes in Duchenne muscular dystrophy.
Rowland, L P
In Duchenne muscular dystrophy, as in other genetic diseases, there must be a biochemical abnormality. This fundamental genetic fault has not been identified, but several indirect lines of evidence suggest that the surface membranes of skeletal muscle are affected. The biochemical evidence implies abnormal egress of soluble enzymes and other proteins from muscle, abnormal permeability, and altered properties of membrane-bound enzymes. As a result of the presumed genetic abnormality, functional properties are altered, and impaired regulation of intracellular calcium content could be responsible for the hallmarks of the disease--progressive weakness and degeneration of muscle. The evidence is by no means conclusive, however, and some of it is contradictory. Technical advances must be made before isolated membranes can be characterized biochemically. Other theories are also being evaluated. PMID:6445503
Insights into bone health in Duchenne muscular dystrophy
Morgenroth, Victor H; Hache, Lauren P; Clemens, Paula R
Poor bone health is a significant problem for patients with Duchenne muscular dystrophy (DMD), a progressive, disabling disease. Although the primary focus of DMD disease pathogenesis is degeneration of striated muscle, impairment of bone health likely has a role in the disease that has only been superficially examined to date. Deficiency of bone mineral density and increased incidence of bone fractures are well-recognized clinical components of the DMD phenotype. Furthermore, therapy with corticosteroids, an approved treatment for DMD that prolongs ambulation, may have multiple effects on bone health in DMD patients. This review examines the evidence in preclinical models and in human DMD disease that provides insight into the role performed by bone in the disease pathogenesis and phenotype of DMD. The information reviewed here points toward the need for mechanistic and therapeutic studies to optimize bone health in DMD patients. PMID:23951421
[A patient with facioscapulohumeral muscular dystrophy accompanied by myasthenia gravis].
Sakuma, H; Shimazaki, S; Saito, H; Ohuchi, M
A patient was a fifty-year-old man, who had a 35 year-history of facioscapulohumeral muscular dystrophy (FSHD). He was admitted to our hospital because of acute progressive weakness involving his lower extremities without any fluctuation in the recent 3 weeks. We clinically followed him for 30 years and he was able to do all daily activities, walked alone, drove a car and climbed stairs with a handrail. His 76-year-old mother had about 60 year-history of FSHD and could walk with support. On admission, neurological examination revealed moderate to marked muscle weakness and atrophy of the face, limb-girdle and all extremities, predominantly in the upper proximal limbs. He could hardly stand and needed a stick for walking. He had no blepharoptosis or ocular movement disturbance, and did not complain of difficulties in swallowing and chewing. CK values and other laboratory data were normal, and serum anti-Jo-1 antibody, anti-SSA/Ro antibody and anticardiolipin IgG antibody were negative. Because EMG examination revealed myopathic changes and an X-ray examination of the lumbar spine was normal. Thus, polymyositis and neurologenic disorders were ruled out. Disturbance in chewing and swallowing, that were uncommon in FSHD, appeared about a month after admission. Repetitive stimulation test revealed typical waning pattern. Edrophonium chloride injection was effective for decreased waning and the clinical symptoms. The titer of serum anti-ACh receptor antibody was 97 nmol/l, confirming the diagnosis of myasthenia gravis. Because of fluctuated dyspnea, thymectomy was done and his condition gradually relieved after administration of corticosteroid and choline esterase inhibitor. From this experience, we learned that we have to consider other neuromuscular disorders, even rare ones, if there existed unusual weakness of underlying muscular dystrophy. PMID:11676158
Symptom Burden in Persons with Myotonic and Facioscapulohumeral Muscular Dystrophy
Smith, Amanda E.; McMullen, Kara; Jensen, Mark P.; Carter, Gregory T.; Molton, Ivan R.
Objective This study examines the prevalence of pain, fatigue, imbalance, memory impairment and vision loss in persons with myotonic and facioscapulohumeral dystrophy, and their association with functioning. Design A survey (n=170) included measures of severity (0ľ10 scales) and course of these symptoms, as well as measures of social integration, home competency, mental health and productive activity. Descriptive and regression analyses examined the associations between symptoms and functioning. Results Fatigue (91%), imbalance (82%) and pain (77%) were most commonly reported. The most severe symptom was fatigue (mean severity 5.14 ▒ 2.81), followed by imbalance (4.95 ▒ 3.25). Symptoms were most likely to stay the same or worsen since onset. Controlling for potential medical and demographic confounds, symptoms were associated with 17% of the mental health variance, 10% of home competency, 10% of social integration, 16% of productive activity for DM1 and 12% of productive activity for FSHD. Conclusions Pain, fatigue and imbalance are common in persons with muscular dystrophy. Interventions may be useful to mitigate their impact on functioning. Further research should examine these relationships to guide clinical practices. PMID:24247759
Decreased Insulin Receptors but Normal Glucose Metabolism in Duchenne Muscular Dystrophy
NASA Astrophysics Data System (ADS)
de Pirro, Roberto; Lauro, Renato; Testa, Ivano; Ferretti, Ginofabrizio; de Martinis, Carlo; Dellantonio, Renzo
Compared to matched controls, 17 patients with Duchenne muscular dystrophy showed decreased insulin binding to monocytes due to decreased receptor concentration. These patients showed no signs of altered glucose metabolism and retrospective analysis of the clinical records of a further 56 such patients revealed no modification in carbohydrate metabolism. These data suggest that reduced insulin receptor number does not produce overt modifications of glucose metabolism in Duchenne muscular dystrophy.
Flexible and semi-early vertebral instrumentation in surgical treatment of Duchenne muscular dystrophy scolioses
L. E. Gayet; G. Duport; P. Pries
1)Purpose of the study. The purpose of this work is to demonstrate the advantage of early surgical intervention for those suffering from Duchenne muscular dystrophy scoliosis.2)Material: This review relates to 37 patients suffering from Duchenne muscular dystrophy. There are detailed results in connection with the first 24, curves offering the longest follow-up period, each a minimum of at least three
Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins
Alessia Angelin; Tania Tiepolo; Patrizia Sabatelli; Paolo Grumati; Natascha Bergamin; Cristina Golfieri; Elisabetta Mattioli; Francesca Gualandi; Alessandra Ferlini; Luciano Merlini; N. M. Maraldi; Paolo Bonaldo; Paolo Bernardi
Ullrich congenital muscular dystrophy is a severe genetically and clinically heterogeneous muscle disorder linked to collagen VI deficiency. The pathogenesis of the disease is unknown. To assess the potential role of mitochondrial dysfunction in the onset of muscle fiber death in this form of dystrophy, we studied biopsies and myoblast cultures obtained from patients with different genetic defects of collagen
Autonomic dysfunction in muscular dystrophy: a theoretical framework for muscle reflex involvement
Smith, Scott A.; Downey, Ryan M.; Williamson, Jon W.; Mizuno, Masaki
Muscular dystrophies are a heterogeneous group of genetically inherited disorders whose most prominent clinical feature is progressive degeneration of skeletal muscle. In several forms of the disease, the function of cardiac muscle is likewise affected. The primary defect in this group of diseases is caused by mutations in myocyte proteins important to cellular structure and/or performance. That being stated, a growing body of evidence suggests that the development of autonomic dysfunction may secondarily contribute to the generation of skeletal and cardio-myopathy in muscular dystrophy. Indeed, abnormalities in the regulation of both sympathetic and parasympathetic nerve activity have been reported in a number of muscular dystrophy variants. However, the mechanisms mediating this autonomic dysfunction remain relatively unknown. An autonomic reflex originating in skeletal muscle, the exercise pressor reflex, is known to contribute significantly to the control of sympathetic and parasympathetic activity when stimulated. Given the skeletal myopathy that develops with muscular dystrophy, it is logical to suggest that the function of this reflex might also be abnormal with the pathogenesis of disease. As such, it may contribute to or exacerbate the autonomic dysfunction that manifests. This possibility along with a basic description of exercise pressor reflex function in health and disease are reviewed. A better understanding of the mechanisms that possibly underlie autonomic dysfunction in muscular dystrophy may not only facilitate further research but could also lead to the identification of new therapeutic targets for the treatment of muscular dystrophy. PMID:24600397
Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy
V. J. Hinton; D. C. De Vivo; R. Fee; E. Goldstein; Y. Stern
Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the ab- sence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the normal range, generally with lower verbal
Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy
ERIC Educational Resources Information Center
Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.
Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within theů
Some Dynamics of Personality Development in Boys Suffering from Muscular Dystrophy
ERIC Educational Resources Information Center
Mearig, Judith S.
Discussed are personality aspects of Duchenne or pseudohypertrophic muscular dystrophy, a progressive wasting of muscular tissue, which afflicts only boys, and usually has its noticeable onset before the age of 6 years; and described is the development of three male dystrophic siblings. (DB)
Functional significance of dystrophin positive fibres in Duchenne muscular dystrophy.
Nicholson, L V; Johnson, M A; Bushby, K M; Gardner-Medwin, D
The age when boys lose the ability to walk independently is one of the milestones in the progression of Duchenne muscular dystrophy (DMD). We have used this as a measure of disease severity in a group of 30 patients with DMD and six patients with intermediate Duchenne/Becker dystrophy (D/BMD). Dystrophin analysis was performed on tissue sections and western blots of muscle biopsy specimens from these patients and the relationships that were found between clinical severity and abundance of dystrophin labelling are reported. All patients with intermediate D/BMD had dystrophin labelling that was detected on sections and blots. Weak dystrophin labelling was found in sections from 21/30 DMD cases and on blots in 18/30 cases. Two non-exclusive patterns of dystrophin labelling were observed on sections: very clear labelling on a small percentage of fibres (usually < 1%) or very weak labelling on a much higher proportion (about 25%). The mean age at loss of mobility among the DMD patients with no dystrophin labelling on tissue sections was 7.9 years (range 6.3-9.5) while the mean age among those with some labelling was 9.9 years (range 8.0-11.9); this is a significant difference. Quantitative estimates of dystrophin abundance were obtained from densitometric analysis of dystrophin bands on blots. In the whole group of 36 patients, a significant positive relationship was found between the abundance of dystrophin and the age at loss of independent mobility. It is concluded that even the very low concentrations of dystrophin found in DMD patients may have some functional significance. Images PMID:8323331
Vascular-targeted therapies for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy-receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy. PMID:23618411
Clinical trials of allopurinol in Duchenne muscular dystrophy.
Thomson, W H
A wide range of different disturbances characteristic of Duchenne muscular dystrophy (DMD) can be attributed to a fundamental chronic shortage of intracellular adenosine 5'-triphosphate (ATP), in turn arising from a basic lack of total adenylate. Purine conservation by the hypoxanthine isomer allopurinol, which promotes salvage and inhibits catabolism, greatly increases muscle ATP and total adenylate, with corresponding clinical benefit. Among subsequent confirmatory clinical trials some gave positive results, while others provided no information. Reasons given why these latter proved uninformative include asking questions either irrelevant and/or incapable of being answered, not least in older boys with too much shrinking fibrous tissue infiltrating too little remaining muscle. Informative results from any metabolic intervention can be expected only where sufficient muscle is left to respond, and this age-linked effect is everywhere evident in the positive trials. Thus, if an effect of allopurinol now seems apparent, and since it is extremely safe and does not enter the genetic material, it is suggested that it be administered shortly after birth before irreversible pathological changes occur. This implies neo-natal male mass screening, easily accomplished by a simple dried-blood spot test, and already carried out successfully elsewhere. PMID:3897804
The Congenital Muscular Dystrophies: Recent Advances and Molecular Insights
Mendell, Jerry R.; BouÚ, Daniel R.; Martin, Paul T.
Over the past decade, molecular understanding of the congenital muscular dystrophies (CMDs) has greatly expanded. The diseases can be classified into 3 major groups based on the affected genes and the location of their expressed protein: abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2, COL6A3), abnormalities of membrane receptors for the extracellular matrix (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE, and ITGA7), and abnormal endoplasmic reticulum protein (SEPN1). The diseases begin in the perinatal period or shortly thereafter. A specific diagnosis can be challenging because the muscle pathology is usually not distinctive. Immunostaining of muscle using a battery of antibodies can help define a disorder that will need confirmation by gene testing. In muscle diseases with overlapping pathological features, such as CMD, careful attention to the clinical clues (e.g., family history, central nervous system features) can help guide the battery of immunostains necessary to target an unequivocal diagnosis. PMID:17163796
Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy
Ogura, Yuji; Tajrishi, Marjan M.; Sato, Shuichi; Hindi, Sajedah M.; Kumar, Ashok
Matrix metalloproteinases (MMPs) are secreted proteinases that have physiologic roles in degradation and remodeling of extracellular matrix (ECM) in almost all tissues. However, their excessive production in disease conditions leads to many pathological features including tissue breakdown, inflammation, cell death, and fibrosis. Duchenne Muscular dystrophy (DMD) is a devastating genetic muscle disorder caused by partial or complete loss of cytoskeletal protein dystrophin. Progressive muscle wasting in DMD is accompanied by myofiber necrosis followed by cycles of regeneration and degeneration and inflammation that eventually result in replacement of myofiber by connective and adipose tissues. Emerging evidence suggests that gene expression and the activity of various MMPs are aberrantly regulated in muscle biopsies from DMD patients and in skeletal muscle of animal models of DMD. Moreover, a few studies employing genetic mouse models have revealed that different MMPs play distinct roles in disease progression in DMD. Modulation of the activity of MMPs improves myofiber regeneration and enhances the efficacy of transplantation and engraftment of muscle progenitor cells in dystrophic muscle in mouse models of DMD. Furthermore, recent reports also suggest that some MMPs especially MMP-9 can serve as a biomarker for diagnosis and prognosis of DMD. In this article, we provide a succinct overview of the regulation of various MMPs and their therapeutic importance in DMD. PMID:25364719
Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy.
Ogura, Yuji; Tajrishi, Marjan M; Sato, Shuichi; Hindi, Sajedah M; Kumar, Ashok
Matrix metalloproteinases (MMPs) are secreted proteinases that have physiologic roles in degradation and remodeling of extracellular matrix (ECM) in almost all tissues. However, their excessive production in disease conditions leads to many pathological features including tissue breakdown, inflammation, cell death, and fibrosis. Duchenne Muscular dystrophy (DMD) is a devastating genetic muscle disorder caused by partial or complete loss of cytoskeletal protein dystrophin. Progressive muscle wasting in DMD is accompanied by myofiber necrosis followed by cycles of regeneration and degeneration and inflammation that eventually result in replacement of myofiber by connective and adipose tissues. Emerging evidence suggests that gene expression and the activity of various MMPs are aberrantly regulated in muscle biopsies from DMD patients and in skeletal muscle of animal models of DMD. Moreover, a few studies employing genetic mouse models have revealed that different MMPs play distinct roles in disease progression in DMD. Modulation of the activity of MMPs improves myofiber regeneration and enhances the efficacy of transplantation and engraftment of muscle progenitor cells in dystrophic muscle in mouse models of DMD. Furthermore, recent reports also suggest that some MMPs especially MMP-9 can serve as a biomarker for diagnosis and prognosis of DMD. In this article, we provide a succinct overview of the regulation of various MMPs and their therapeutic importance in DMD. PMID:25364719
Sarcopenia and sarcopenic obesity in patients with muscular dystrophy.
Merlini, Luciano; Vagheggini, Alessandro; Cocchi, Daniela
Aging sarcopenia and muscular dystrophy (MD) are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called "sarcopenic obesity" characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with MD, we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual-energy X-ray absorptiometry (DXA), for muscle strength hand-held dynamometry (HHD), and for physical performance gait speed. The study involved 14 adult patients with different types of MD. We were able to demonstrate that all patients were sarcopenic obese. We showed, in fact, that all were sarcopenic based on appendicular lean, fat and bone free, mass index (ALMI). In addition, all resulted obese according to the percentage of body fat determined by DXA in contrast to their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by HHD, and physical performances determined by gait speed and respiratory function. Finally, we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggests the relevance of a proper evaluation of body composition in MD and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia. PMID:25339901
Sarcopenia and Sarcopenic Obesity in Patients with Muscular Dystrophy
Merlini, Luciano; Vagheggini, Alessandro; Cocchi, Daniela
Aging sarcopenia and muscular dystrophy (MD) are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called ôsarcopenic obesityö characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with MD, we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual-energy X-ray absorptiometry (DXA), for muscle strength hand-held dynamometry (HHD), and for physical performance gait speed. The study involved 14 adult patients with different types of MD. We were able to demonstrate that all patients were sarcopenic obese. We showed, in fact, that all were sarcopenic based on appendicular lean, fat and bone free, mass index (ALMI). In addition, all resulted obese according to the percentage of body fat determined by DXA in contrast to their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by HHD, and physical performances determined by gait speed and respiratory function. Finally, we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggests the relevance of a proper evaluation of body composition in MD and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia. PMID:25339901
Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone.
Lehmann-Horn, Frank; Weber, Marc-AndrÚ; Nagel, Armin M; Meinck, Hans-Michael; Breitenbach, Simon; Scharrer, Johannes; Jurkat-Rott, Karin
Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place. PMID:22655515
Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy.
Phillips, M F; Smith, P E; Carroll, N; Edwards, R H; Calverley, P M
REM-related oxygen desaturation occurs in advanced Duchenne muscular dystrophy (DMD) and might be an independent predictor of disease progression. We have followed 18 patients for 10 yr after an initial respiratory sleep study or until death or onset of nasal ventilation. We measured baseline spirometry, blood gas tensions, maximal respiratory pressures, and body mass index. In 11 cases, VC was recorded serially. Median survival was 50 (range, 13 to 89) mo from initial study and unrelated to age at time of study, BMI, or mouth pressures but correlated with PaCO2 (r = -0.72, p < 0.005, n = 17), minimal nocturnal SaO2 (r = 0.62, p < 0.007, n = 18) and VC (r = 0. 65, p < 0.005, n = 17). Cox regression analysis showed a VC of less than 1 L at the time of study to be the best single predictor of subsequent survival. The only measure associated with age of death was the age at which the VC fell below 1 L (r = 0.79, p < 0.004). These data suggest measurement of PaCO2 or serial assessment of VC should be studied further as valid methods of assessing prognosis in DMD. PMID:10390400
Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy
Zhu, Yuling; Zhang, Huili; Sun, Yiming; Li, Yaqin; Deng, Langhui; Wen, Xingxuan; Wang, Huaqiao; Zhang, Cheng
Background. Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. Methods. The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. Results. The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 ▒ 59?U/L versus 45 ▒ 9?U/L, resp., p < 0.05). Conclusions. Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed.
Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy
De Pasquale, L.; D'Amico, A.; Verardo, M.; Petrini, S.; Bertini, E.
Objectives: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status. Methods: Expression levels of IL-17, Foxp3, tumor necrosis factor-? (TNF-?), monocyte chemoattractant protein-1 (MCP-1), IL-6, and transforming growth factor-? (TGF-?) were analyzed by real-time PCR in muscle biopsy samples from patients with DMD (n = 27) and juvenile dermatomyositis (JDM) (n = 8). Motor outcome of patients with DMD was evaluated by North Star Ambulatory Assessment score. Results: In DMD, we found higher levels of IL-17 and lower levels of Foxp3 mRNA compared with those for a typical inflammatory myopathy, JDM. Moreover, the IL-17/Foxp3 ratio was higher in DMD than in JDM biopsy samples. IL-17 mRNA levels appeared to be related to the expression levels of other proinflammatory cytokines (TNF-? and MCP-1) and significantly associated with clinical outcome of patients. Conclusions: The association of IL-17 expression with levels of other inflammatory cytokines and with the clinical course of DMD suggests a possible pathogenic role of IL-17. PMID:22496194
Laminin-111: A Potential Therapeutic Agent for Duchenne Muscular Dystrophy
Goudenege, SÚbastien; Lamarre, Yann; Dumont, Nicolas; Rousseau, JoŰl; Frenette, JÚr˘me; Skuk, Daniel; Tremblay, Jacques P
Duchenne muscular dystrophy (DMD) still needs effective treatments, and myoblast transplantation (MT) is considered as an approach to repair damaged skeletal muscles. DMD is due to the complete loss of dystrophin from muscles. The lack of link between the contracting apparatus and the extracellular matrix leads to frequent damage to the sarcolemma triggering muscle fiber necrosis. Laminins are major proteins in the extracellular matrix. Laminin-111 is normally present in skeletal and cardiac muscles in mice and humans but only during embryonic development. In this study, we showed that intramuscular injection of laminin-111 increased muscle strength and resistance in mdx mice. We also used laminin-111 as a coadjuvant in MT, and we showed this protein decreased considerably the repetitive cycles of degeneration, inflammatory reaction, and regeneration. Moreover, MT is significantly improved. To explain the improvement, we confirmed with the same myoblast cell batch that laminin-111 improves proliferation and drastically increases migration in vitro. These results are extremely important because DMD could be treated only by the injection of a recombinant protein, a simple and safe therapy to prevent loss of muscle function. Moreover, the improvement in MT would be significant to treat the muscles of DMD patients who are already weak. PMID:20683444
Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy
Sharma, Alok; Sane, Hemangi; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna
Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation. PMID:23841012
Scoliosis in Duchenne muscular dystrophy: aspects of orthotic treatment.
Heller, K D; Forst, R; Forst, J; Hengstler, K
The x-linked Duchenne muscular dystrophy (DMD) is the most frequent generalized muscle disorder arising from a lack of the sarcolemmic protein "dystrophin". Patients with DMD develop in the majority a progressive scoliosis when they cease walking and/or standing at the age of 10 years and become confined to a wheelchair. Increasing muscle weakness leads to a progression of the curvature, the pelvic tilt and problems in sitting. Together with the simultaneous progressive weakness of the respiratory muscles a restrictive pulmonary insufficiency will occur. Surgical stabilization of the spine (> 20 degrees Cobb, forced vital capacity > 35%) by an adequate multisegmental instrumentation enabling early mobilization is now the treatment of choice. However, orthotic treatment may offer an acceptable compromise in exceptional cases, if the patient rejects surgical intervention or is in the late (inoperable) stages of the disease. Such a treatment is superior to a primary sitting support provision with insufficient possibilities of correction. The authors' experiences with 48 scoliosis orthoses made for 28 patients with DMD are reported. A "double plaster" cast has emerged as the best method to optimize adaption, especially in severe curvatures and the time taken for manufacturing the orthosis. A great deal of experience, patience and the consideration of the patients' individual demands are inevitable for a successful orthotic treatment. PMID:9453095
Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy.
Sharma, Alok; Paranjape, Amruta; Sane, Hemangi; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna
Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation. PMID:23841012
Becker Muscular Dystrophy-Like Myopathy Regarded as So-Called ôFatty Muscular Dystrophyö in a Pig: A Case Report and Its Diagnostic Method
HORIUCHI, Noriyuki; AIHARA, Naoyuki; MIZUTANI, Hiroshi; KOUSAKA, Shinichi; NAGAFUCHI, Tsuneyuki; OCHIAI, Mariko; OCHIAI, Kazuhiko; KOBAYASHI, Yoshiyasu; FURUOKA, Hidefumi; ASAI, Tetsuo; OISHI, Koji
ABSTRACT We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin-embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called ôfatty muscular dystrophyö. Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig. PMID:24162004
The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy
Marshall, Jamie L.; Kwok, Yukwah; McMorran, Brian; Baum, Linda G.; Crosbie-Watson, Rachelle H.
Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and ?7?1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082
Growth and psychomotor development of patients with Duchenne muscular dystrophy.
Sarrazin, Elisabeth; von der Hagen, Maja; Schara, Ulrike; von Au, Katja; Kaindl, Angela M
Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment. PMID:24100172
Oculopharyngeal Muscular Dystrophy as a Paradigm for Muscle Aging
Raz, Yotam; Raz, Vered
Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging. PMID:25426070
Carrier detection in Duchenne muscular dystrophy using molecular methods
Sakthivel Murugan, S.M.; Arthi, C.; Thilothammal, N.; Lakshmi, B.R.
Background & objectives: Duchenne and Becker muscular dystrophies are X-linked allelic disorders which are caused by mutations in the DMD gene. Carrier analysis in DMD is complicated due to the heterozygous nature of the X chromosome. Several techniques have been tried for carrier analysis in families where the mutation is identified including quantitative multiplex PCR (qmPCR), Southern blot, and now multiplex ligation-dependent probe amplification (MLPA). Linkage analysis is used in cases without identifiable mutations. The present study was undertaken to determine the status of probable carriers in families where the DMD deletion/duplication has been identified for the affected index cases. Methods: Carrier status was present in 150 probable carriers from 110 apparently unrelated families where the patientsĺ mutations were known. Of these 110 families, 100 were deletions, 9 duplications and 1 point mutation. Multiplex ligation-dependent probe amplification (MLPA) was used to assess the copy number changes and direct sequencing was used for the case with the point mutation. Results: Of the 150 cases, 49 were found to be carriers. Among the sporadic cases, it was observed that the rate of de novo mutations was very high (71%) as compared to the hereditary cases (29%), which was higher than the calculated rate (30%). It was observed that this difference was more apparent in deletion mutations than in duplications. Interpretation & conclusions: Identifying the DMD carrier rates in the families with unidentified deletions and duplications and where the causative mutation could be small insertions/deletions or point mutations could throw more light into this observation. MLPA was found to be useful in detecting copy number changes in DMD carriers and this could be the method of choice for DMD carrier analysis, when the mutation is detected in the affected child. PMID:23852291
Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears
G, Ricci; M, Zatz; R, Tupler
Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (?8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as ôpermissiveö specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.
Muscle histology vs MRI in Duchenne muscular dystrophy
Kinali, M.; Arechavala-Gomeza, V.; Cirak, S.; Glover, A.; Guglieri, M.; Feng, L.; Hollingsworth, K.G.; Hunt, D.; Jungbluth, H.; Roper, H.P.; Quinlivan, R.M.; Gosalakkal, J.A.; Jayawant, S.; Nadeau, A.; Hughes-Carre, L.; Manzur, A.Y.; Mercuri, E.; Morgan, J.E.; Straub, V.; Bushby, K.; Sewry, C.; Rutherford, M.
Objective: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. Methods: We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0ľ4 (normalľsevere). Results: In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3ľ4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10ľ16.6 years. Conclusion: This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials. PMID:21263136
A novel treatment regimen for Duchenne muscular dystrophy.
Li, Mei; Cai, Yunting; Zhong, Min; Zou, Lin; Gong, Caihui
Duchenne muscular dystrophy (DMD) is the most common, X-linked genetic, skeletal muscle disease, with various regimens of treatment. The objective of this study was to determine the safety and efficacy of a novel treatment regimen for this disease. Thirty boys with DMD were administered prednisone according to the following regimen: in the first year, 1.5 mg/kg/day for the first 3 months, 1.0 mg/kg/day for the next 3 months, 0.75 mg/kg/day for the next 3 months, and 0.5 mg/kg/day for the last 3 months. In the second year, prednisone was administered 0.5 mg/kg on the alternate day for 12 months. The muscle strength (Medical Research Council sum score and Gower's sign), serum enzymes (creatine kinase, creatine kinase isoenzyme-2, and lactate dehydrogenase), pulmonary function (forced vital capacity, maximum voluntary ventilation), body weight, height, and BMI were determined before treatment and 3, 6, 9, 12, and 24 months after treatment. The results showed that the patients' mean Medical Research Council sum score increased from 46.1 at the baseline to 53.6 at 12 months and was maintained at 24 months. Gower's sign disappeared in 22 (73.3%) patients at 12 months and 21 (70.0%) at 24 months. The serum levels of creatine kinase, creatine kinase isoenzyme-2, and lactate dehydrogenase decreased and pulmonary function improved after 24 months of treatment. Significantly increased weight gain, osteoporosis, and cushingoid features were not observed. Our results suggested that this novel prednisone regimen for DMD has similar efficacy and safety as other regimens. PMID:24045777
Immunoproteasome in animal models of Duchenne muscular dystrophy
Chen, Chiao-nan (Joyce); Graber, Ted G.; Bratten, Wendy M.; Ferrington, Deborah A.; Thompson, LaDora V.
Increased proteasome activity has been implicated in the atrophy and deterioration associated with dystrophic muscles of Duchenne muscular dystrophy (DMD). While proteasome inhibitors show promise in the attenuation of muscle degeneration, proteasome inhibition-induced toxicity was a major drawback of this therapeutic strategy. Inhibitors that selectively target the proteasome subtype that is responsible for the loss in muscle mass and quality would reduce side effects and be less toxic. This study examined proteasome activity and subtype populations, along with muscle function, morphology and damage in wild-type (WT) mice and two murine models of DMD, dystrophin-deficient (MDX) and dystrophin- and utrophin-double-knockout (DKO) mice. We found that immunoproteasome content was increased in dystrophic muscles while the total proteasome content was unchanged among the three genotypes of mice. Proteasome proteolytic activity was elevated in dystrophic muscles, especially in DKO mice. These mice also exhibited more severe muscle atrophy than either WT or MDX mice. Muscle damage and regeneration, characterized by the activity of muscle creatine kinase in the blood and the percentage of central nuclei were equally increased in dystrophic mice. Accordingly, the overall muscle function was similarly reduced in both dystrophic mice compared with WT. These data demonstrated that there was transformation of standard proteasomes to immunoproteasomes in dystrophic muscles. In addition, DKO that showed greatest increase in proteasome activities also demonstrated more severe atrophy compared with MDX and WT. These results suggest a putative role for the immunoproteasome in muscle deterioration associated with DMD and provide a potential target for therapeutic intervention. PMID:24934129
Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy
Statland, Jeffrey; Donlin-Smith, Colleen M; Tapscott, Stephen J; van der Maarel, Silvere; Tawil, Rabi
Background Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. Objective To identify potential serum biomarkers in FSHD for possible use in future clinical trials. Methods We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0). Results 169 markers had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P<0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P<0.0001), myoglobin (2.23 fold change, P=0.0001), epidermal growth factor (EGF, 2.33 fold change, P=0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P=0.0004), CD 40 ligand (1.89 fold change, P=0.001), and vitronectin (VTN, 1.28 fold change, P=0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT, serpin peptidase inhibitor, and VTN) were correlated with each other in FSHD but not healthy controls. Conclusions Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study. PMID:25705588
Gene replacement therapies for Duchenne muscular dystrophy using adeno-associated viral vectors
Seto, Jane T.; Ramos, Julian N.; Muir, Lindsey; Chamberlain, Jeffrey S.
The muscular dystrophies collectively represent a major health challenge, as few significant treatment options currently exist for any of these disorders. Recent years have witnessed a proliferation of novel approaches to therapy, spanning increased testing of existing and new pharmaceuticals, DNA delivery (both anti-sense oligonucleotides and plasmid DNA), gene therapies and stem cell technologies. While none of these has reached the point of being used in clinical practice, all show promise for being able to impact different types of muscular dystrophies. Our group has focused on developing direct gene replacement strategies to treat recessively inherited forms of muscular dystrophy, particularly Duchenne and Becker muscular dystrophy (DMD/BMD). Both forms of dystrophy are caused by mutations in the dystrophin gene and all cases can in theory be treated by gene replacement using synthetic forms of the dystrophin gene. The major challenges for success of this approach are the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carries by such a shuttle, and achieving safe and effective delivery. This review summarizes the current state of the art in terms of using adeno-associated viral vectors to deliver synthetic dystrophin genes for the purpose of developing gene therapy for DMD. PMID:22533379
Merosin-negative congenital muscular dystrophy: diffusion-weighted imaging findings of brain.
Alkan, Alpay; Sigirci, Ahmet; Kutlu, Ramazan; Aslan, Mehmet; Doganay, Selim; Yakinci, Cengiz
Merosin-negative congenital muscular dystrophy is a rare genetic disease of childhood involving the central and peripheral nervous system. There were high signal intensities throughout the centrum semiovale, periventricular, and sub-cortical white matters on T2-weighted images in a 4-year-old girl with merosin-negative congenital muscular dystrophy. An apparent diffusion coefficient map revealed increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. It may be attributable to increased water content in the white matter because of an abnormal blood-brain barrier rather than to decreased or abnormal myelination. PMID:17690079
Analysis of Genetic Variations of Lamin A\\/C Gene (LMNA) by Denaturing High-Performance Liquid Chromatography
Matthew R. G. Taylor; Misi L. Robinson; Luisa Mestroni
The human LMNA gene, when mutated, has been shown to cause at least 7 human diseases: dilated cardiomyopathy, Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, familial partial lipodystrophy, Charcot Marie tooth disease type II, mandibuloacral dysplasia, and Hutchinson-Gilford Progeria (OMIM #176670). This article describes a high-throughput method for screening the human lamin A\\/C (LMNA) gene for genetic mutations and
Modulation of Myoblast Fusion by Caveolin-3 in Dystrophic Skeletal Muscle Cells: Implications for Duchenne Muscular Dystrophy and Limb-Girdle Muscular Dystrophy1C
Daniela Volonte; Aaron J. Peoples; Ferruccio Galbiati
Caveolae are vesicular invaginations of the plasma membrane. Caveolin-3 is the principal structural component of caveolae in skeletal muscle cells in vivo. We have recently generated caveolin-3 transgenic mice and demonstrated that overexpression of wild-type caveolin-3 in skeletal muscle fibers is sufficient to induce a Duchenne-like muscular dystrophy phenotype. In addition, we have shown that caveolin-3 null mice display mild
Immunoblot analysis of sarcoplasmic calcium binding proteins in Duchenne muscular dystrophy
Irena Niebrˇj-Dobosz; Miroslawa ?ukasiuk
The Western blotting technique was used to detect parvalbumin and S-100 protein in muscles from 10 Duchenne muscular dystrophy (DD) patients, 13 patients with other muscle diseases and 5 age-matched healthy subjects. DD muscles were found to contain decreased amounts of parvalbumin and the S-100 protein. The parvalbumin level did not relate to the age of the patients and the
Duchenne Muscular Dystrophy: A 30Year Population-Based Incidence Study
Joseph Dooley; Kevin E. Gordon; Linda Dodds; Judith MacSween
Duchenne muscular dystrophy (DMD) is among the most common lethal genetic diseases. It has been proposed that genetic counseling and prenatal diagnosis have begun to lower the incidence. We reviewed the records of all patients with confirmed DMD who were born between 1969 and 2008. Statistics Canada data on annual male births in Nova Scotia were obtained for each year.The
Absence of ?-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12
Daniel Jung; Yoshihide Sunada; Franck Duclos; Fernando M. S. TomÚ; Carolyn Moomaw; Luciano Merlini; Kemal Azibi; Malika Chaouch; Clive Slaughter; Michel Fardeau; Jean-Claude Kaplan; Kevin P. Campbell
We have partially sequenced rabbit skeletal muscle ?-sarcoglycan an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a ?-sarcoglycan peptide and used to examine the expression of ?-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these
Transgenic Overexpression of Dystroglycan Does Not Inhibit Muscular Dystrophy in mdx Mice
Hoyte, Kwame; Jayasinha, Vianney; Xia, Bing; Martin, Paul T.
Recently, there have been a number of studies demonstrating that overexpression of molecules in skeletal muscle can inhibit or ameliorate aspects of muscular dystrophy in the mdx mouse, a model for Duchenne muscular dystrophy. Several such studies involve molecules that increase the expression of dystroglycan, an important component of the dystrophin-glycoprotein complex. To test whether dystroglycan itself inhibits muscular dystrophy in mdx mice, we created dystroglycan transgenic mdx mice (DG/mdx). The ? and ? chains of dystroglycan were highly overexpressed along the sarcolemmal membrane in most DG/mdx muscles. Increased dystroglycan expression, however, did not correlate with increased expression of utrophin or sarcoglycans, but rather caused their decreased expression. In addition, the percentage of centrally located myofiber nuclei and the level of serum creatine kinase activity were not decreased in DG/mdx mice relative to mdx animals. Therefore, dystroglycan overexpression does not cause the concomitant overexpression of a utrophin-glycoprotein complex in mdx muscles and has no effect on the development of muscle pathology associated with muscular dystrophy. PMID:14742274
Paraffin wax embedded muscle is suitable for the diagnosis of muscular dystrophy
Sheriffs, I; Rampling, D; Smith, V
AimŚAt present, the diagnosis of muscular dystrophy is made by means of immunohistochemistry on frozen sections. The aim of this study was to develop a sensitive and reproducible immunohistochemical method for use on formalin fixed, paraffin wax embedded sections for the demonstration of dystrophin associated proteins and other muscle associated antigens. MethodsŚAll the cases studied were from the files of the department of histopathology, Great Ormond Street Hospital for Children NHS Trust. Immunohistochemistry was performed on paraffin wax embedded sections with heat mediated antigen retrieval and overnight incubation with the antibodies at room temperature. Four different pretreatment buffers were tested in the attempt to optimise the immunostaining. Frozen sections were run in parallel for direct comparison. ResultsŚAll the antibodies except ? sarcoglycan gave strong, consistent immunostaining in paraffin wax embedded sections, comparable with the frozen sections. The most consistent results were obtained using citrate/EDTA as the pretreatment buffer. ConclusionŚA reliable and reproducible technique has been established, using a heat mediated citrate/EDTA buffer antigen retrieval method, which works well for most of the antibodies needed to make the diagnosis of muscular dystrophy in formalin fixed, paraffin wax embedded sections. This technique overcomes some of the inherent problems encountered using frozen muscle tissue and it could become a valuable tool for the diagnosis of muscular dystrophy. Key Words: immunohistochemistry Ľ muscle biopsies Ľ muscular dystrophy Ľ paraffin wax sections PMID:11429422
De novo LMNA mutations cause a new form of congenital muscular dystrophy
Susana Quijano-Roy; Blaise Mbieleu; Carsten G. B÷nnemann; Pierre-Yves Jeannet; Jaume Colomer; Nigel F. Clarke; Jean-Marie Cuisset; Helen Roper; Linda De Meirleir; Adele D'Amico; Rabah Ben Yaou; AndrÚs Nascimento; Annie Barois; Laurence Demay; Enrico Bertini; Ana Ferreiro; Caroline A. Sewry; Norma B. Romero; Monique Ryan; Francesco Muntoni; Pascale Guicheney; Pascale Richard; GisŔle Bonne; Brigitte Estournet
Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results: The 15 patients presented with muscle weakness in the first year of
Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy
Technology Transfer Automated Retrieval System (TEKTRAN)
The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...
Priorities in the discovery of the implications of water channels in epilepsy and duchenne muscular dystrophy.
Benga, I
In addition to the priority in the discovery of the first water channel protein in the red blood cell membrane the group of Gheorghe Benga in Cluj-Napoca, Romania, also has a world priority in the discovery of the implications of water channel proteins in epilepsy and Duchenne muscular dystrophy. This priority is briefly presented here. In 1977 Benga and Morariu reported a decreased water permeability of red blood cells in children with idiopathic epilepsy (cases selected by Ileana Benga). This investigation was performed as part of a program of research of hydroelectrolytic alterations in child epilepsy. On the other hand the group of Gheorghe Benga has reported a decreased water permeability of RBC in patients with Duchenne muscular dystrophy. These findings were interpreted as an expression of generalized membrane defects affecting water permeability in epilepsy and Duchenne muscular dystrophy. In recent years this idea was confirmed by reports indicating aquaporin abnormalities in the brain of epileptic patients and in the muscle of Duchenne muscular dystrophy patients. PMID:17543221
Parents' Perspectives on Coping with Duchenne Muscular Dystrophy and Concomitant Specific Learning Disabilities
ERIC Educational Resources Information Center
Webb, Carol L.
This study addresses parental perspectives and coping strategies related to Duchenne muscular dystrophy and specific learning disabilities. Data were collected through individual semi-structured in-depth interviews with fifteen sets of parents. Participants were selected based on variables such as age of children, number of children with bothů
Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy
ERIC Educational Resources Information Center
Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.
The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildlyů
Improving the Reading Skills of Young People with Duchenne Muscular Dystrophy in Preparation for Adulthood
ERIC Educational Resources Information Center
Hoskin, Janet; Fawcett, Angela
Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34ů
Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.
PlantiÚ, Emilie; Migocka-Patrza?ek, Marta; Daczewska, Ma?gorzata; Jagla, Krzysztof
Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs. PMID:25859781
Analysis of calpain-3 protein in muscle biopsies of different muscular dystrophies from India
Renjini, R.; Gayathri, N.; Nalini, A.; Bharath, M.M. Srinivas
Background & objectives: Calpain-3, a Ca2+-dependent protease has been implicated in the pathology of neuromuscular disorders (NMDs). The current study aimed to analyze calpain-3 expression in cases diagnosed as muscular dystrophy from the Indian population. Methods: Calpain-3 Western blot analysis in muscle biopsies of immunohistochemically confirmed cases of Duchenne muscular dystrophy (DMD) (n=10), dysferlinopathy (n=30) and sarcoglycanopathy (n=8) was carried out. Calpain-3 Western blotting was also used in a blinded study to identify cases of calpain-3 deficiency in 28 NMD patients with potential muscular dystrophy. Results: Calpain-3 appeared as a full length 94 kDa band with an autolytic product (~60 kDa) on Western blots with antibody NCL-CALP-12A2 (Ab-2). Eight of the 10 DMD samples showed absence of 94 kDa band but presence of 60 kDa band while one case of sarcoglycanopathy showed absence of both. Twenty one of the 30 dysferlinopathy samples showed both bands while six showed only the 60 kDa band and three showed absence of both. In the blinded study, five NMD cases with potential muscular dystrophy that showed complete absence of both bands in retrospect exhibited clinical features of limb girdle muscular dystrophy 2A (LGMD2A). Interpretation & conclusions: While the study revealed a consistent pattern of calpain-3 in DMD, one sarcoglycanopathy and three dysferlinopathy samples exhibited secondary reduction in calpain-3. It was recognized that both calpain-3 bands should be considered to confirm calpain deficiency. Further, western blot offers an economical and fast preliminary screening method for LGMD2A especially in cases of complete absence of calpain-3 prior to conclusive diagnosis by genetic testing. PMID:22825607
A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.
Dai, Yi; Wei, Xiaoming; Zhao, Yanhuan; Ren, Haitao; Lan, Zhangzhang; Yang, Yun; Chen, Lin; Cui, Liying
Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population. PMID:25987458
Decreased mechanical stiffness in LMNA-\\/- cells is caused by defective nucleo-cytoskeletal integrity : implications for the development of laminopathies
Jos L. V. Broers; Emiel A. G. Peeters; Helma J. H. Kuijpers; Jorike Endert; Frans C. S. Ramaekers; Cees W. J. Oomens; Frank P. T. Baaijens
Q1 (LMNA ). A prominent feature in several of these diseases is muscle wasting, as seen in Emery-Dreifuss muscle dystrophy, dilated cardiomyopathy and limb-girdle muscular dystrophy. Although the mechanisms underlying this phenotype remain largely obscure, two major working hypotheses are currently being investigated, namely, defects in gene regulation and\\/or abnormalities in nuclear architec- ture causing cellular fragility. In this study,
Becker's X-linked muscular dystrophy histological, enzyme-histochemical, and ultrastructural studies of two cases, originally reported by Becker
H. H. Goebel; H. Prange; F. Gullotta; H. Kiefer; M. Z. Jones
Muscle biopsies of two patients originally reported in the G÷ttingen family by Becker (1962) that formed the basis of separating a benign X-linked muscular dystrophy from the rapidly progressive Duchenne-type X-linked muscular dystrophy, revealed mild pathological changes in the younger patient and more advanced in the older one, consisting of increased spectra of fiber diameters, endomysial fibrosis, angulated fibers, pyknotic
Genotype/phenotype analysis in Chinese laminin-?2 deficient congenital muscular dystrophy patients.
Xiong, H; Tan, D; Wang, S; Song, S; Yang, H; Gao, K; Liu, A; Jiao, H; Mao, B; Ding, J; Chang, X; Wang, J; Wu, Y; Yuan, Y; Jiang, Y; Zhang, F; Wu, H; Wu, X
Laminin-?2 deficient congenital muscular dystrophy (CMD) is an autosomal recessive disorder characterized by severe muscular dystrophy, which is typically associated with abnormal white matter. In this study, we assessed 43 CMD patients with typical white matter abnormality and laminin-?2 deficiency (complete or partial) diagnosed by immunohistochemistry to determine the clinical and molecular genetic characteristics of laminin-?2 deficient CMD. LAMA2 gene mutation analysis was performed by direct sequencing of genomic DNAs. Exonic deletion or duplication was identified by multiplex ligation-dependent probe amplification (MLPA) and verified by high-density oligonucleotide-based CGH microarrays. Gene mutation analysis revealed 86 LAMA2 mutations (100%); 15 known and 37 novel. Among these mutations, 73.9% were nonsense, splice-site or frameshift and 18.8% were deletions of one or more exons. Genetic characterization of affected families will be valuable in prenatal diagnosis of CMD in the Chinese population. PMID:24611677
Adhalin gene mutations in patients with autosomal recessive childhood onset muscular dystrophy with adhalin deficiency.
Kawai, H; Akaike, M; Endo, T; Adachi, K; Inui, T; Mitsui, T; Kashiwagi, S; Fujiwara, T; Okuno, S; Shin, S
Homozygous adhalin gene mutations were found in three patients from two consanguineous families with autosomal recessive childhood onset muscular dystrophy. Muscle biopsies from patients in each family showed complete absence of adhalin. Sequencing of adhalin cDNA prepared from skeletal muscle by reverse transcription PCR demonstrated a cytosine to thymidine substitution at nt 229 in the patient in family 1 and an adenine to guanine substitution at nt 410 and a 15-base insertion between nt 408 and 409 in the two patients in family 2. Sequencing of genomic DNA prepared from peripheral blood leukocytes by PCR confirmed these mutations. The parents in each family were found to be heterozygous for the respective mutations. These adhalin gene mutations are presumed to be responsible for the absence of adhalin in the skeletal muscle. Adhalin deficiency likely causes disruption of the muscle cell membrane, resulting in dystrophic changes in the skeletal muscle similar to dystrophin deficiency in Duchenne muscular dystrophy. Images PMID:7657792
An ex vivo Gene Therapy Approach to Treat Muscular Dystrophy Using inducible Pluripotent Stem Cells
Filareto, Antonio; Parker, Sarah; Darabi, Radbod; Borges, Luciene; Iacovino, Michelina; Schaaf, Tory; Mayerhofer, Timothy; Chamberlain, Jeffrey S; Ervasti, James M.; McIvor, R. Scott; Kyba, Michael; Perlingeiro, Rita C.R.
Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem (iPS) cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic iPS cells using a Sleeping Beauty transposon carrying the micro-utrophin (?UTRN) gene, differentiate these cells into skeletal muscle progenitors, and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance toward the future treatment of muscular dystrophies using genetically corrected autologous iPS cells. PMID:23462992
Analysis using histograms of muscle CT images in patients with Duchenne muscular dystrophy.
Nakayama, Takahiro; Kuru, Satoshi; Kawai, Mitsuru
We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with Duchenne muscular dystrophy, and this shape of the histogram will employ a new analytical method. CT images of the middle part of the thigh were acquired in a patient with Duchenne muscular dystrophy once a year from 6 to 11 years of age. Regions apparently corresponding to subcutaneous fat, bone and bone marrow were manually excluded, and the CT values were calculated to prepare histograms. His motor disability was also evaluated employing Vignos functional rating scale. A single peak was noted in the muscle CT value range in the histogram at the youngest age. The muscle-to-fat ratio in muscle decreased with the worsening of his disease disability level and the peak of the histogram shifted from the muscle to the fat CT value. PMID:23729708
Peter Becker and his Nazi past: the man behind Becker muscular dystrophy and Becker myotonia.
Zeidman, Lawrence A; Kondziella, Daniel
Peter Becker was a German neurologist who helped classify the muscular dystrophies, and described Becker muscular dystrophy and Becker myotonia. His involvement in National Socialism began in 1933, when he was compelled by his peers to join the SA (brown shirts). He later joined the Nazi party, the Nazi Doctors Association, and the Nazi Lecturers' Association. He renewed his SA membership to maintain his position at a genetics institute. Colleagues stated postwar that he was not an active Nazi, and he was de-Nazified in 1947, able to continue his career. Later, Becker admitted to most, but not all, of his Nazi memberships in his autobiography, and wrote 2 books exploring the origins of Nazism and racial hygiene. The "neurologic court of opinion" must weigh in on how we should best remember Becker, and at the very least, we as neurologists must learn the dangers of career opportunism at any cost. PMID:23576413
Cardiac structure and function in female carriers of a canine model of Duchenne muscular dystrophy.
Kane, A M; DeFrancesco, T C; Boyle, M C; Malarkey, D E; Ritchey, J W; Atkins, C E; Cullen, J M; Kornegay, J N; Keene, B W
This investigation tested the hypothesis that carriers of golden retriever muscular dystrophy (GRMD), a genetically homologous condition of Duchenne muscular dystrophy (DMD), have quantifiable abnormalities in myocardial function, structure, or cardiac rhythm. Eleven GRMD carriers and four matched controls had cardiac evaluations and postmortem examinations. 24-h ECG Holter monitoring disclosed ventricular ectopy in 10 of 11 carriers and 2 of 4 controls. Conventional echocardiography failed to demonstrate significant differences between carriers and controls in systolic function. All carriers had multifocal, minimal to marked myofiber necrosis, fibrosis, mineralization, inflammation, and/or fatty change in their hearts. Immunohistochemistry revealed a mosaic dystrophin deficiency in scattered cardiac myofibers in all carriers. No controls had cardiac histologic lesions; all had uniform dystrophin staining. Despite cardiac mosaic dystrophin expression and degenerative cardiac lesions, GRMD carriers at up to 3 years of age could not be distinguished statistically from normal controls by echocardiography or 24-h Holter monitoring. PMID:23231955
Antisense Oligo-Mediated Multiple Exon Skipping in a Dog Model of Duchenne Muscular Dystrophy
Yokota, Toshifumi; Hoffman, Eric; Takeda, Shinĺichi
Exon skipping is currently one of the most promising molecular therapies for Duchenne muscular dystrophy (DMD). We have recently developed multiple exon skipping targeting exons 6 and 8 in dystrophin mRNA of canine X-linked muscular dystrophy (CXMD), an animal model of DMD, which exhibits severe dystrophic phenotype in skeletal muscles and cardiac muscle. We have induced efficient exon skipping both in vitro and in vivo by using cocktail antisense 2ĺ O-methyl oligonucleotides (2ĺOMePS) and cocktail phosphorodiamidate morpholino oligomers (morpholinos, or PMOs) and ameliorated phenotype of dystrophic dogs by systemic injections. The multiple exon skipping (double exon skipping) shown here provides the prospect of choosing deletions that optimize the functionality of the truncated dystrophin protein for DMD patients by using a common cocktail that could be validated as a single drug and also potentially applicable for more than 90% of DMD patients. PMID:21194037
Analysis using histograms of muscle CT images in patients with Duchenne muscular dystrophy
Nakayama, Takahiro; Kuru, Satoshi; Kawai, Mitsuru
We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with Duchenne muscular dystrophy, and this shape of the histogram will employ a new analytical method. CT images of the middle part of the thigh were acquired in a patient with Duchenne muscular dystrophy once a year from 6 to 11?years of age. Regions apparently corresponding to subcutaneous fat, bone and bone marrow were manually excluded, and the CT values were calculated to prepare histograms. His motor disability was also evaluated employing Vignos functional rating scale. A single peak was noted in the muscle CT value range in the histogram at the youngest age. The muscle-to-fat ratio in muscle decreased with the worsening of his disease disability level and the peak of the histogram shifted from the muscle to the fat CT value. PMID:23729708
Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.
O'Grady, Gina L; Best, Heather A; Oates, Emily C; Kaur, Simranpreet; Charlton, Amanda; Brammah, Susan; Punetha, Jaya; Kesari, Akanchha; North, Kathryn N; Ilkovski, Biljana; Hoffman, Eric P; Clarke, Nigel F
Variants in ACTA1, which encodes ?-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal ?-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal ?-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression. PMID:25182138
Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain
NASA Astrophysics Data System (ADS)
Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas
Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.
Muscular dystrophy due to a sarcoglycan deficiency in a female Dobermann dog.
Munday, J S; Shelton, G D; Willox, S; Kingsbury, D D
A four-month-old female Dobermann presented with myalgia, dysphagia, progressive weakness and loss of body condition. Diagnostic evaluation at nine months of age revealed markedly elevated serum creatine kinase activity, electromyographic abnormalities and histological evidence of chronic-active muscle necrosis. Imaging confirmed dysphagia and aspiration pneumonia. Muscular dystrophy was suspected and immunohistochemical staining of muscle cryosections demonstrated reduced sarcoglycans. Treatment consisted of gastrostomy, and over the next 5 months the dog gained weight, despite continued loss of muscle mass. The dog died at 14 months of age after developing clinical signs of aspiration pneumonia. To the authors' knowledge, this is the first report of muscular dystrophy in a Dobermann and only the second detailed report of a canine sarcoglycanopathy. Supportive care resulted in an acceptable quality of life for 10 months after clinical signs were first observed. PMID:25482856
Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations
Mafalda Cacciottolo; Gelsomina Numitone; Stefania Aurino; Imma Rosaria Caserta; Marina Fanin; Luisa Politano; Carlo Minetti; Enzo Ricci; Giulio Piluso; Corrado Angelini; Vincenzo Nigro
Dysferlin is a 237-kDa transmembrane protein involved in calcium-mediated sarcolemma resealing. Dysferlin gene mutations cause limb-girdle muscular dystrophy (LGMD) 2B, Miyoshi myopathy (MM) and distal myopathy of the anterior tibialis. Considering that a secondary Dysferlin reduction has also been described in other myopathies, our original goal was to identify cases with a Dysferlin deficiency without dysferlin gene mutations. The dysferlin
ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies
Cirak, Sebahattin; Foley, Aileen Reghan; Herrmann, Ralf; Willer, Tobias; Yau, Shu; Stevens, Elizabeth; Torelli, Silvia; Brodd, Lina; Kamynina, Alisa; Vondracek, Petr; Roper, Helen; Longman, Cheryl; Korinthenberg, Rudolf; Marrosu, Gianni; NŘrnberg, Peter; Michele, Daniel E.; Plagnol, Vincent; Hurles, Matt; Moore, Steven A.; Sewry, Caroline A.; Campbell, Kevin P.; Voit, Thomas
Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, WalkerľWarburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of ?-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of ?-dystroglycan with extracellular matrix proteins such as laminin-?2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ?50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of WalkerľWarburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of ?-dystroglycan, which not only causes the severe WalkerľWarburg syndrome but is also a common cause of the milder forms of dystroglycanopathy. PMID:23288328
Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis
Background The diagnosis of neuromuscular diseases is strongly based on the histological characterization of muscle biopsies. However, this morphological analysis is mostly a subjective process and difficult to quantify. We have tested if network science can provide a novel framework to extract useful information from muscle biopsies, developing a novel method that analyzes muscle samples in an objective, automated, fast and precise manner. Methods Our database consisted of 102 muscle biopsy images from 70 individuals (including controls, patients with neurogenic atrophies and patients with muscular dystrophies). We used this to develop a new method, Neuromuscular DIseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images. NDICIA characterizes muscle tissues by representing each image as a network, with fibers serving as nodes and fiber contacts as links. Results After a Ĺtrainingĺ phase with control and pathological biopsies, NDICIA was able to quantify the degree of pathology of each sample. We validated our method by comparing NDICIA quantification of the severity of muscular dystrophies with a pathologistĺs evaluation of the degree of pathology, resulting in a strong correlation (R?=?0.900, P <0.00001). Importantly, our approach can be used to quantify new images without the need for prior Ĺtrainingĺ. Therefore, we show that network science analysis captures the useful information contained in muscle biopsies, helping the diagnosis of muscular dystrophies and neurogenic atrophies. Conclusions Our novel network analysis approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials. PMID:23514382
Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle
NASA Astrophysics Data System (ADS)
Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.
A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.
Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function
Bibee, Kristin P.; Cheng, Ya-Jian; Ching, James K.; Marsh, Jon N.; Li, Allison J.; Keeling, Richard M.; Connolly, Anne M.; Golumbek, Paul T.; Myerson, Jacob W.; Hu, Grace; Chen, Junjie; Shannon, William D.; Lanza, Gregory M.; Weihl, Conrad C.; Wickline, Samuel A.
Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.ŚBibee, K. P., Cheng, Y.-J., Ching, J. K., Marsh, J. N., Li, A. J., Keeling, R. M., Connolly, A. M., Golumbek, P. T., Myerson, J. W., Hu, G., Chen, J., Shannon, W. D., Lanza, G. M., Weihl, C. C., Wickline, S. A. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. PMID:24500923
Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy.
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel; Kaur, Amanjot; Sparwasser, Tim; Tidball, James G; Margeta, Marta; Spencer, Melissa J; Bluestone, Jeffrey A
We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wild-type mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-? (IFN-?) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD. PMID:25320234
Merosin-Deficient Congenital Muscular Dystrophy (MDCMD): A Case Report with MRI, MRS and DTI Findings
Ip, Janice JK; Hui, Peter KT; Chau, MT; Lam, Wendy WM
Congenital muscular dystrophy (CMD) comprises a heterogeneous group of disorders present at birth with muscle weakness, hypotonia and contractures. Congenital muscular dystrophy (CMD) comprises a heterogeneous group of disorders with muscle weakness, hypotonia and contractures present at birth. A particular subset of classic CMD is characterized by a complete absence of merosin. Merosin-deficient congenital muscular dystrophy (MDCMD) is a rare genetic disease involving the central and peripheral nervous system in the childhood. High signal intensities are often observed throughout the centrum semiovale, periventricular, and sub-cortical white matters on T2-weighted images in MRI brain in children with MDCMD. Apparent diffusion coefficient (ADC) map may reveal increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. These white matter findings, observed in late infancy, decrease in severity with age. The pathogenesis of these changes remains uncertain at present. In this article, we outline the specific MR imaging findings seen in a patient with documented MDCMD and also suggest the causes. PMID:23365711
QRS Prolongation in Myotonic Muscular Dystrophy and Diffuse Fibrosis on Cardiac Magnetic Resonance
Nazarian, Saman; Bluemke, David A.; Wagner, Kathryn R.; Zviman, Menekhem M.; Turkbey, Evrim; Caffo, Brian S.; Shehata, Monda; Edwards, David; Butcher, Barbara; Calkins, Hugh; Berger, Ronald D.; Halperin, Henry R.; Tomaselli, Gordon F.
Current noninvasive surrogates of cardiac involvement in myotonic muscular dystrophy have low positive predictive value for sudden death. We hypothesized that the cardiac MR signal-to-noise ratio variance (SNRV) is a surrogate of the spatial heterogeneity of myocardial fibrosis and correlates with electrocardiography changes in myotonic muscular dystrophy. The SNRV for contrast enhanced cardiac MR images was calculated over the entire left ventricle in 43 patients with myotonic muscular dystrophy. All patients underwent standard electrocardiography, and a subset of 23 patients underwent signal averaged electrocardiography. After correcting for body mass index, age, and ejection fraction, SNRV was predictive of QRS duration on standard electrocardiography (1.35-msec increased QRS duration/unit increase in SNRV, P < 0.001). SNRV was also predictive of the low-amplitude late-potential duration (1.49-msec increased low-amplitude late-potential duration/unit increase in SNRV, P < 0.001). Ten-fold cross-validation yielded an area under the receiver operating characteristic curve of 0.87 for the predictive value of SNRV for QRS duration greater than 120 msec. The SNRV of the left ventricle is associated with QRS prolongation, likely due to late depolarization of tissue within islands of patchy fibrosis. The association of SNRV with future clinical events warrants further study. PMID:20572151
From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies
Muscular dystrophies are a large heterogeneous group of inherited diseases that cause progressive muscle weakness and permanent muscle damage. Very few muscular dystrophies show sufficient specific clinical features to allow a definite diagnosis. Because of the currently limited capacity to screen for numerous genes simultaneously, muscle biopsy is a time and cost-effective test for many of these disorders. Protein analysis interpreted in correlation with the clinical phenotype is a useful way of directing genetic testing in many types of muscular dystrophies. Immunohistochemistry and western blot are complementary techniques used to gather quantitative and qualitative information on the expression of proteins involved in this group of diseases. Immunoanalysis has a major diagnostic application mostly in recessive conditions where the absence of labelling for a particular protein is likely to indicate a defect in that gene. However, abnormalities in protein expression can vary from absence to very subtle reduction. It is good practice to test muscle biopsies with antibodies for several proteins simultaneously and to interpret the results in context. Indeed, there is a degree of direct or functional association between many of these proteins that is reflected by the presence of specific secondary abnormalities that are of value, especially when the diagnosis is not straightforward. PMID:21798100
Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies.
Ayoglu, Burcu; Chaouch, Amina; LochmŘller, Hanns; Politano, Luisa; Bertini, Enrico; Spitali, Pietro; Hiller, Monika; Niks, Eric H; Gualandi, Francesca; PontÚn, Fredrik; Bushby, Kate; Aartsma-Rus, Annemieke; Schwartz, Elena; Le Priol, Yannick; Straub, Volker; UhlÚn, Mathias; Cirak, Sebahattin; 't Hoen, Peter A C; Muntoni, Francesco; Ferlini, Alessandra; Schwenk, Jochen M; Nilsson, Peter; Al-Khalili Szigyarto, Cristina
Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. PMID:24920607
Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies
Ayoglu, Burcu; Chaouch, Amina; LochmŘller, Hanns; Politano, Luisa; Bertini, Enrico; Spitali, Pietro; Hiller, Monika; Niks, Eric H; Gualandi, Francesca; PontÚn, Fredrik; Bushby, Kate; Aartsma-Rus, Annemieke; Schwartz, Elena; Le Priol, Yannick; Straub, Volker; UhlÚn, Mathias; Cirak, Sebahattin; Ĺt Hoen, Peter A C; Muntoni, Francesco; Ferlini, Alessandra; Schwenk, Jochen M; Nilsson, Peter; Al-Khalili Szigyarto, Cristina
Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. PMID:24920607
Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of ?-Dystroglycan
Carss, KerenáJ.; Stevens, Elizabeth; Foley, A.áReghan; Cirak, Sebahattin; Riemersma, Moniek; Torelli, Silvia; Hoischen, Alexander; Willer, Tobias; vanáScherpenzeel, Monique; Moore, StevenáA.; Messina, Sonia; Bertini, Enrico; B÷nnemann, CarstenáG.; Abdenur, JoseáE.; Grosmann, CarlaáM.; Kesari, Akanchha; Punetha, Jaya; Quinlivan, Ros; Waddell, LeigháB.; Young, HelenáK.; Wraige, Elizabeth; Yau, Shu; Brodd, Lina; Feng, Lucy; Sewry, Caroline; MacArthur, DanieláG.; North, KathrynáN.; Hoffman, Eric; Stemple, DerekáL.; Hurles, MatthewáE.; vanáBokhoven, Hans; Campbell, KevináP.; Lefeber, DirkáJ.; Lin, Yung-Yao; Muntoni, Francesco
Congenital muscular dystrophies with hypoglycosylation of ?-dystroglycan (?-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of ?-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated ?-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including ?-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced ?-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of ?-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of ?-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of ?-DG. PMID:23768512
The Zebrafish runzel Muscular Dystrophy is Linked to the Titin Gene
Steffen, Leta S; Guyon, Jeffrey R; Vogel, Emily D; Howell, Melanie H; Zhou, Yi; Weber, Gerhard J; Zon, Leonard I; Kunkel, Louis M
Titin (also called connectin) acts as a scaffold for signaling proteins in muscle, and is responsible for establishing and maintaining the structure and elasticity of sarcomeres in striated muscle. Several human muscular dystrophies and cardiomyopathies have previously been linked to mutations in the titin gene. This study reports linkage of the runzel homozygous lethal muscular dystrophy in the zebrafish Danio rerio to a genomic interval containing the titin gene. Analysis of the genomic sequence suggests that zebrafish contain two adjacent titin loci. One titin locus lies within the genetic linkage interval and its expression is significantly reduced in runzel mutants by both immunofluorescence and protein electrophoresis. Morpholino downregulation of this same titin locus in wildtype embryos results in decreased muscle organization and mobility, phenocopying runzel mutants. Additional protein analysis demonstrates that, in wildtype zebrafish, titin isoform sizes are rapidly altered during the development of striated muscle, likely requiring a previously unrecognized need for vertebrate sarcomere remodeling to incorporate developmentally-regulated titin isoforms. Decreases of affected titin isoforms in runzel mutants during this time correlate with a progressive loss of sarcomeric organization and suggest that the unaffected titin proteins are capable of sarcomerogenesis but not sarcomere maintenance. In addition, microarray analysis of the ruz transcriptome suggests a novel mechanism of dystrophy pathogenesis, involving mild increases in calpain-3 expression and upregulation of heat shock proteins. These studies should lead to a better understanding of titinĺs role in normal and diseased muscle. PMID:17678642
Learning about Myotonic Dystrophy
... FAQ Top of page Additional Resources on Myotonic Muscular Dystrophy Myotonic dystrophy [ghr.nlm.gov] From Genetics Home ... the CNBP gene. From Genetics Home Reference NINDS Muscular Dystrophy Information Page [ninds.nih.gov] From the National ...
The empowerment of translational research: lessons from laminopathies.
Benedetti, Sara; Bernasconi, Pia; Bertini, Enrico; Biagini, Elena; Boriani, Giuseppe; Capanni, Cristina; Carboni, Nicola; Cenacchi, Giovanna; Columbaro, Marta; D'Adamo, Monica; D'Amico, Adele; D'Apice, Maria Rosaria; Fontana, Marianna; Gambineri, Alessandra; Lattanzi, Giovanna; Liguori, Rocco; Maraldi, Nadir M; Mazzanti, Laura; Mercuri, Eugenio; Mongini, Tiziana; Morandi, Lucia O; Neri, Iria; Nigro, Giovanni; Novelli, Giuseppe; Ortolani, Michela; Pasquali, Renato; Pini, Antonella; Petrini, Stefania; Politano, Luisa; Previtali, Stefano; Pucci, Lisa; Rapezzi, Claudio; Ricci, Giulia; Rodolico, Carmelo; Sbraccia, Paolo; Scarano, Emanuela; Siciliano, Gabriele; Squarzoni, Stefano; Toscano, Antonio; Vercelli, Liliana; Ziacchi, Matteo
The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy. PMID:22691392
Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1)
Eugenio Mercuri; Beril Talim; Behzad Moghadaszadeh; Nathalie Petit; Martin Brockington; Serena Counsell; Pascale Guicheney; Francesco Muntoni; Luciano Merlini
We report clinical and imaging findings in six cases from five families affected by the form of congenital muscular dystrophy with rigid spine linked to the locus rigid spine muscular dystrophy 1 on chromosome 1p35-36. All cases showed rigidity of the spine, predominant neck and trunk weakness and frequent and severe thoracic scoliosis. Respiratory impairment was always observed in the
Genetic linkage relationships between the Xg blood group system and two X chromosome DNA polymorphisms in families with Duchenne and Becker muscular dystrophy
M. Sarfarazi; P. S. Harper; H. M. Kingston; J. M. Murray; T. O'Brien; K. E. Davies; R. Williamson; P. Tippett; R. Sanger
The existence of linkage has been investigated between the Xg blood group system, two DNA restriction fragment length polymorphisms (RFLPs) located on the short arm of the X chromosome, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). No linkage was found between the Xg locus and the more proximal RFLP (L1.28); close linkage between Xg and the more distal
Muscle Quantitative MR Imaging and Clustering Analysis in Patients with Facioscapulohumeral Muscular Dystrophy Type 1
Lareau-Trudel, Emilie; Le Troter, Arnaud; Ghattas, Badih; Pouget, Jean; Attarian, Shahram; Bendahan, David; Salort-Campana, Emmanuelle
Background Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest. Methods and Findings Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI) combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score) on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS) scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ▒ 20.4%) than in volunteers (3.6 ▒ 2.8%) (p<0.001). In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001). However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p?0.01) and was inversely correlated with MMT score, MFM subscore D1 (p?0.01) further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy. Conclusion The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients. PMID:26181385
Overexpression of the Cytotoxic T Cell (CT) Carbohydrate Inhibits Muscular Dystrophy in the dyW Mouse Model of Congenital Muscular Dystrophy 1A
Xu, Rui; Chandrasekharan, Kumaran; Yoon, Jung Hae; Camboni, Marybeth; Martin, Paul T.
A number of recent studies have demonstrated therapeutic effects of transgenes on the development of muscle pathology in the mdx mouse model for Duchenne muscular dystrophy, but none have been shown also to be effective in mouse models for laminin ?2-deficient congenital muscular dystrophy (MDC1A). Here, we show that overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) is effective in inhibiting the development of muscle pathology in the dyW mouse model of MDC1A, much as we had previously shown in mdx animals. Embryonic overexpression of Galgt2 in skeletal muscles using transgenic mice or postnatal overexpression using adeno-associated virus both reduced the extent of muscle pathology in dyW/dyW skeletal muscle. As with mdx mice, embryonic overexpression of the Galgt2 transgene in dyW/dyW myofibers inhibited muscle growth, whereas postnatal overexpression did not. Both embryonic and postnatal overexpression of Galgt2 in dyW/dyW muscle increased the expression of agrin, a protein that, in recombinant form, has been shown to ameliorate disease, whereas laminin ?1, another disease modifier, was not expressed. Galgt2 over-expression also stimulated the glycosylation of a glycolipid with the CT carbohydrate, and glycolipids accounted for most of the CT-reactive material in postnatal overexpression experiments. These experiments demonstrate that Galgt2 overexpression is effective in altering disease progression in skeletal muscles of dyW mice and should be considered as a therapeutic target in MDC1A. PMID:17591965
Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel mutation in the LMNA gene.
Bonati, Ulrike; Bechtel, Nina; Heinimann, Karl; Rutz, Erich; Schneider, Jacques; Frank, Stephan; Weber, Peter; Fischer, Dirk
Mutations in A-type nuclear lamins are known to cause a variety of diseases, which can affect almost all organs of the human body including striated muscle. For lamin-related congenital muscular dystrophy two different phenotypes are known to date. Here, we describe a 3-year-old, white Caucasian girl with a novel de novo mutation in the LMNA gene with marked hypotonia of neck and trunk muscles with dropped head posture, loss of cervical lordosis and marked joint laxity. In addition to this novel mutation, the patient also had cerebral white matter lesions on MRI and cognitive impairment on developmental testing. This is only the second A-type lamin-related congenital muscular dystrophy patient in which white matter lesions are described. Thus, white matter involvement might be a feature in A-type lamin-related congenital muscular dystrophy, warranting screening of these patients for both white matter lesions and cognitive impairment. PMID:24684859
Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection.
Anaya-Segura, Monica Alejandra; GarcÝa-MartÝnez, Froylan Arturo; Montes-Almanza, Luis Angel; DÝaz, BenjamÝn-Gomez; Avila-RamÝrez, Guillermina; Alvarez-Maya, Ikuri; Coral-Vazquez, Ramˇn Mauricio; Mondragˇn-Terßn, Paul; Escobar-Cedillo, Rosa Elena; GarcÝa-Calderˇn, NoemÝ; Vazquez-Cardenas, Norma Alejandra; GarcÝa, Silvia; Lˇpez-Hernandez, Luz Berenice
Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 and matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 1, myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid na´ve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression. PMID:26091074
Rapid carrier and prenatal diagnosis of Duchenne and Becker muscular dystrophy
Roberts, R.G.; Cole, C.G.; Hart, K.A.; Bobrow, M.; Bentley, D.R. (Guy's Hospital, London (England))
Carrier and prenatal diagnosis of Duchenne and Becker muscular dystrophy (DMD and BMD) by DNA methods uses Southern blotting to detect either the informative segregation of restriction fragment length polymorphisms (RFLPs) or the absence of restriction fragments in affected males. Recently, the use of the polymerase chain reaction (PCR) for rapid detection of deletions in some affected males was reported eliminating the need for Southern blotting of 37% of all samples. This approach is not applicable, however, to non-deletion cases or for carrier diagnosis. The authors have used PCR for rapid analysis of intragenic RFLPs to permit both carrier and prenatal diagnosis in the majority of familial cases.
Scoliosis repair in a teenager with Duchenne's muscular dystrophy: who calls the shots?
Miles, Fiona; Dare, Tim
In this exchange, a clinician (the first author) presents a case scenario for comment by an ethicist (the second author). The case concerns a 15-year-old boy with Duchenne's muscular dystrophy requested palliative surgical correction of a 60 degree thoraco-lumbar scoliosis. The surgical team were initially reluctant to offer surgery given their assessment of the perioperative and postoperative risks (anesthetic review suggested an 80% chance of surviving the surgery and 50% likelihood of returning home), but the operation proceeded. The case raises issues of the rights of patients to insist on nonfutile but high risk surgery, risk perception, resource allocation, autonomy, and the integrity of clinicians. PMID:19619186
The Molecular Basis of Muscular Dystrophy in the mdx Mouse: A Point Mutation
NASA Astrophysics Data System (ADS)
Sicinski, Piotr; Geng, Yan; Ryder-Cook, Allan S.; Barnard, Eric A.; Darlison, Mark G.; Barnard, Pene J.
The mdx mouse is an X-linked myopathic mutant, an animal model for human Duchenne muscular dystrophy. In both mouse and man the mutations lie within the dystrophin gene, but the phenotypic differences of the disease in the two species confer much interest on the molecular basis of the mdx mutation. The complementary DNA for mouse dystrophin has been cloned, and the sequence has been used in the polymerase chain reaction to amplify normal and mdx dystrophin transcripts in the area of the mdx mutation. Sequence analysis of the amplification products showed that the mdx mouse has a single base substitution within an exon, which causes premature termination of the polypeptide chain.
Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation 1 as augmentation therapeutic strategy approaches in muscular dystrophy
Afzal, Ehsan; Zakeri, Saba; Keyhanvar, Peyman; Bagheri, Meisam; Mahjoubi, Parvin; Asadian, Mahtab; Omoomi, Nogol; Dehqanian, Mohammad; Ghalandarlaki, Negar; Darvishmohammadi, Tahmineh; Farjadian, Fatemeh; Golvajoee, Mohammad Sadegh; Afzal, Shadi; Ghaffari, Maryam; Cohan, Reza Ahangari; Gravand, Amin; Ardestani, Mehdi Shafiee
Backgrond Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion ľ like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. Methods In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. Results The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation. PMID:23966782
[Congenital muscular dystrophy with laminin-a2 deficiency in early infancy: diagnosis and long-term follow-up].
Panteliadis, C; Karatza, E; Xinias, I; Flaris, N; Tzitiridou, M; Ramantani, G
Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders characterized by muscle weakness and hypotonia at birth or within the first few months of life. It is inherited in an autosomal recessive pattern. About half of the patients have a deficiency of the alpha-2-chain of laminin (merosin). We describe a case of congenital muscular dystrophy in an infant with laminin-a2-chain deficiency, which appeared hypotonia in early infancy. Diagnosis was made by clinical features and the histological and immunohistochemical studies on muscle biopsy. PMID:16167276
Elevated liver enzymes indicating a diagnosis of limb-girdle muscular dystrophy.
Lash, Tyler; Kraemer, Ryan R
A 27-year-old man presented to an internal medicine clinic to establish primary care. His past medical history was significant for elevated liver transaminases found during laboratory monitoring while taking isotretinoin for acne. He had an extensive workup spanning 7 years including serial hepatic function panels after withholding isotretinoin, viral serologies, and two liver biopsies, which eventually led to a diagnosis of an idiopathic elevation in serum transaminases. During his present evaluation, he endorsed complaints of significant muscle soreness with strenuous activity despite conditioning. Creatine kinase was found to be elevated at 11,778 U/l. Nerve conduction studies and electromyogram indicated a myopathy. DNA sequencing confirmed a diagnosis of limb-girdle muscular dystrophy. The aminotransferases are most notable for their association with liver pathology; however, they are also present in other tissues such as heart, kidney, and skeletal muscle. Muscle pathology, including the inherited muscular dystrophies, are often identified by elevations in creatine kinase, but can also be suggested by elevations of aminotransferases. This case illustrates that myopathies should be considered in patients with otherwise unexplained elevations in liver aminotransferases. PMID:24452419
Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy.
Mead, A F; Petrov, M; Malik, A S; Mitchell, M A; Childers, M K; Bogan, J R; Seidner, G; Kornegay, J N; Stedman, H H
Ventilatory insufficiency remains the leading cause of death and late stage morbidity in Duchenne muscular dystrophy (DMD). To address critical gaps in our knowledge of the pathobiology of respiratory functional decline, we used an integrative approach to study respiratory mechanics in a translational model of DMD. In studies of individual dogs with the Golden Retriever muscular dystrophy (GRMD) mutation, we found evidence of rapidly progressive loss of ventilatory capacity in association with dramatic morphometric remodeling of the diaphragm. Within the first year of life, the mechanics of breathing at rest, and especially during pharmacological stimulation of respiratory control pathways in the carotid bodies, shift such that the primary role of the diaphragm becomes the passive elastic storage of energy transferred from abdominal wall muscles, thereby permitting the expiratory musculature to share in the generation of inspiratory pressure and flow. In the diaphragm, this physiological shift is associated with the loss of sarcomeres in series (? 60%) and an increase in muscle stiffness (? 900%) compared with those of the nondystrophic diaphragm, as studied during perfusion ex vivo. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of respiratory failure in DMD. PMID:24408990
Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.
Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Mßrcio Nogueira; Brˇlio, Marina Pandolphi; Miglino, Maria AngÚlica; Ambrˇsio, Carlos Eduardo
Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. PMID:25081087
Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy.
Azakir, Bilal A; Erne, Beat; Di Fulvio, Sabrina; Stirnimann, Guido; Sinnreich, Michael
No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases. PMID:25143362
Corticosteroid Treatments in Males With Duchenne Muscular Dystrophy: Treatment Duration and Time to Loss of Ambulation.
Kim, Sunkyung; Campbell, Kimberly A; Fox, Deborah J; Matthews, Dennis J; Valdez, Rodolfo
This population-based study examines the association between corticosteroid treatment and time to loss of ambulation, stratifying by treatment duration (short: 0.25-3 years, long: >3 years), among 477 Duchenne muscular dystrophy cases identified by the Muscular Dystrophy Surveillance Tracking and Research Network (MDSTARnet). Those cases who received short-term corticosteroid treatment had a time to loss of ambulation that was 0.8 years shorter (t test) and an annual risk of losing ambulation 77% higher than the untreated (Cox regression). Conversely, cases who received long-term corticosteroid treatment had a time to loss of ambulation that was 2 years longer and an annual risk of losing ambulation 82% lower than the untreated, up to age 11 years; after which the risks were not statistically different. The relationship of corticosteroids and time to loss of ambulation is more complex than depicted by previous studies limited to treatment responders or subjects who lost ambulation during study follow-up. PMID:25414237
Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model
Brinkmeyer-Langford, Candice; Kornegay, Joe N.
Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan and abilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein, which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation; the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to this variation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers. This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limited to treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease and hold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility of comparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD, Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, more personalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomic background of individual patients. PMID:24403852
Soleus muscle in glycosylation-deficient muscular dystrophy is protected from contraction-induced injury
Gumerson, Jessica D.; Kabaeva, Zhyldyz T.; Davis, Carol S.; Faulkner, John A.
The glycosylation of dystroglycan is required for its function as a high-affinity laminin receptor, and loss of dystroglycan glycosylation results in congenital muscular dystrophy. The purpose of this study was to investigate the functional defects in slow- and fast-twitch muscles of glycosylation-deficient Largemyd mice. While a partial alteration in glycosylation of dystroglycan in heterozygous Largemyd/+ mice was not sufficient to alter muscle function, homozygous Largemyd/myd mice demonstrated a marked reduction in specific force in both soleus and extensor digitorum longus (EDL) muscles. Although EDL muscles from Largemyd/myd mice were highly susceptible to lengthening contraction-induced injury, Largemyd/myd soleus muscles surprisingly showed no greater force deficit compared with wild-type soleus muscles even after five lengthening contractions. Despite no increased susceptibility to injury, Largemyd/myd soleus muscles showed loss of dystroglycan glycosylation and laminin binding activity and dystrophic pathology. Interestingly, we show that soleus muscles have a markedly higher sarcolemma expression of ?1-containing integrins compared with EDL and gastrocnemius muscles. Therefore, we conclude that ?1-containing integrins play an important role as matrix receptors in protecting muscles containing slow-twitch fibers from contraction-induced injury in the absence of dystroglycan function, and that contraction-induced injury appears to be a separable phenotype from the dystrophic pathology of muscular dystrophy. PMID:20844247
Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy
Hathout, Yetrib; Brody, Edward; Clemens, Paula R.; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P.; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K.; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H. Lee; Williams, Steve; Gold, Larry
Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular DystrophyľCincinnati Childrenĺs Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. PMID:26039989
From representation to mediation: the shaping of collective mobilization on muscular dystrophy in France.
Rabeharisoa, Vololona
How, and to what extent, do patient organisations renew traditional forms of social participation and protest? This question is examined, drawing on a socio-historical case study of the Association Franšaise contre les Myopathies--French Muscular Dystrophy Organisation (AFM). The originality of the AFM is that it has not been content to endorse the classic role of representation of people with muscular dystrophy (MD) and their families. It has also articulated and structured different social spaces that allow people suffering from genetic diseases and severe disabilities to be considered as fully-fledged human beings, persons, and citizens within those spaces. Based on quantitative data and methods, this paper aims to characterize this reconfiguration of social spaces that the AFM has undertaken. My contention is that it has given shape to a different form of collective mobilization, one in which the patient organisation is a mediator between different social actors, as much as a patients' representative. It helps a new issue, here MD, to emerge so that the largest possible collective designate it as a general public concern. As we shall discuss, this renews the question of patients' collective identity and citizenship. PMID:16051407
Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.
Hathout, Yetrib; Brody, Edward; Clemens, Paula R; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H Lee; Williams, Steve; Gold, Larry
Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. PMID:26039989
Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy
Mead, A. F.; Petrov, M.; Malik, A. S.; Mitchell, M. A.; Childers, M. K.; Bogan, J. R.; Seidner, G.; Kornegay, J. N.
Ventilatory insufficiency remains the leading cause of death and late stage morbidity in Duchenne muscular dystrophy (DMD). To address critical gaps in our knowledge of the pathobiology of respiratory functional decline, we used an integrative approach to study respiratory mechanics in a translational model of DMD. In studies of individual dogs with the Golden Retriever muscular dystrophy (GRMD) mutation, we found evidence of rapidly progressive loss of ventilatory capacity in association with dramatic morphometric remodeling of the diaphragm. Within the first year of life, the mechanics of breathing at rest, and especially during pharmacological stimulation of respiratory control pathways in the carotid bodies, shift such that the primary role of the diaphragm becomes the passive elastic storage of energy transferred from abdominal wall muscles, thereby permitting the expiratory musculature to share in the generation of inspiratory pressure and flow. In the diaphragm, this physiological shift is associated with the loss of sarcomeres in series (?60%) and an increase in muscle stiffness (?900%) compared with those of the nondystrophic diaphragm, as studied during perfusion ex vivo. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of respiratory failure in DMD. PMID:24408990
Multiplex Western Blotting System for the Analysis of Muscular Dystrophy Proteins
Anderson, Louise V. B.; Davison, Keith
A multiplex system of Western blotting is presented in which most of the current muscular dystrophy proteins can be analyzed simultaneously on one pair of blots. This represents a significant improvement in efficiency and cost for this type of analysis. The final diagnosis is more quickly achieved in patients where several possible diagnoses are indicated after clinical appraisal, and those with unusual presentations may be quickly resolved. The method uses a biphasic polyacrylamide gel system, which enables the corresponding blot to be probed simultaneously with a cocktail of monoclonal antibodies. The gel is optimized so that large proteins of more than 200 kd (eg, dystrophin, dysferlin, and myosin heavy chain) can be analyzed in the top part, while smaller proteins under 150 kd (eg, calpain 3, the 80-kd fragment of laminin ?2 chain, all of the sarcoglycans, and caveolin 3) are separated in the lower phase. This basic system could be used for different combinations of antibodies as new muscular dystrophy proteins are identified and require examination. In addition, analysis of the laminin ?2 chain of merosin showed that this protein was expressed as a doublet or triplet set of bands in many patients with active muscle pathology. This may indicate the existence of an embryonic isoform, which is re-expressed in regenerating fibers. PMID:10233840
MMP-10 is required for efficient muscle regeneration in mouse models of injury and muscular dystrophy.
Bobadilla, MÝriam; Sßinz, Neira; Rodriguez, JosÚ Antonio; Abizanda, Gloria; Orbe, Josune; de Martino, Alba; GarcÝa Verdugo, JosÚ Manuel; Pßramo, JosÚ A; Prˇsper, Felipe; PÚrez-Ruiz, Ana
Matrix metalloproteinases (MMPs), a family of endopeptidases that are involved in the degradation of extracellular matrix components, have been implicated in skeletal muscle regeneration. Among the MMPs, MMP-2 and MMP-9 are upregulated in Duchenne muscular dystrophy (DMD), a fatal X-linked muscle disorder. However, inhibition or overexpression of specific MMPs in a mouse model of DMD (mdx) has yielded mixed results regarding disease progression, depending on the MMP studied. Here, we have examined the role of MMP-10 in muscle regeneration during injury and muscular dystrophy. We found that skeletal muscle increases MMP-10 protein expression in response to damage (notexin) or disease (mdx mice), suggesting its role in muscle regeneration. In addition, we found that MMP-10-deficient muscles displayed impaired recruitment of endothelial cells, reduced levels of extracellular matrix proteins, diminished collagen deposition, and decreased fiber size, which collectively contributed to delayed muscle regeneration after injury. Also, MMP-10 knockout in mdx mice led to a deteriorated dystrophic phenotype. Moreover, MMP-10 mRNA silencing in injured muscles (wild-type and mdx) reduced muscle regeneration, while addition of recombinant human MMP-10 accelerated muscle repair, suggesting that MMP-10 is required for efficient muscle regeneration. Furthermore, our data suggest that MMP-10-mediated muscle repair is associated with VEGF/Akt signaling. Thus, our findings indicate that MMP-10 is critical for skeletal muscle maintenance and regeneration during injury and disease. PMID:24123596
Duchenne muscular dystrophy: alpha-dystroglycan immunoexpression in skeletal muscle and cognitive performance.
Pereira, ConceišŃo Campanario da Silva; Kiyomoto, Beatriz Hitomi; Cardoso, Ricardo; Oliveira, Acary Souza Bulle
The Duchenne muscular dystrophy (DMD) is a muscular dystrophy with cognitive impairment present in 20-30% of the cases. In the present study, in order to study the relationship between the alpha-dystroglycan (alpha-DG) immunostaining in skeletal muscle and cognitive performance in DMD patients, 19 were assessed. Twelve patients performed the intelligence quotient (IQ) below the average. Among the 19 patients, two were assessed by the Stanford-Binet test and 17 by Wechsler Intelligence Scale for Children-III (WISC-III). Nine patients performed a verbal IQ below the average, only three patients performed an average verbal IQ. The muscle biopsies immunostained with antibodies to alpha-DG showed that 17 patients presented a low expression, below 25% of the total fibers. Two patients presented alpha-DG immunostaining above 40% and an IQ within the average. No significant statistical relationship was demonstrated among total IQ, verbal IQ and execution IQ and alpha-DG immunostaining at these patients muscle samples. PMID:16400417
Electrical impedance myography for the assessment of children with muscular dystrophy: a preliminary study
NASA Astrophysics Data System (ADS)
Rutkove, S. B.; Darras, B. T.
Electrical impedance myography (EIM) provides a non-invasive approach for quantifying the severity of neuromuscular disease. Here we determine how well EIM data correlates to functional and ultrasound (US) measures of disease in children with Duchenne muscular dystrophy (DMD) and healthy subjects. Thirteen healthy boys, aged 2-12 years and 14 boys with DMD aged 4-12 years underwent both EIM and US measurements of deltoid, biceps, wrist flexors, quadriceps, tibialis anterior, and medial gastrocnemius. EIM measurements were performed with a custom-designed probe using a commercial multifrequency bioimpedance device. US luminosity data were quantified using a gray-scale analysis approach. Children also underwent the 6-minute walk test, timed tests and strength measurements. EIM and US data were combined across muscles. EIM 50 kHz phase was able to discriminate DMD children from healthy subjects with 98% accuracy. In the DMD patients, average EIM phase measurements also correlated well with standard functional measures. For example the 50 kHz phase correlated with the Northstar Ambulatory Assessment test (R = 0.83, p = 0.02). EIM 50 kHz phase and US correlated as well, with R = -0.79 (p < 0.001). These results show that EIM provides valuable objective measures Duchenne muscular dystrophy severity.
Genitourinary health in a population-based cohort of males with Duchenne and Becker muscular dystrophies
Zhu, Yong; Romitti, Paul A.; Conway, Kristin M. Caspers; Kim, Sunkyung; Zhang, Ying; Yang, Michele; Mathews, Katherine D.
Introduction Genitourinary (GU) health among patients with Duchenne and Becker muscular dystrophies (DBMD) has not been explored using population-based data. Methods Medical records of 918 males ascertained by the Muscular Dystrophy Surveillance, Tracking, and Research Network were reviewed for documentation of GU-related hospitalizations and prescribed medications. Percentages of males who received these medical interventions were calculated, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for associations with sociodemographics (study site, race/ethnicity), symptoms (early-versus late-onset, ambulation status, scoliosis), and treatments (respiratory support, steroids). Results Among the 918 males, 81 (9%) had a GU condition; voiding dysfunction (n=40), GU tract infection (n=19), and kidney/ureter calculus (n=9) were most common. A Kaplan-Meier curve produced a cumulative probability of 27%. Cox regression showed GU conditions were more common when males were non-ambulatory (HR=2.7, 95% CI=1.3-5.6). Discussion These findings highlight increased awareness of GU health and multidisciplinary care of DBMD patients. PMID:25297835
[Challenge toward gene-therapy using iPS cells for Duchenne muscular dystrophy].
Oshimura, Mitsuo; Kazuki, Yasuhiro; Uno, Narumi
Human artificial chromosomes (HACs) are stable episomal gene vectors that can carry large gene inserts. We have reported complete correction of a genetic deficiency following the transfer of a HAC carrying the genomic dystrophin sequence (DYS-HAC) into induced pluripotent stem (iPS) cells derived from either a Duchenne muscular dystrophy (DMD) model mouse or a human DMD patient. The engineered iPS cells could differentiate in immunodeficient nude mice, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice generated from the engineered cells showed tissue-specific expression of dystrophin. Recently, Giulio's group has isolated and characterized a population of blood vessel-associated stem cells, called mesoangioblasts, that can differentiate into multiple mesoderm cell types, including skeletal muscle. The DYS-HAC was transferred to mesoangioblasts from the DMD-model mouse. Thus, when delivered in the arterial circulation, mesoangioblasts crossed the blood vessel wall and participated in skeletal muscle regeneration, ameliorating signs of muscular dystrophy in the DMD model mice. Most recently, the iPS cells from a DMD patient corrected with the DYS-HAC, were successfully differentiated to mesoangioblasts. Therefore, autologous transfer of genetically corrected iPS cells and muscle progenitor cells will be desirable therapeutic cells because immune suppression would not be required. PMID:23196542
Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance
We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with ôcryptogenicö hypertransaminasemia. PMID:23114028
The prognostic value of pre-operative predicted forced vital capacity in corrective spinal surgery for Duchenne's muscular dystrophy
C. M. Harper; G. Ambler; G. Edge
Summary The majority of patients with Duchenne's muscular dystrophy require corrective spinal surgery for scoliosis to maintain seated balance and to slow the progression of respiratory compromise, thereby facilitating nursing and enhancing their quality of life. Traditionally patients with a pre-operative forced vital capacity (PFVC) of 30% or below predicted have been denied this surgery as it was thought that
Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and ?7 integrin.
Marshall, Jamie L; Oh, Jennifer; Chou, Eric; Lee, Joy A; Holmberg, Johan; Burkin, Dean J; Crosbie-Watson, Rachelle H
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of ?7?1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of ?7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or ?7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and ?7?1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and ?7?1 integrin. PMID:25504048
Development of an Evaluation Scale for Sitting and Standing From the Ground for Children With Duchenne Muscular Dystrophy
Renata Escorcio; Fßtima Aparecida Caromano; Michele Emy Hukuda; LÝlian Aparecida Yoshimura Fernandes
The authors developed an evaluation scale for sitľstand from the ground for children with Duchenne muscular dystrophy (DMD) and tested its reliability. The construction occurred in stages: (a) the characterization of the movement in healthy children, (b) the characterization of the movement in children with DMD, (c) the elaboration of the 1st version of the scale and the manual, (d)
Functional Behavioral Assessment for a Boy with Duchenne Muscular Dystrophy and Problem Behavior: A Case Study from Greece
ERIC Educational Resources Information Center
Theodoridou, Zoe; Koutsoklenis, Athanasios
This article focuses on the application of functional behavioral assessment (FBA) to design a positive behavior intervention (PBI) for a boy with Duchenne muscular dystrophy (DMD) who encounters serious difficulties at the mainstream school because of behavioral problems and physical limitations. After the definition of problem behavior and itsů
Skeletal Muscle Homeostasis in Duchenne Muscular Dystrophy: Modulating Autophagy as a Promising Therapeutic Strategy
De Palma, Clara; Perrotta, Cristiana; Pellegrino, Paolo; Clementi, Emilio; Cervia, Davide
Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting. PMID:25104934
Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis
Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K., E-mail: firstname.lastname@example.com
The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin{sup -/-} (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of mpcs, the EOMCD34 cells, that are retained in significantly higher percentages in normal, mdx and DKO mice EOM, appear to be resistant to elevated levels of oxidative stress and toxins, and actively proliferate throughout life. Current studies are focused on further defining the EOMCD34 cell subtype molecularly, with the hopes that this may shed light on a cell type with potential therapeutic use in patients with sarcopenia, cachexia, or muscular dystrophy.
Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family
Frydman, M.; Straussberg, R.; Shomrat, R.; Legum, C. [Tel Aviv Univ. (Israel)] [and others
A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. {open_quotes}Idiopathic{close_quotes} hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia. 13 refs., 3 figs., 1 tab.
Genetic risk: women's understanding of carrier risks in Duchenne muscular dystrophy.
Parsons, E P; Clarke, A J
This paper reports a study of 48 women (16 mothers and 32 daughters representing 28 families) who had lived with Duchenne muscular dystrophy (DMD) in their family. It looks at the way the women talked about their carrier risks during the course of an unstructured interview. It points to a significant difference between lay and health professionals' perspectives, in particular the thresholds they used to distinguish between high and low risk. A number of women, when quoting their risk in a mathematical form, confused their reproductive risks with their carrier risk, another indication of differential perceptions between the women and health professionals. There was evidence that several of the women did not retain their risk in a mathematical form but had translated it into a descriptive category which resolved their risk into greater certainty. PMID:8411028
Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents
Wilton, Steve D; Fletcher, Sue
The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD) was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms. PMID:23776365
Initial Pulmonary Respiration Causes Massive Diaphragm Damage and Hyper-CKemia in Duchenne Muscular Dystrophy Dog
Nakamura, Akinori; Kobayashi, Masanori; Kuraoka, Mutsuki; Yuasa, Katsutoshi; Yugeta, Naoko; Okada, Takashi; Takeda, Shin'ichi
The molecular mechanism of muscle degeneration in a lethal muscle disorder Duchene muscular dystrophy (DMD) has not been fully elucidated. The dystrophic dog, a model of DMD, shows a high mortality rate with a marked increase in serum creatine kinase (CK) levels in the neonatal period. By measuring serum CK levels in cord and venous blood, we found initial pulmonary respiration resulted in massive diaphragm damage in the neonates and thereby lead to the high serum CK levels. Furthermore, molecular biological techniques revealed that osteopontin was prominently upregulated in the dystrophic diaphragm prior to the respiration, and that immediate-early genes (c-fos and egr-1) and inflammation/immune response genes (IL-6, IL-8, COX-2, and selectin E) were distinctly overexpressed after the damage by the respiration. Hence, we segregated dystrophic phases at the molecular level before and after mechanical damage. These molecules could be biomarkers of muscle damage and potential targets in pharmaceutical therapies. PMID:23851606
Psychological Aspects in Children Affected by Duchenne De Boulogne Muscular Dystrophy
Parisi, Lucia; Roccella, Michele
Impairment of intelligence in Duchenne muscular dystrophy (DMD) patients was described by Duchenne de Boulogne himself in 1868. Further studies report intelligence disorders with mayor impairment of memory. The aim of the present study was to assess the presence of affective and personality disorders in a group of children affected by DMD. Twenty six male DMD patients, mean age eleven and four months years old, were assessed for their affective and personality disorder. Only eight subjects had a total IQ below average with major difficulties in verbal and visual-spatial memory, comprehension, arithmetic and vocabulary. All the subjects presented some disorders: tendency to marginalization and isolation, self-depreciation, sense of insecurity, hypochondriac thoughts and marked state of anxiety. These disorders are often a dynamic prolongation of a psychological process which starts when the diagnosis is made and continues, in a slow and latent fashion, throughout the evolution of the disease. PMID:25478112
[Mitral valve replacement for a manifesting carrier of duchenne muscular dystrophy].
Ishii, Hirohito; Nakamura, Kunihide; Nagahama, Hiroyuki; Matsuyama, Masakazu; Endo, Jouji; Nishimura, Masanori
Duchenne muscular dystrophy (DMD) is an X-linked disease, but female carriers infrequently have some symptoms, who are called manifesting carriers. Here we report a case of a manifesting carrier of DMD with skeletal muscle weakness and cardiac abnormalities such as deterioration of cardiac function and left ventricular dilatation, who successfully underwent cardiac surgery. A 79-year-old female with acute heart failure for severe mitral regurgitation was admitted to our hospital. Surgical replacement of the mitral valve was performed under general anesthesia with intravenous anesthetics and non-depolarizing muscle relaxant. Cardiac surgery on a manifesting carrier of DMD is rare and requires a careful preoperative assessment of the heart function and anesthetic management. PMID:25743350
Abnormal Collagen Metabolism in Cultured Skin Fibroblasts from Patients with Duchenne Muscular Dystrophy
NASA Astrophysics Data System (ADS)
Rodemann, H. Peter; Bayreuther, Klaus
Total collagen synthesis is decreased by about 29% (P < 0.01) in skin fibroblasts established in vitro from male patients with Duchenne muscular dystrophy (DMD) as compared with that in normal male skin fibroblasts in vitro. The reduction in collagen synthesis is associated with an approximately 2-fold increase in collagen degradation in DMD fibroblasts. Correlated to these alterations in the metabolism of collagen, DMD fibroblasts express a significantly higher hydroxyproline/proline ratio (DMD: 1.36-1.45; P < 0.01) than do normal fibroblasts (controls: 0.86-0.89). The increased hydroxylation of proline residues of collagen (composed of type I and type III) could be the cause for the enhanced degradation of collagen in DMD fibroblasts.
Emerging gene editing strategies for Duchenne muscular dystrophy targeting stem cells
Bertoni, Carmen
The progressive loss of muscle mass characteristic of many muscular dystrophies impairs the efficacy of most of the gene and molecular therapies currently being pursued for the treatment of those disorders. It is becoming increasingly evident that a therapeutic application, to be effective, needs to target not only mature myofibers, but also muscle progenitors cells or muscle stem cells able to form new muscle tissue and to restore myofibers lost as the result of the diseases or during normal homeostasis so as to guarantee effective and lost lasting effects. Correction of the genetic defect using oligodeoxynucleotides (ODNs) or engineered nucleases holds great potential for the treatment of many of the musculoskeletal disorders. The encouraging results obtained by studying in vitro systems and model organisms have set the groundwork for what is likely to become an emerging field in the area of molecular and regenerative medicine. Furthermore, the ability to isolate and expand from patients various types of muscle progenitor cells capable of committing to the myogenic lineage provides the opportunity to establish cell lines that can be used for transplantation following ex vivo manipulation and expansion. The purpose of this article is to provide a perspective on approaches aimed at correcting the genetic defect using gene editing strategies and currently under development for the treatment of Duchenne muscular dystrophy (DMD), the most sever of the neuromuscular disorders. Emphasis will be placed on describing the potential of using the patient own stem cell as source of transplantation and the challenges that gene editing technologies face in the field of regenerative biology. PMID:24795643
Delayed bone regeneration is linked to chronic inflammation in murine muscular dystrophy
Abou-Khalil, Rana; Yang, Frank; Mortreux, Marie; Lieu, Shirley; Yu, Yan-Yiu; Wurmser, Maud; Pereira, Catia; Relaix, FrÚdÚric; Miclau, Theodore; Marcucio, Ralph S.; Colnot, CÚline
Duchenne muscular dystrophy (DMD) patients exhibit skeletal muscle weakness with continuous cycles of muscle fiber degeneration/regeneration, chronic inflammation, low bone mineral density and increased risks of fracture. Fragility fractures and associated complications are considered as a consequence of the osteoporotic condition in these patients. Here, we aimed to establish the relationship between muscular dystrophy and fracture healing by assessing bone regeneration in mdx mice, a model of DMD with absence of osteoporosis. Our results illustrate that muscle defects in mdx mice impact the process of bone regeneration at various levels. In mdx fracture calluses, both cartilage and bone deposition were delayed followed by a delay in cartilage and bone remodeling. Vascularization of mdx fracture calluses was also decreased during the early stages of repair. Dystrophic muscles are known to contain elevated numbers of macrophages contributing to muscle degeneration. Accordingly, we observed increased macrophage recruitment in the mdx fracture calluses and abnormal macrophage accumulation throughout the process of bone regeneration. These changes in the inflammatory environment subsequently had an impact on the recruitment of osteoclasts and the remodeling phase of repair. Further damage to the mdx muscles, using a novel model of muscle trauma, amplified both the chronic inflammatory response and the delay in bone regeneration. In addition, PLX3397 treatment of mdx mice, a cFMS inhibitor in monocytes, partially rescued the bone repair defect through increasing cartilage deposition and decreasing macrophage number. In conclusion, chronic inflammation in mdx mice contributes to the fracture healing delay and is associated with a decrease in angiogenesis and a transient delay in osteoclast recruitment. By revealing the role of dystrophic muscle in regulating the inflammatory response during bone repair, our results emphasize the implication of muscle in the normal bone repair process and may lead to improved treatment of fragility fractures in DMD patients. PMID:23857747
NBD delivery improves the disease phenotype of the golden retriever model of Duchenne muscular dystrophy
Background Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and afflicts skeletal and cardiac muscles. Previous studies showed that DMD is associated with constitutive activation of NF-?B, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn-/-;mdx) double knock out (dko) mouse models, inhibition of NF-?B with the Nemo Binding Domain (NBD) peptide led to significant improvements in both diaphragm and cardiac muscle function. Methods A trial in golden retriever muscular dystrophy (GRMD) canine model of DMD was initiated with four primary outcomes: skeletal muscle function, MRI of pelvic limb muscles, histopathologic features of skeletal muscles, and safety. GRMD and wild type dogs at 2 months of age were treated for 4 months with NBD byáintravenousáinfusions. Results were compared with those collected from untreated GRMD and wild type dogs through a separate, natural history study. Results Results showed that intravenous delivery of NBD in GRMD dogs led to a recovery of pelvic limb muscle force and improvement of histopathologic lesions. In addition, NBD-treated GRMD dogs had normalized postural changes and a trend towards lower tissue injury on magnetic resonance imaging. Despite this phenotypic improvement, NBD administration over time led to infusion reactions and an immune response in both treated GRMD and wild type dogs. Conclusions This GRMD trial was beneficial both in providing evidence that NBD is efficacious in a large animal DMD model and in identifying potential safety concerns that will be informative moving forward with human trials. PMID:25789154
Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies
Kornegay, Joe N.; Bogan, Janet R.; Bogan, Daniel J.; Childers, Martin K.; Li, Juan; Nghiem, Peter; Detwiler, David A.; Larsen, C. Aaron; Grange, Robert W.; Bhavaraju-Sanka, Ratna K.; Tou, Sandra; Keene, Bruce P.; Howard, James F.; Wang, Jiahui; Fan, Zheng; Schatzberg, Scott J.; Styner, Martin A.; Flanigan, Kevin M.; Xiao, Xiao; Hoffman, Eric P.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID:22218699
Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy
BarthÚlÚmy, InŔs; Pinto-Mariz, Fernanda; Yada, Erica; Desquilbet, Lo´c; Savino, Wilson; Silva-Barbosa, Suse Dayse; Faussat, Anne-Marie; Mouly, Vincent; Voit, Thomas; Blot, StÚphane; Butler-Browne, Gillian
In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4+CD49dhi T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease. PMID:25261568
Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location
Milic Rasic, V; Vojinovic, D; Pesovic, J; Mijalkovic, G; Lukic, V; Mladenovic, J; Kosac, A; Novakovic, I; Maksimovic, N; Romac, S; Todorovic, S; Savic Pavicevic, D
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70
A computerized MRI biomarker quantification scheme for a canine model of Duchenne muscular dystrophy
Wang, Jiahui; Fan, Zheng; Vandenborne, Krista; Walter, Glenn; Shiloh-Malawsky, Yael; An, Hongyu; Kornegay, Joe N.; Styner, Martin A.
Purpose Golden retriever muscular dystrophy (GRMD) is a widely used canine model of Duchenne muscular dystrophy (DMD). Recent studies have shown that magnetic resonance imaging (MRI) can be used to non-invasively detect consistent changes in both DMD and GRMD. In this paper, we propose a semi-automated system to quantify MRI biomarkers of GRMD. Methods Our system was applied to a database of 45 MRI scans from 8 normal and 10 GRMD dogs in a longitudinal natural history study. We first segmented six proximal pelvic limb muscles using two competing schemes: 1) standard, limited muscle range segmentation and 2) semi-automatic full muscle segmentation. We then performed pre-processing, including: intensity inhomogeneity correction, spatial registration of different image sequences, intensity calibration of T2-weighted (T2w) and T2-weighted fat suppressed (T2fs) images, and calculation of MRI biomarker maps. Finally, for each of the segmented muscles, we automatically measured MRI biomarkers of muscle volume and intensity statistics over MRI biomarker maps, and statistical image texture features. Results The muscle volume and the mean intensities in T2 value, fat, and water maps showed group differences between normal and GRMD dogs. For the statistical texture biomarkers, both the histogram and run-length matrix features showed obvious group differences between normal and GRMD dogs. The full muscle segmentation shows significantly less error and variability in the proposed biomarkers when compared to the standard, limited muscle range segmentation. Conclusion The experimental results demonstrated that this quantification tool can reliably quantify MRI biomarkers in GRMD dogs, suggesting that it would also be useful for quantifying disease progression and measuring therapeutic effect in DMD patients. PMID:23299128
Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy.
Dadgar, Sherry; Wang, Zuyi; Johnston, Helen; Kesari, Akanchha; Nagaraju, Kanneboyina; Chen, Yi-Wen; Hill, D Ashley; Partridge, Terence A; Giri, Mamta; Freishtat, Robert J; Nazarian, Javad; Xuan, Jianhua; Wang, Yue; Hoffman, Eric P
We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor ?-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues. PMID:25313409
Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy
Dadgar, Sherry; Wang, Zuyi; Johnston, Helen; Kesari, Akanchha; Nagaraju, Kanneboyina; Chen, Yi-Wen; Hill, D. Ashley; Partridge, Terence A.; Giri, Mamta; Freishtat, Robert J.; Nazarian, Javad; Xuan, Jianhua; Wang, Yue
We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor ?ľcentered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues. PMID:25313409
SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy
Pegoraro, E.; Hoffman, E.P.; Piva, L.; Gavassini, B.F.; Cagnin, S.; Ermani, M.; Bello, L.; Soraru, G.; Pacchioni, B.; Bonifati, M.D.; Lanfranchi, G.; Angelini, C.; Kesari, A.; Lee, I.; Gordish-Dressman, H.; Devaney, J.M.; McDonald, C.M.
Objective: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patientľpatient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Methods: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Results: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%ľ19% less grip strength (CINRG cohort p = 0.0003). Conclusions: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects. PMID:21178099
Specific profiles of neurocognitive and reading functions in a sample of 42 Italian boys with Duchenne Muscular Dystrophy.
Lorusso, Maria Luisa; Civati, Federica; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo; D'Angelo, Maria Grazia
A group of 42 Italian boys with Duchenne Muscular Dystrophy was compared with a control group of 10 boys with Spinal Muscular Atrophy and Osteogenesis Imperfecta on tests assessing general intellectual ability, language, neuropsychological functions, and reading skills with the aim of describing a comprehensive profile of the various functions and investigating their interrelationships. The influence of general intellectual level on performance was analyzed. Further, correlations between various neuropsychological measures and language performances were computed for the group with Duchenne Muscular Dystrophy, as well as the correlations between reading scores and other cognitive and linguistic measures. A general lowering in VIQ, PIQ, and FSIQ scores was found to characterize the group with Duchenne Muscular Dystrophy. Expressive language skills were within the normal range, while syntactic and grammatical comprehension were significantly impaired. The presence of below-average reading performances was further confirmed. However, unlike previous studies on irregular orthographies, the present results show that (a) the mild reading difficulties found in the sample essentially concern speed rather than accuracy; (b) they concern word rather than nonword reading; (c) lower reading performances are related to lower scores in general IQ; (d) no correlations emerge with phonological abilities, verbal short-term memory, or working memory, but rather with long-term memory and lexical skills. This may suggest that language-specific effects modulate the cognitive expressions of Duchenne Muscular Dystrophy and raises the possibility that the dysfunctions underlying the reading difficulties observed in affected readers of regular orthographies involve different neurocognitive systems than the cortico-cerebellar circuits usually invoked. PMID:22385039
Symptomatic female carriers of Duchenne muscular dystrophy (DMD): genetic and clinical characterization.
Giliberto, Florencia; Radic, Claudia Pamela; Luce, Leonela; Ferreiro, Verˇnica; de Brasi, Carlos; Szijan, Irene
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the dystrophin gene and is characterized by muscle degeneration and death. DMD affects males; females being asymptomatic carriers of mutations. However, some of them manifest symptoms due to a translocation between X chromosome and an autosome or to a heterozygous mutation leading to inactivation of most of their normal X chromosome. Six symptomatic female carriers and two asymptomatic were analyzed by: I) Segregation of STRs-(CA)n and MLPA assays to detect a hemizygous alteration, and II) X chromosome inactivation pattern to uncover the reason for symptoms in these females. The symptomatic females shared mild but progressive muscular weakness and increased serum creatin kinase (CK) levels. Levels of dystrophin protein were below normal or absent in many fibers. Segregation of STRs-(CA)n revealed hemizygous patterns in three patients, which were confirmed by MLPA. In addition, this analysis showed a duplication in another patient. X chromosome inactivation assay revealed a skewed X inactivation pattern in the symptomatic females and a random inactivation pattern in the asymptomatic ones. Our results support the hypothesis that the DMD phenotype in female carriers of a dystrophin mutation has a direct correlation with a skewed X-chromosome inactivation pattern. PMID:24135430
Percent-Predicted 6-Minute Walk Distance in Duchenne Muscular Dystrophy to Account for Maturational Influences
Henricson, Erik; Abresch, Richard; Han, Jay J.; Nicorici, Alina; Goude Keller, Erica; Elfring, Gary; Reha, Allen; Barth, Jay; McDonald, Craig M.
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter. PMID:22306689
Percent-predicted 6-minute walk distance in duchenne muscular dystrophy to account for maturational influences.
Henricson, Erik; Abresch, Richard; Han, Jay J; Nicorici, Alina; Goude Keller, Erica; Elfring, Gary; Reha, Allen; Barth, Jay; McDonald, Craig M
We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter. PMID:22306689
Non-surgical prevention and management of scoliosis for children with Duchenne muscular dystrophy: what is the evidence?
Harvey, Adrienne; Baker, Louise; Williams, Katrina
A review was performed to examine the evidence for non-surgical interventions for preventing scoliosis and the need for scoliosis surgery in children with Duchenne muscular dystrophy. Medline and Embase databases and reference lists from key articles were searched. After the inclusion and exclusion criteria were applied, 13 studies were critically appraised independently by two reviewers. The included studies examined spinal orthoses and steroid therapy. There were no studies with high levels of evidence (randomised or other controlled trials). The studies with the highest level of evidence were non-randomised experimental trials. There is some evidence that children with Duchenne muscular dystrophy who receive steroid therapy might have delayed onset of scoliosis, but more evidence is required about the long-term risks versus benefits of this intervention. There is weak evidence that spinal orthoses do not prevent and only minimally delay the onset of scoliosis. PMID:23560735
A Novel Missense Mutation in POMT1 Modulates the Severe Congenital Muscular Dystrophy Phenotype Associated with POMT1 Nonsense Mutations
Wallace, Stephanie E.; Conta, Jessie H.; Winder, Thomas L.; Willer, Tobias; Eskuri, Jamie M.; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P.; Moore, Steven A.; Gospe, Sidney M.
Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID:24491487
Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography
NASA Astrophysics Data System (ADS)
Klyen, Blake R.; Shavlakadze, Thea; Radley-Crabb, Hannah G.; Grounds, Miranda D.; Sampson, David D.
Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with co-registered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology. OCT could identify morphological features of interest and necrotic lesions within the muscle tissue samples based on intrinsic optical contrast. These findings demonstrate the utility of 3D-OCT for the evaluation of small-animal skeletal muscle morphology and pathology, particularly for studies of mouse models of muscular dystrophy.
Limb-girdle muscular dystrophy with obesity for elective cesarean section: Anesthetic management and brief review of the literature
Ranjan, R. V.; Ramachandran, T. R.; Manikandan, S.; John, Roshan
Limb-girdle muscular dystrophy (LGMD) is an autosomal recessive disorder in which the pelvic or shoulder girdle musculature is predominantly or primarily involved. We report the management of a 27-year-old primigravida with LGMD associated with obesity posted for elective cesarean section. She was successfully managed with epidural anesthesia assisted with noninvasive positive pressure ventilation. She had an uncomplicated intra- and post-operative course. PMID:25886439
Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy.
Sabharwal, Rasna; Cicha, Michael Z; Sinisterra, Ruben D M; De Sousa, Frederico B; Santos, Robson A; Chapleau, Mark W
Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different typesáof muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-?), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F). Previously, we have reported that Sgcd-deficient (Sgcd-/-) mice exhibit AngII (angiotensin II)-induced autonomic and skeletal muscle dysfunction at a young age, which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory RAS (renin-angiotensin system) pathways have been identified: deleterious actions of AngII acting on the AT1R (AngII typeá1 receptor) compared with the protective actions of Ang-(1-7) [angiotensin-(1-7)] acting on the receptor Mas. We propose that the balance between the AngII/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd-/- mice. Control C57BL/6J and Sgcd-/- mice were treated with Ang-(1-7) included in hydroxypropyl ?-cyclodextrin (in drinking water) for 8-9áweeks beginning at 3áweeks of age. Ang-(1-7) treatment restored the AngII/AT1R compared with Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd-/- mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang-(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy. PMID:24502705
Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS
Martins-J˙nior, Helio A.; Simas, Rosineide C.; Brolio, Marina P.; Ferreira, Christina R.; Perecin, Felipe; Nogueira, Guilherme de P.; Miglino, Maria A.; Martins, Daniele S.; Eberlin, Marcos N.; Ambrˇsio, Carlos E.
Golden retriever muscular dystrophy (GRMD) provides the best animal model for characterizing the disease progress of the human disorder, Duchenne muscular dystrophy (DMD). The purpose of this study was to determine steroid hormone concentration profiles in healthy golden retriever dogs (control group - CtGR) versus GRMD-gene carrier (CaGR) and affected female dogs (AfCR). Therefore, a sensitive and specific analytical method was developed and validated to determine the estradiol, progesterone, cortisol, and testosterone levels in the canine serum by isotope dilution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). To more accurately understand the dynamic nature of the serum steroid profile, the fluctuating levels of these four steroid hormones over the estrous cycle were compared across the three experimental groups using a multivariate statistical analysis. The concentration profiles of estradiol, cortisol, progesterone, and testosterone revealed a characteristic pattern for each studied group at each specific estrous phase. Additionally, several important changes in the serum concentrations of cortisol and estradiol in the CaGR and AfCR groups seem to be correlated with the status and progression of the muscular dystrophy. A comprehensive and quantitative monitoring of steroid profiles throughout the estrous cycle of normal and GRMD dogs were achieved. Significant differences in these profiles were observed between GRMD and healthy animals, most notably for estradiol. These findings contribute to a better understanding of both dog reproduction and the muscular dystrophy pathology. Our data open new venues for hormonal behavior studies in dystrophinopathies and that may affect the quality of life of DMD patients. PMID:26010907
Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin
Le Thiet Thanh; Nguyen Thi Man; G. E. Morris; C. A. Sewry; V. Dubowitz
We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions
Sabharwal, Rasna; Cicha, Michael Z.; Sinisterra, Ruben D.M.; de Sousa, Frederico B.; Santos, Robson A.; Chapleau, Mark W.
Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying etiologies but they all have a common hallmark of myofiber degeneration, atrophy and decreased mobility. Mutation in sarcoglycan-delta (Sgcd), a subunit of dystrophin glycoprotein complex, causes Limb Girdle Muscular Dystrophy 2F (LGMD2F). Previously we have reported that Sgcd deficient (Sgcd?/?) mice exhibit angiotensin II (Ang II) induced autonomic and skeletal muscle dysfunction at a young age which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory renin angiotensin system (RAS) pathways have been identified ľ deleterious actions of angiotensin II (Ang II) acting on type 1 receptor (AT1R) versus protective actions of Ang-(1-7) acting on Mas receptors. We propose that the balance between the Ang II/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd?/? mice. Control C57BL/6 and Sgcd?/? mice were treated with Ang-(1-7) included in hydroxypropyl ?-cyclodextrin (drinking water) for 8ľ9 weeks beginning at 3 weeks of age. Ang-(1-7) treatment restored Ang II/AT1R vs. Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd?/? mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy. PMID:24502705
Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p
Bashir, R.; Keers, S.; Strachan, T. [Univ. of Newcastle upon Tyne (United Kingdom)] [and others] [Univ. of Newcastle upon Tyne (United Kingdom); and others
The limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of disorders, different forms of which have been mapped to at least six distinct genetic loci. We have mapped to at least six distinct genetic loci. We have mapped an autosomal recessive form of LGMD (LGMD2B) to chromosome 2p13. Two other conditions have been shown to map to this region or to the homologous region in mouse: a gene for a form of autosomal recessive distal muscular dystrophy, Miyoshi myopathy, shows linkage to the same markers on chromosome 2p as LGMD2B, and an autosomal recessive mouse mutation mnd2, in which there is rapidly progressive paralysis and muscle atrophy, has been mapped to mouse chromosome 6 to a region showing conserved synteny with human chromosome 2p12-p13. We have assembled a 6-cM YAC contig spanning the LGMD2B locus and have mapped seven genes and 13 anonymous polymorphic microsatellites to it. Using haplotype analysis in the linked families, we have narrowed our region of interest to a 0-cM interval between D2S2113 and D2S145, which does not overlap with the critical region for mnd2 in mouse. Use of these most closely linked markers will help to determine the relationship between LGMD2B and Miyoshi myopathy. YACs selected from our contig will be the starting point for the cloning of the LGMD2B gene and thereby establish the biological basis for this form of muscular dystrophy and its relationship with the other limb-girdle muscular dystrophies. 26 refs., 6 figs.
Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and a Glucocorticoid Treatment Effect
Campbell, Katie; Viollet, Laurence; Wang, Wei; Gomez, Ana Maria; Walker, Christopher M.
Abstract Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4+ helper and/or CD8+ cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials. PMID:24010700
Longitudinal assessment of grip strength using bulb dynamometer in Duchenne Muscular Dystrophy
Pizzato, Tatiana M.; Baptista, Cyntia R. J. A.; Souza, Mariana A.; Benedicto, Michelle M. B.; Martinez, Edson Z.; Mattiello-Sverzut, Ana C.
BACKGROUND: Grip strength is used to infer functional status in several pathological conditions, and the hand dynamometer has been used to estimate performance in other areas. However, this relationship is controversial in neuromuscular diseases and studies with the bulb dynamometer comparing healthy children and children with Duchenne Muscular Dystrophy (DMD) are limited. OBJECTIVE: The evolution of grip strength and the magnitude of weakness were examined in boys with DMD compared to healthy boys. The functional data of the DMD boys were correlated with grip strength. METHOD: Grip strength was recorded in 18 ambulant boys with DMD (Duchenne Group, DG) aged 4 to 13 years (mean 7.4▒2.1) and 150 healthy volunteers (Control Group, CG) age-matched using a bulb dynamometer (North Coast- NC70154). The follow-up of the DG was 6 to 33 months (3-12 sessions), and functional performance was verified using the Vignos scale. RESULTS: There was no difference between grip strength obtained by the dominant and non-dominant side for both groups. Grip strength increased in the CG with chronological age while the DG remained stable or decreased. The comparison between groups showed significant difference in grip strength, with CG values higher than DG values (confidence interval of 95%). In summary, there was an increment in the differences between the groups with increasing age. Participants with 24 months or more of follow-up showed a progression of weakness as well as maintained Vignos scores. CONCLUSIONS: The amplitude of weakness increased with age in the DG. The bulb dynamometer detected the progression of muscular weakness. Functional performance remained virtually unchanged in spite of the increase in weakness. PMID:25003277
Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.
Lemmers, Richard J L F; van den Boogaard, Marlinde L; van der Vliet, Patrick J; Donlin-Smith, Colleen M; Nations, Sharon P; Ruivenkamp, Claudia A L; Heard, Patricia; Bakker, Bert; Tapscott, Stephen; Cody, Jannine D; Tawil, Rabi; van der Maarel, SilvŔre M
Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. PMID:25820463
CINRG Pilot trial of Coenzyme Q10 in steroid treated Duchenne Muscular Dystrophy
Spurney, Christopher F.; Rocha, Carolina Tesi; Henricson, Erik; Florence, Julaine; Mayhew, Jill; Gorni, Ksenija; Pasquali, Livia; Pestronk, Alan; Martin, Gerard R.; Hu, Fengming; Nie, Lei; Connolly, Anne M.; Escolar, Diana M.
Introduction Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin deficient muscle. Methods We performed an open label, ôadd-onö pilot study of CoQ10 in thirteen 5ľ10 year old DMD patients on steroids. The primary outcome measure was the total Quantitative Muscle Testing (QMT) score. Results Twelve of 16 children (mean age 8.03▒1.64 years) completed the trial. Target serum levels of CoQ10 (?2.5 ?g/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in 8.5 % increase in muscle strength (p=0.03). Discussion This pilot study found the addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. PMID:21698649
A protein anomaly in erythrocyte membranes of patients with Duchenne muscular dystrophy
Raman spectroscopic comparisons of erythrocyte membranes from 20 patients with Duchenne muscular dystrophy and 8 age-matched controls indicate a prominent and consistent protein anomaly in the patient samples. This was apparent in the following: (a) CH-stretching signals from control membranes reveal a thermotropic transition at 15.6 degrees C, attributable to a protein/lipid phase that is lacking in dystrophic membranes. (b) CH-stretching signals from control membranes also show a protein transition at 39 degrees C [pH 7.4] that is shifted to 45 degrees in dystrophic membranes. (c) A reduction in pH to 5.7 shifts this transition from 39 degrees C to 7 degrees C in normal membranes and from 45 degrees C to 24 degrees C in dystrophic membranes. (d) The Amide I/Amide III regions indicate a significant proportion of beta- structured peptide in dystrophic but not normal membranes. (e) Analysis of tyrosine signals indicates greater polar exposure of tyrosine hydroxyl groups in dystrophic vs normal membranes. All of the differences between dystrophic and normal membranes are highly significant (P less than 0.001). PMID:6854213
Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy
RodrÝguez-Cruz, Maricela; Sanchez, Ra˙l; Escobar, Rosa E.; Cruz-Guzmßn, Oriana del RocÝo; Lˇpez-Alarcˇn, Mardia; Bernabe GarcÝa, Mariela; Coral-Vßzquez, Ramˇn; Matute, Guadalupe; Velßzquez Wong, Ana Claudia
Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16ľ74.69) and 50 (OR = 8.73; 95% CI = 1.17ľ65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR.
Dystrophin hydrophobic regions in the pathogenesis of Duchenne and Becker muscular dystrophies
Liang, Yingyin; Chen, Songlin; Zhu, Jianzong; Zhou, Xiangxue; Yang, Chen; Yao, Lu; Zhang, Cheng
The aim of our study was to determine the role of dystrophin hydrophobic regions in the pathogenesis of Duchenne (DMD) and Becker (BMD) muscular dystrophies, by the Kyte-Doolittle scale mean hydrophobicity profile and 3D molecular models. A total of 1038 cases diagnosed with DMD or BMD with the in-frame mutation were collected in our hospital and the Leiden DMD information database in the period 2002-2013. Correlation between clinical types and genotypes were determined on the basis of these two sources. In addition, the Kyte-Doolittle scale mean hydrophobicity of dystrophin was analyzed using BioEdit software and the models of the hydrophobic domains of dystrophin were constructed. The presence of four hydrophobic regions is confirmed. They include the calponin homology CH2 domain on the actin-binding domain (ABD), spectrin-type repeat 16, hinge III and the EF Hand domain. The severe symptoms of DMD usually develop as a result of the mutational disruption in the hydrophobic regions I, II and IV of dystrophin ľ those that bind associated proteins of the dystrophin-glycoprotein complex (DGC). On the other hand, when the hydrophobic region III is deleted, the connection of the ordered repeat domains of the central rod domain remains intact, resulting in the less severe clinical presentation. We conclude that mutational changes in the structure of hydrophobic regions of dystrophin play an important role in the pathogenesis of DMD. PMID:26042512
Label-Free Fluorescent Copper Nanoclusters for Genotyping of Deletion and Duplication of Duchenne Muscular Dystrophy.
Chen, Chung-An; Wang, Chun-Chi; Jong, Yuh-Jyh; Wu, Shou-Mei
Real applications in clinical diagnosis of label-free fluorescent copper nanoclusters (CuNCs) are demonstrated. Double-strand DNA (dsDNA) can act as an effective template for the formation of CuNCs, which can be used to distinguish the deletion or duplication genotypes of Duchenne muscular dystrophy (DMD) due to different fluorescent intensities. After PCR, the DMD amplicons reacted with copper ion by reduction of ascorbic acid and generated fluorescence. The exons of the DMD gene were taken as the model analytes for genetic diagnosis. In this sensing system, the deletion type does not show fluorescence; on the other hand, the duplication type emits higher fluorescence than normal type. Parameters of this sensing system were optimized, including PCR conditions, levels of copper ion and ascorbate, and reaction time. The DMD-dominated exons 45, 46, and 47 were detected, and the method was applied to six samples of DMD patients. The results were consistent with those of the multiplex ligation-dependent probe amplification method. This strategy was feasible to detect all exons of this disease. PMID:25982038
Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA.
Long, Chengzu; McAnally, John R; Shelton, John M; Mireault, Alex A; Bassel-Duby, Rhonda; Olson, Eric N
Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. DMD is characterized by progressive muscle weakness and a shortened life span, and there is no effective treatment. We used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)-mediated genome editing to correct the dystrophin gene (Dmd) mutation in the germ line of mdx mice, a model for DMD, and then monitored muscle structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. The degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected cells and their contribution to regenerating muscle. With the anticipated technological advances that will facilitate genome editing of postnatal somatic cells, this strategy may one day allow correction of disease-causing mutations in the muscle tissue of patients with DMD. PMID:25123483
Biochemical and Functional Comparisons of mdx and Sgcg (-/-) Muscular Dystrophy Mouse Models.
Roberts, Nathan W; Holley-Cuthrell, Jenan; Gonzalez-Vega, Magdalis; Mull, Aaron J; Heydemann, Ahlke
Mouse models have provided an essential platform to investigate facets of human diseases, from etiology, diagnosis, and prognosis, to potential treatments. Muscular dystrophy (MD) is the most common human genetic disease occurring in approximately 1 in 2500 births. The mdx mouse, which is dystrophin-deficient, has long been used to model this disease. However, this mouse strain displays a rather mild disease course compared to human patients. The mdx mice have been bred to additional genetically engineered mice to worsen the disease. Alternatively, other genes which cause human MD have been genetically disrupted in mice. We are now comparing disease progression from one of these alternative gene disruptions, the ?-sarcoglycan null mouse Sgcg (-/-) on the DBA2/J background, to the mdx mouse line. This paper aims to assess the time-course severity of the disease in the mouse models and determine which is best for MD research. The Sgcg (-/-) mice have a more severe phenotype than the mdx mice. Muscle function was assessed by plethysmography and echocardiography. Histologically the Sgcg (-/-) mice displayed increased fibrosis and variable fiber size. By quantitative Evan's blue dye uptake and hydroxyproline content two key disease determinants, membrane permeability and fibrosis respectively, were also proven worse in the Sgcg (-/-) mice. PMID:26064876
Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish
Zhang, Meiling; Sun, Tao; Jian, Chongshu; Lei, Lei; Han, Peidong; Lv, Quanlong; Yang, Ran; Zhou, Xiaohai; Xu, Jiejia; Hu, Yingchun; Men, Yongfan; Huang, Yanyi; Zhang, Chuanmao; Zhu, Xiaojun; Wang, Xianhua; Cheng, Heping; Xiong, Jing-Wei
Mitochondrial flash (mitoflash) is a highly-conserved, universal, and physiological mitochondrial activity in isolated mitochondria, intact cells, and live organisms. Here we investigated developmental and disease-related remodeling of mitoflash activity in zebrafish skeletal muscles. In transgenic zebrafish expressing the mitoflash reporter cpYFP, in vivo imaging revealed that mitoflash frequency and unitary properties underwent multiphasic and muscle type-specific changes, accompanying mitochondrial morphogenesis from 2 to 14 dpf. In particular, short (S)-type mitoflashes predominated in early muscle formation, then S-, transitory (T)- and regular (R)-type mitoflashes coexisted during muscle maturation, followed by a switch to R-type mitoflashes in mature skeletal muscles. In early development of muscular dystrophy, we found accelerated S- to R-type mitoflash transition and reduced mitochondrial NAD(P)H amidst a remarkable cell-to-cell heterogeneity. This study not only unravels a profound functional and morphological remodeling of mitochondria in developing and diseased skeletal muscles, but also underscores mitoflashes as a useful reporter of mitochondrial function in milieu of live animals under physiological and pathophysiological conditions. PMID:26186000
Autologous Myoblast Transplantation for Oculopharyngeal Muscular Dystrophy: a Phase I/Iia Clinical Study
PÚriÚ, Sophie; Trollet, Capucine; Mouly, Vincent; Vanneaux, ValÚrie; Mamchaoui, Kamel; Bouazza, Bela´d; Marolleau, Jean Pierre; Laforŕt, Pascal; Chapon, Franšoise; Eymard, Bruno; Butler-Browne, Gillian; Larghero, JÚrome; St Guily, Jean Lacau
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients. PMID:23831596
MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy
Shi, Hao; Boadu, Emmanuel; Mercan, Fatih; Le, Annie M.; Flach, Rachel J. Roth; Zhang, Lei; Tyner, Kristina J.; Olwin, Bradley B.; Bennett, Anton M.
In skeletal muscle, the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a critical negative regulator of the MAPKs. Since the MAPKs have been reported to be both positive and negative for myogenesis, the physiological role of MKP-1 in skeletal muscle repair and regeneration has remained unclear. Here, we show that MKP-1 plays an essential role in adult regenerative myogenesis. In a cardiotoxin-induced muscle injury model, lack of MKP-1 impaired muscle regeneration. In mdx mice, MKP-1 deficiency reduced body weight, muscle mass, and muscle fiber cross-sectional area. In addition, MKP-1-deficient muscles exhibit exacerbated myopathy accompanied by increased inflammation. Lack of MKP-1 compromised myoblast proliferation and induced precocious differentiation, phenotypes that were rescued by pharmacological inhibition of p38?/? MAPK. MKP-1 coordinates both myoblast proliferation and differentiation. Mechanistically, MyoD bound to the MKP-1 promoter and activated MKP-1 expression in proliferating myoblasts. Later, during myogenesis, MyoD uncoupled from the MKP-1 promoter leading to the down-regulation of MKP-1 and facilitation of promyogenic p38?/? MAPK signaling. Hence, MKP-1 plays a critical role in muscle stem cells and in the immune response to coordinate muscle repair and regeneration.ŚShi, H., Boadu, E., Mercan, F., Le, A. M., Roth Flach, R. J., Zhang, L., Tyner, K. J., Olwin, B. B., Bennett, A. M. MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy. PMID:20371627
A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome
Background The complexity of the skeletal muscle and the identification of numerous human disease-causing mutations in its constitutive proteins make it an interesting tissue for proteomic studies aimed at understanding functional relationships of interacting proteins in both health and diseases. Method We undertook a large-scale study using two-hybrid screens and a human skeletal-muscle cDNA library to establish a proteome-scale map of protein-protein interactions centered on proteins involved in limb-girdle muscular dystrophies (LGMD). LGMD is a group of more than 20 different neuromuscular disorders that principally affect the proximal pelvic and shoulder girdle muscles. Results and conclusion The interaction network we unraveled incorporates 1018 proteins connected by 1492 direct binary interactions and includes 1420 novel protein-protein interactions. Computational, experimental and literature-based analyses were performed to assess the overall quality of this network. Interestingly, LGMD proteins were shown to be highly interconnected, in particular indirectly through sarcomeric proteins. In-depth mining of the LGMD-centered interactome identified new candidate genes for orphan LGMDs and other neuromuscular disorders. The data also suggest the existence of functional links between LGMD2B/dysferlin and gene regulation, between LGMD2C/?-sarcoglycan and energy control and between LGMD2G/telethonin and maintenance of genome integrity. This dataset represents a valuable resource for future functional investigations. PMID:23414517
The mdx mouse model as a surrogate for Duchenne muscular dystrophy
Partridge, Terence A.
Research into fundamental principles and the testing of therapeutic hypotheses for treatment of human disease is commonly conducted on mouse models of human diseases. Although this is often the only practicable approach, it carries a number of caveats arising from differences between the two species. This article is centred on the example of skeletal muscle disease, in particular muscular dystrophy, to identify some of the principal classes of obstacle to the translation of data from mouse to man. Of these, the difference in scale is one of the most commonly ignored and is of particular interest because it has quite major repercussions for evaluation of some classes of intervention and of assessment criteria while having comparatively little bearing on others. Likewise, interspecies differences and similarities in cell and molecular biological mechanisms underlying development, growth and response to pathological processes should be considered on an individual basis. An awareness of such distinctions is crucial if we are to avoid misjudgement of the likely efficacy in man of results obtained on mouse models. PMID:23551987
Biochemical and Functional Comparisons of mdx and Sgcg?/? Muscular Dystrophy Mouse Models
Roberts, Nathan W.; Holley-Cuthrell, Jenan; Gonzalez-Vega, Magdalis; Mull, Aaron J.; Heydemann, Ahlke
Mouse models have provided an essential platform to investigate facets of human diseases, from etiology, diagnosis, and prognosis, to potential treatments. Muscular dystrophy (MD) is the most common human genetic disease occurring in approximately 1 in 2500 births. The mdx mouse, which is dystrophin-deficient, has long been used to model this disease. However, this mouse strain displays a rather mild disease course compared to human patients. The mdx mice have been bred to additional genetically engineered mice to worsen the disease. Alternatively, other genes which cause human MD have been genetically disrupted in mice. We are now comparing disease progression from one of these alternative gene disruptions, the ?-sarcoglycan null mouse Sgcg?/? on the DBA2/J background, to the mdx mouse line. This paper aims to assess the time-course severity of the disease in the mouse models and determine which is best for MD research. The Sgcg?/? mice have a more severe phenotype than the mdx mice. Muscle function was assessed by plethysmography and echocardiography. Histologically the Sgcg?/? mice displayed increased fibrosis and variable fiber size. By quantitative Evan's blue dye uptake and hydroxyproline content two key disease determinants, membrane permeability and fibrosis respectively, were also proven worse in the Sgcg?/? mice.
Living with severe physical impairment, Duchenne's muscular dystrophy and home mechanical ventilation
Dreyer, Pia S.; Steffensen, Birgit F.; Pedersen, Birthe D.
Aim To study life-experiences of people living with Duchenne's muscular dystrophy (DMD), home mechanical ventilation (HMV) and physical impairment. Background Since the introduction of invasive HMV in the late 1980s people with DMD in Denmark live longer and have the experience of adulthood and a high degree of physical dependency. Method Nineteen patients with DMD and invasive HMV were interviewed in 2007. The interviews were recorded, transcribed verbatim and analysed according to a method inspired by Ricoeur's theory of interpretation. Findings HMV not only extended the participants lifespan, it also gave them the capacity to live an active life. They were totally dependent in everyday living, but in spite of this, they did not see themselves as physically impaired. They realised that there were activities that were physically impossible, but they considered themselves to be just the same person they had always been. This dependency was described as ôindependent dependencyö. Conclusion The lived-experience of physical impairment is found to be ôindependent dependencyö in an active life. To solve problems with loneliness, society needs to work with prejudice and misunderstanding and for better physical accessibility to enable full participation. PMID:20689774
Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran
BARZEGAR, Mohammad; HABIBI, Parinaz; BONYADY, Mortaza; TOPCHIZADEH, Vahideh; SHIVA, Shadi
Objective Duchene and Becker Muscular Dystrophy (DMD/ BMD) are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different populations. This study investigates the deletion rate, type, and distribution of this gene in the Azeri Turk population of North West Iran. Materials &Methods In this study, 110 patients with DMD/ BMD were studied for intragenic deletions in 24 exons and promoter regions of dystrophin genes by using multiplex PCR. Results Deletions were detected in 63 (57.3%) patients, and around 83% localized in the mid-distal hotspot of the gene (on exons 44ľ52), 21 cases (33.3 %) with single-exon deletions, and 42 cases (66.6%) with multi-exonic deletions. The most frequent deleted exons were exon 50 (15 %) and exon 49 (14%). No deletion was detected in exon 3. Conclusion This study suggests that the frequency and pattern of dystrophin gene deletions in DMD/ BMD in the Azeri Turk population of North West Iran occur in the same pattern when compared with other ethnic groups. PMID:25767538
Drosophila as a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy
Pantoja, Mario; Ruohola-Baker, Hannele
Progress into developing therapeutics for rare diseases can be accelerated for those diseases that can be modeled in genetically tractable organisms. Here we comment on one disease, Duchenne Muscular Dystrophy (DMD), modeled in Drosophila that brought together disparate lines of research toward the goal of developing a therapeutic. Though the bioactive lipid sphingosine 1-phosphate (S1P) has been implicated in many anabolic processes in many cell types and tissues, including muscle, this work confirmed the therapeutic potential of assessing this pathway for DMD. Genetic dissection of sphingolipid metabolism showed the suppression of muscle structural and functional defects in flies. Moreover, improvement of muscle defects using known pharmacological agents that raise S1P levels in vivo highlight the potential of Drosophila as a drug-screening tool for DMD. We and others have extended S1P studies into the mouse model of DMD and have shown a partial amelioration of symptoms associated with DMD. Translation of this work to mammals makes the sphingolipid metabolism pathway a promising target for further drug development that may benefit the human condition. PMID:25002997
MelanocytesŚA Novel Tool to Study Mitochondrial Dysfunction in Duchenne Muscular Dystrophy
Pellegrini, Camilla; Zulian, Alessandra; Gualandi, Francesca; Manzati, Elisa; Merlini, Luciano; Michelini, Maria E; Benassi, Luisa; Marmiroli, Sandra; Ferlini, Alessandra; Sabatelli, Patrizia; Bernardi, Paolo; Maraldi, Nadir M
Dystrophin is a subsarcolemmal protein that, by linking the actin cytoskeleton to the extracellular matrix via dystroglycans, is critical for the integrity of muscle fibers. Here, we report that epidermal melanocytes, obtained from conventional skin biopsy, express dystrophin with a restricted localization to the plasma membrane facing the dermalľepidermal junction. In addition the full-length muscle isoform mDp427 was clearly detectable in melanocyte cultures as assessed by immunohistochemistry, RNA, and Western blot analysis. Melanocytes of Duchenne muscular dystrophy (DMD) patients did not express dystrophin, and the ultrastructural analysis revealed typical mitochondrial alterations similar to those occurring in myoblasts from the same patients. Mitochondria of melanocytes from DMD patients readily accumulated tetramethylrhodamine methyl ester, indicating that they are energized irrespective of the presence of dystrophin but, at variance from mitochondria of control donors, depolarized upon the addition of oligomycin, suggesting that they are affected by a latent dysfunction unmasked by inhibition of the ATP synthase. Pure melanocyte cultures can be readily obtained by conventional skin biopsies and may be a feasible and reliable tool alternative to muscle biopsy for functional studies in dystrophinopathies. The mitochondrial dysfunction occurring in DMD melanocytes could represent a promising cellular biomarker for monitoring dystrophinopathies also in response to pharmacological treatments. J. Cell. Physiol. 228: 1323ľ1331, 2013. ę 2012 Wiley Periodicals, Inc. PMID:23169061
Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy.
Pellegrini, Camilla; Zulian, Alessandra; Gualandi, Francesca; Manzati, Elisa; Merlini, Luciano; Michelini, Maria E; Benassi, Luisa; Marmiroli, Sandra; Ferlini, Alessandra; Sabatelli, Patrizia; Bernardi, Paolo; Maraldi, Nadir M
Dystrophin is a subsarcolemmal protein that, by linking the actin cytoskeleton to the extracellular matrix via dystroglycans, is critical for the integrity of muscle fibers. Here, we report that epidermal melanocytes, obtained from conventional skin biopsy, express dystrophin with a restricted localization to the plasma membrane facing the dermal-epidermal junction. In addition the full-length muscle isoform mDp427 was clearly detectable in melanocyte cultures as assessed by immunohistochemistry, RNA, and Western blot analysis. Melanocytes of Duchenne muscular dystrophy (DMD) patients did not express dystrophin, and the ultrastructural analysis revealed typical mitochondrial alterations similar to those occurring in myoblasts from the same patients. Mitochondria of melanocytes from DMD patients readily accumulated tetramethylrhodamine methyl ester, indicating that they are energized irrespective of the presence of dystrophin but, at variance from mitochondria of control donors, depolarized upon the addition of oligomycin, suggesting that they are affected by a latent dysfunction unmasked by inhibition of the ATP synthase. Pure melanocyte cultures can be readily obtained by conventional skin biopsies and may be a feasible and reliable tool alternative to muscle biopsy for functional studies in dystrophinopathies. The mitochondrial dysfunction occurring in DMD melanocytes could represent a promising cellular biomarker for monitoring dystrophinopathies also in response to pharmacological treatments. PMID:23169061
Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers.
Goyenvalle, AurÚlie; Griffith, Graziella; Babbs, Arran; El Andaloussi, Samir; Ezzat, Kariem; Avril, AurÚlie; Dugovic, Branislav; Chaussenot, RÚmi; Ferry, Arnaud; Voit, Thomas; Amthor, Helge; BŘhr, Claudia; SchŘrch, Stefan; Wood, Matthew J A; Davies, Kay E; Vaillend, Cyrille; Leumann, Christian; Garcia, Luis
Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment. PMID:25642938
A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.
Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod; Gomez, Ana M; Flanigan, Kevin M; Lowes, Linda P; Alfano, Lindsay N; Berry, Katherine; Meadows, Eric; Lewis, Sarah; Braun, Lyndsey; Shontz, Kim; Rouhana, Maria; Clark, Kelly Reed; Rosales, Xiomara Q; Al-Zaidy, Samiah; Govoni, Alessandra; Rodino-Klapac, Louise R; Hogan, Mark J; Kaspar, Brian K
Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3?Î?10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6?Î?10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases. PMID:25322757
Limb-girdle muscular dystrophies: Where next after six decades from the first proposal (Review)
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders, which has led to certain investigators disputing its rationality. The mutual feature of LGMD is limb-girdle affection. Magnetic resonance imaging (MRI), perioral skin biopsies, blood-based assays, reverse-protein arrays, proteomic analyses, gene chips and next generation sequencing are the leading diagnostic techniques for LGMD and gene, cell and pharmaceutical treatments are the mainstay therapies for these genetic disorders. Recently, more highlights have been shed on disease biomarkers to follow up disease progression and to monitor therapeutic responsiveness in future trials. In this study, we review LGMD from a variety of aspects, paying specific attention to newly evolving research, with the purpose of bringing this information into the clinical setting to aid the development of novel therapeutic strategies for this hereditary disease. In conclusion, substantial progress in our ability to diagnose and treat LGMD has been made in recent decades, however enhancing our understanding of the detailed pathophysiology of LGMD may enhance our ability to improve disease outcome in subsequent years. PMID:24626787
Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B
Takahashi, Toshiaki; Aoki, Masashi; Suzuki, Naoki; Tateyama, Maki; Yaginuma, Chikako; Sato, Hitomi; Hayasaka, Miho; Sugawara, Hitomi; Ito, Mariko; Abe-Kondo, Emi; Shimakura, Naoko; Ibi, Tohru; Kuru, Satoshi; Wakayama, Tadashi; Sobue, Gen; Fujii, Naoki; Saito, Toshio; Matsumura, Tsuyoshi; Funakawa, Itaru; Mukai, Eiichiro; Kawanami, Toru; Morita, Mitsuya; Yamazaki, Mineo; Hasegawa, Takashi; Shimizu, Jun; Tsuji, Shoji; Kuzuhara, Shigeki; Tanaka, Hiroyasu; Yoshioka, Masaru; Konno, Hidehiko; Onodera, Hiroshi; Itoyama, Yasuto
Objective and methods Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. Results and conclusions Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations. PMID:23243261
The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations.
McDonald, Craig M; Henricson, Erik K; Han, Jay J; Abresch, R Ted; Nicorici, Alina; Atkinson, Leone; Elfring, Gary L; Reha, Allen; Miller, Langdon L
In this study we used the 6-minute walk distance (6MWD) to characterize ambulation over time in Duchenne/Becker muscular dystrophy (DBMD). The 6MWD was assessed in 18 boys with DBMD and 22 healthy boys, ages 4-12 years, over mean [range] intervals of 58 [39-87] and 69 [52-113] weeks, respectively. Height and weight increased similarly in both groups. At 52 weeks, 6MWD decreased in 12 of 18 (67%) DBMD subjects (overall mean [range]: 357 [125-481] to 300 [0-510] meters; ? -57 meters, -15.9%), but increased in 14 of 22 (64%) healthy subjects (overall mean [range]: 623 [479-754] to 636 [547-717] meters; ? +13 meters, +2.1%). Two DBMD subjects lost ambulation. Changes in 6MWD depended on stride length and age; improvements usually occurred by 7-8 years of age; older DBMD subjects worsened, whereas older healthy subjects were stable. The 6MWD changes at 1 year confirm the validity of this endpoint and emphasize that preserving ambulation must remain a major goal of DBMD therapy. PMID:21038378
The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy.
McDonald, Craig M; Henricson, Erik K; Han, Jay J; Abresch, R Ted; Nicorici, Alina; Elfring, Gary L; Atkinson, Leone; Reha, Allen; Hirawat, Samit; Miller, Langdon L
Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials. PMID:19941337
Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice.
Meinen, Sarina; Lin, Shuo; Thurnherr, Raphael; Erb, Michael; Meier, Thomas; RŘegg, Markus A
Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini-agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients. PMID:21674808
Safety of a pandemic influenza vaccine and the immune response in patients with duchenne muscular dystrophy.
Saito, Tomoko; Ohfuji, Satoko; Matsumura, Tsuyoshi; Saito, Toshio; Maeda, Kazuhiro; Maeda, Akiko; Fukushima, Wakaba; Fujimura, Harutoshi; Sakoda, Saburo; Hirota, Yoshio
Objective To examine the safety of and immune response to the influenza A(H1N1)pdm09 vaccine in patients with Duchenne muscular dystrophy (DMD). Methods Forty-four non-ambulatory patients with DMD hospitalized in a muscle disease ward and 41 healthy healthcare workers each received one dose of the influenza A(H1N1)pdm09 vaccine. Serum samples were collected before and four weeks after vaccination to measure the hemagglutinin inhibition antibody titers. Results No severe adverse events were noted in any of the subjects. The immune responses of the patients were comparable to those of the healthcare workers. Among the patients, tube feeding and a lower total protein level in the serum were identified to be significantly associated with a lower immune response. Conclusion A single dose of the vaccine was found to be safe and induced an optimal level of immunity in the DMD patients. The nutritional status may be associated with the immune response in patients with DMD. PMID:25986256
Use of a Lower Dosage Liver-Detargeted AAV Vector to Prevent Hamster Muscular Dystrophy
Rotundo, Ida Luisa; Lancioni, Alessio; Savarese, Marco; D'Orsi, Luca; Iacomino, Michele; Nigro, Gerardo; Piluso, Giulio; Auricchio, Alberto
Abstract The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting. PMID:23427808
Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy
Barbezier, Nicolas; Chartier, Aymeric; Bidet, Yannick; Buttstedt, Anja; Voisset, CÚcile; Galons, HervÚ; Blondel, Marc; Schwarz, Elisabeth; Simonelig, Martine
Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules. PMID:21204267
Hoagland, Charles L.; Shank, Robert E.; Lavin, George I.
Results have been presented of the application of a simplified technique of ultraviolet photomicrography to a study of the specific lesions in muscle in subjects with progressive muscular dystrophy. An exact description of the histological changes occurring in this syndrome, as revealed by photomicrographs in ultraviolet light, is difficult at this time because of the lack of an adequate system of nomenclature. Attention has been drawn, however, to lesions of consistent character, found in sections of muscle removed at biopsy, which appear to be specific for the disease. The method of simplified ultraviolet photomicrography possesses certain marked advantages over those classical methods of histology and pathology which depend on staining and examination of specimens in visible light. Not only is greater resolution achieved with ultraviolet light photomicrography but the image which is obtained in the ultraviolet may provide some idea of the chemical nature of the tissue as well, since it results chiefly from the selective absorption of light by proteins, nucleoproteins, and nucleic acids. PMID:19871400
Exon-skipping Therapy for Muscular Dystrophy: A Roadblock, Detour, or Bump in the Road?
Hoffman, Eric P.; McNally, Elizabeth M.
Duchenne muscular dystrophy (DMD) affects 1in 5,000 newborn males. These boys appear healthy as infants and young children, but then experience a heartbreaking decline, as muscle tissue gradually wastes away, leaving patients nonambulant by their late teens. The heart and respiratory muscles are similarly weakened, compromising life span. DMD has served as a test bed for population genetics in the 1950ĺs, gene identification methods (reverse genetics) in the 1980ĺs, and the integration of molecular diagnostics into patient diagnosis and family counseling. Additional landmarks are held by the dystrophin gene: It is the largest in the human genomeŚ2.3 million base pairsŚand has the highest known spontaneous mutation rate of all human genes. Although we have made robust progress in understanding the molecular basis of DMD, translation of these advances to improvements in patient care has been painfully slow. Early hints of success with stem cell transplantation and replacement gene therapy hit technical roadblocks of delivery and immunological barriers that have remained persistently impassable. PMID:24695683
Respiratory Muscle Strength and Cough Capacity in Patients with Duchenne Muscular Dystrophy
Kang, Yeoun-Seung; Sohn, Hong-Seok; Park, Jung-Hyun; Moon, Jae-Ho
The function of inspiratory muscles is crucial for effective cough as well as expiratory muscles in patients with Duchenne muscular dystrophy (DMD). However, there is no report on the correlation between cough and inspiratory muscle strength. To investigate the relationships of voluntary cough capacity, assisted cough techniques, and inspiratory muscle strength as well as expiratory muscle strength in patients with DMD (n = 32). The vital capacity (VC), maximum insufflation capacity (MIC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured. Unassisted peak cough flow (UPCF) and three different techniques of assisted PCF were evaluated. The mean value of MICs (1918 ▒ 586 mL) was higher than that of VCs (1474 ▒ 632 mL) (p < 0.001). All three assisted cough methods showed significantly higher value than unassisted method (212 ▒ 52 L/min) (F = 66.13, p < 0.001). Combined assisted cough technique (both manual and volume assisted PCF; 286 ▒ 41 L/min) significantly exceeded manual assisted PCF (MPCF; 246 ▒ 49 L/min) and volume assisted PCF (VPCF; 252 ▒ 45 L/min) (F = 66.13, p < 0.001). MIP (34 ▒ 13 cmH2O) correlated significantly with both UPCF and all three assisted PCFs as well as MEP (27 ▒ 10 cmH2O) (p < 0.001). Both MEP and MIP, which are the markers of respiratory muscle weakness, should be taken into account in the study of cough effectiveness. PMID:16642546
Surgical management of severe scoliosis with high-risk pulmonary dysfunction in Duchenne muscular dystrophy
Nakazawa, Toshiyuki; Imura, Takayuki; Takahira, Naonobu; Itoman, Moritoshi; Takahashi, Kazuhisa; Yamazaki, Masashi; Otori, Seiji; Akazawa, Tsutomu; Minami, Shohei; Kotani, Toshiaki
Between 2005 and 2007, 14 patients who had severe scoliosis in Duchenne muscular dystrophy (DMD) and a poor forced vital capacity (FVC) of <30% at admission underwent scoliosis surgery. FVC on admission was 21.6% (range, 16ľ27%). The patients were given respiratory muscle training using a pulmonary trainer (Threshold IMT, Philips Respironics, Inc.) for sixáweeks before operation. FVC increased to 26.2% (range, 22ľ31%) the day before operation. The mean preoperative scoliosis was 98░ (range, 81░ľ130░). All patients underwent posterior fusion and all-screw construction and were extubated on the operative day. No patients developed any respiratory complications. The postoperative scoliosis was 34░ (range, 20░ľ40░) (65%). FVC remained stable at sixáweeks after operation. FVC decreased to 19.8% (range, 16ľ25%) and the mean scoliosis was 35░ (range, 23░ľ40░)(64%) at twoáyears after operation. DMD patients with severe scoliosis and FVC considered too low to permit reasonable surgical risk could undergo surgery and could benefit from surgery. PMID:19340426
Evaluation scale development, reliability for sitting and standing from the chair for Duchenne muscular dystrophy.
Hukuda, Michele Emy; Escorcio, Renata; Fernandes, Lilian Aparecida Yoshimura; de Carvalho, Eduardo Vital; Caromano, Fßtima Aparecida
The authors aimed to (a) develop a scale to evaluate non-wheelchair-dependent children with Duchenne muscular dystrophy (DMD) while sitting and standing from the chair, (b) test its reliability, and (c) correlate the scores of this scale with the time, the age and the Vignos. Thirty DMD boys performed sit-to-stand and stand-to-sit from the chair 4 times. Scale development was based on a previous movement characterization in healthy children and in DMD children and on suggestions by physical therapists with expertise in DMD. The final version of the scale was submitted to the analysis of reliability. The sitting evaluation consists of phases: flexion, contact of the hip with the chair, extension. The standing evaluation comprehends the phases: flexion; transference; extension. Sitting and standing phases presented an excellent reliability (intraclass correlation coefficient [ICC] ? 0.91) and a good reproducibility (ICC ? 0.89). The scores generated by sitting on the chair correlated to the time taken to perform the tasks (r = .69) and to the age of the patient (r = .44) and the score of standing from the chair also correlated to the time of performance (r = .66). The sit-to-stand functional evaluation scale DMD is a reliable assessment tool that allows the description and quantification of the functional performance of DMD children. PMID:23488586
Impact of Biopsychosocial Factors on Chronic Pain in Persons With Myotonic and Facioscapulohumeral Muscular Dystrophy
Mirˇ, Jordi; Raichle, Katherine A.; Carter, Gregory T.; OĺBrien, Sarah A.; Abresch, Richard T.; McDonald, Craig M.; Jensen, Mark P.
To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD. PMID:19414560
Tongue pressure during swallowing is decreased in patients with Duchenne muscular dystrophy.
Hamanaka-Kondoh, Sato; Kondoh, Jugo; Tamine, Ken-Ichi; Hori, Kazuhiro; Fujiwara, Shigehiro; Maeda, Yoshinobu; Matsumura, Tsuyoshi; Yasui, Kumiko; Fujimura, Harutoshi; Sakoda, Saburo; Ono, Takahiro
Although dysphagia is a life-threatening problem in patients with Duchenne muscular dystrophy (DMD), the pathophysiology of oral stage dysphagia is yet to be understood. The present study investigated the tongue motor deficit during swallowing in patients with DMD and its relationship with disease-specific palatal morphology. Tongue pressure during swallowing water was recorded in 11 male patients with DMD and 11 age- and sex-matched healthy subjects using an intra-oral sensor with five measuring points, and the state of tongue pressure production was compared between the groups. Palatal morphology was assessed by a non-contact three-dimensional scanner on maxillary plaster models. In patients with DMD, the normal sequential order of tongue-palate contact was lost and the maximal magnitude and integrated value of tongue pressure on the mid-anterior part of palate were smaller than those in healthy subjects. The width of the palate in patients was greater than that in healthy subjects and the depth of the palate in patients had a negative correlation with tongue pressure magnitude on the median palate. Our results suggested that the deteriorated tongue motor kinetics prevented tongue movement during swallowing that was appropriate for the depth of the palate and affects the state of tongue pressure production during swallowing. PMID:24684858
Strategies of hip management in neuromuscular disorders: Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita.
Canavese, F; Sussman, M D
Joint contractures, subluxation and dislocation are common problem in children with neuromuscular disorders. Medical, surgical and rehabilitative approaches can be used to maintain patient function and comfort. Contracture release, hip dysplasia correction and procedures to address or prevent hip subluxation or dislocation, are not always necessary since patients can be asymptomatic and surgical treatment will not always be successful in maintaining a reduced hip. In fact, controversy surrounds the management of hip disorder in children with Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita. Patients with neuromuscular disorders also frequently develop a progressive scoliosis with pelvic obliquity which may affect sitting balance and become painful. Most subluxations and dislocations have the tendency to occur on the high side of a tilted pelvis. Spinal stabilisation is sometimes necessary to improve the pelvic tilt and to prevent further increase. The present article provides an overview of the current strategies of hip management in neuromuscular disorders. PMID:19306247
[Successful anesthetic management of laparoscopic rectopexy using rocuronium and sugammadex in a patient with Becker muscular dystrophy].
Yamaguchi, Satoshi; Ohno, Giichiro; Kitamura, Jiro
A 70-year-old man with Becker muscular dystrophy (BMD) underwent laparoscopic rectopexy under general anesthesia. For anesthetic induction, we administered total 0.6 mg Ě kg-1 of rocuronium with titration. Eight minutes later, train-of-four (TOF) count reached to 0 and the patient was intubated smoothly. One hundred and five minutes later, TOF ratio recovered to 100% and we administered rocuronium 10 mg additionally. Surgery was finished without any problems 95 minutes after thereafter. TOF ratio was 45% and we administered sugammadex 3 mg Ě kg-1, reversing neuromuscular blockade to TOF ratio 100% within 1.5 minute. The patient awoke clearly and respiratory condition was good. He was extubated without remaining neuromuscular blockade. Postoperative course was stable and there was no serious adverse effect on his muscular function intra- and post-operatively. In conclusion, rocuronium and sugammadex can be used safely and effectively in general anesthetic management for patients with muscular dystrophy. However, as the onset times and durations of these agents can be longer, we should administer these agents with titration carefully under periodic neuromuscular monitoring. PMID:25693344
Nanoparticle Delivery of Antisense Oligonucleotides and Their Application in the Exon Skipping Strategy for Duchenne Muscular Dystrophy
Falzarano, Maria Sofia; Passarelli, Chiara
Antisense therapy is a powerful tool for inducing post-transcriptional modifications and thereby regulating target genes associated with disease. There are several classes of antisense oligonucleotides (AONs) with therapeutic use, such as double-stranded RNAs (interfering RNAs, utilized for gene silencing, and single-stranded AONs with various chemistries, which are useful for antisense targeting of micro-RNAs and mRNAs. In particular, the use of AONs for exon skipping, by targeting pre-mRNA, is proving to be a highly promising therapy for some genetic disorders like Duchenne muscular dystrophy and spinal muscular atrophy. However, AONs are unable to cross the plasma membrane unaided, and several other obstacles still remain to be overcome, in particular their instability due to their nuclease sensitivity and their lack of tissue specificity. Various drug delivery systems have been explored to improve the bioavailability of nucleic acids, and nanoparticles (NPs) have been suggested as potential vectors for DNA/RNA. This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy. PMID:24506782
Lack of Functional Benefit with Glutamine versus Placebo in Duchenne Muscular Dystrophy: A Randomized Crossover Trial
Mok, Elise; Letellier, Guy; Cuisset, Jean-Marie; Denjean, AndrÚ; Gottrand, FrÚdÚric; Alberti, Corinne; Hankard, RÚgis
Background Oral glutamine decreases whole body protein breakdown in Duchenne muscular dystrophy (DMD). We evaluated the functional benefit of 4 months oral glutamine in DMD. Methodology/Principal Findings 30 ambulant DMD boys were included in this double-blind, randomized crossover trial with 2 intervention periods: glutamine (0.5 g/kg/d) and placebo, 4 months each, separated by a 1-month wash-out, at 3 outpatient clinical investigation centers in France. Functional benefit was tested by comparing glutamine versus placebo on change in walking speed at 4 months. Secondary outcome measures were: 2-minute walk test, work, power, muscle mass (urinary creatinine), markers of myofibrillar protein breakdown (urinary 3-methyl-histidine/creatinine), serum creatine phospho-kinase, body composition (fat free mass, fat mass percentage), safety and oral nutrient intake. There was no improvement in the primary end point (walking speed) or in secondary measures of muscle function (2-minute walk test, work, power) in the glutamine group compared with placebo. However, subjects receiving glutamine or placebo showed no deterioration in functional measures over the course of the 9-month trial. No differences in muscle mass, markers of protein breakdown or serum creatine phosho-kinase were observed, except for a blunted increase in fat free mass in the glutamine group which led to a greater increase in fat mass percentage. Glutamine was safe and well-tolerated. Conclusions This trial did not identify additional benefit of 4 months oral glutamine over placebo on muscle mass or function in ambulatory DMD boys. Although apparently safe, current data cannot support routine supplementation in this population as a whole, until further research proves otherwise. Trial Registration ClinicalTrials.gov NCT00296621 PMID:19421321
Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy.
Jiang, Chunhui; Wen, Yefei; Kuroda, Kazuki; Hannon, Kevin; Rudnicki, Michael A; Kuang, Shihuan
Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7+ and Myf5-) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD. PMID:24906372
Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy.
McDonald, Abby A; Hebert, Sadie L; Kunz, Matthew D; Ralles, Steven J; McLoon, Linda K
The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12ámonths. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12ámonths. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus. PMID:25921779
Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy
Gonzßlez-Navarro, FÚlix F.; Belanche-Mu˝oz, LluÝs A.; Silva-Colˇn, Karen A.
The Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant neuromuscular disorder whose incidence is estimated in about one in 400,000 to one in 20,000. No effective therapeutic strategies are known to halt progression or reverse muscle weakness and atrophy. It is known that the FSHD is caused by modifications located within a D4ZA repeat array in the chromosome 4q, while recent advances have linked these modifications to the DUX4 gene. Unfortunately, the complete mechanisms responsible for the molecular pathogenesis and progressive muscle weakness still remain unknown. Although there are many studies addressing cancer databases from a machine learning perspective, there is no such precedent in the analysis of the FSHD. This study aims to fill this gap by analyzing two specific FSHD databases. A feature selection algorithm is used as the main engine to select genes promoting the highest possible classification capacity. The combination of feature selection and classification aims at obtaining simple models (in terms of very low numbers of genes) capable of good generalization, that may be associated with the disease. We show that the reported method is highly efficient in finding genes to discern between healthy cases (not affected by the FSHD) and FSHD cases, allowing the discovery of very parsimonious models that yield negligible repeated cross-validation error. These models in turn give rise to very simple decision procedures in the form of a decision tree. Current biological evidence regarding these genes shows that they are linked to skeletal muscle processes concerning specific human conditions. PMID:24349187
Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD).
Mosqueira, Matias; Willmann, Gabriel; Ruohola-Baker, Hannele; Khurana, Tejvir S
Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips« and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ? CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD. PMID:20975992
Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)
Mosqueira, Matias; Willmann, Gabriel; Ruohola-Baker, Hannele; Khurana, Tejvir S.
Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips« and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ? CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD. PMID:20975992
Circumferential Strain Analysis Identifies Strata of Cardiomyopathy in Duchenne Muscular Dystrophy
Hor, Kan N; Wansapura, Janaka; Markham, Larry W; Mazur, Wojciech; Cripe, Linda H; Fleck, Robert; Benson, D. Woodrow; Gottliebson, William M
Objectives This study sought to evaluate the natural history of occult cardiac dysfunction in Duchenne Muscular Dystrophy (DMD). Background DMD is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (?cc) would decrease in DMD prior to global systolic functional abnormalities regardless of age or ventricular ejection fraction (EF). Methods We evaluated cardiac magnetic resonance image (CMR) data from 70 DMD patients and 16 aged-matched control subjects. Standard imaging data included steady-state free precession (SSFP) short-axis cine stack images, cine myocardial tagged images and myocardial delayed enhancement (MDE, an indicator of myocardial fibrosis) sequences. Analysis was performed using QMASS« and HARP« softwares. DMD patient data was subdivided by age (< 10 years or > 10 years), EF (> 55% or <55%) and the presence or absence of MDE. Results DMD patients with normal EF had reduced ?cc at an early age (<10 years) compared to control subjects (p< 0.01). DMD patients >10 years with normal EF had further decline in ?cc compared to younger DMD patients (p<0.01). There was further decline in ?cc with age in patients with reduced EF (p<0.01) without MDE. The oldest patients, with both reduced EF and positive MDE, exhibited the lowest ?cc. None of the patients had ventricular hypertrophy. Conclusions Myocardial strain abnormalities are prevalent in young DMD patients despite normal EF, and these strain values continue to decline with advancing age. Strain analysis in combination with standard CMR and MDE imaging provides a means to stratify DMD cardiomyopathy. PMID:19341862
Evolutionary analysis of the 3.3 kb tandem repeat sequence associated with facioscapulohumeral muscular dystrophy
Hewitt, J.E.; Clark, L.N.; Wienberg, J. [and others
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant progressive disorder affecting primarily the facial and shoulder girdle muscles. The FSHD gene has been localized to distal 4q35. Genetic and physical mapping has identified a polymorphic 3.3 kb tandem repeat (D4Z4) which is closely lined to the disease. In the majority of sporadic cases there are de novo DNA rearrangements resulting in loss of an integral number of D4Z4 repeats. Sequencing of D4Z4 showed it to contain two homeoboxes and a previously identified human repeat sequences (L Sau). At present, it is not known how these rearrangements affect the pathogenesis of FSHD; however, D4Z4 clearly has an important function. It is part of a complex, dispersed human tandem repeat family which is evolutionarily conserved with a marked difference in copy number in humans and great apes compared to other species. Given the unique structure and organization of the D4Z4 repeat and its role in the FSHD disease mechanism, we have further investigated the evolutionary conservation of D4Z4. Comparison of Southern blot data from Old and New World monkeys, great apes, and humans shows that this increase in the number of D4Z4-like loci occurred after the divergence of great apes and Old World monkeys. The localization of these loci in great apes has been investigated using fluorescent in situ hybridization. These studies provide evidence that the D4Z4 repeat has evolved very recently in the great ape lineage. An understanding of how this repeat family has arisen and identification of the ancestral locus in Old World monkeys should provide clues as to the role of this sequence in FSHD.
Myocardial atrophy in children with mitochondrial disease and Duchenne muscular dystrophy
Lee, Tae Ho; Choi, Jae Young; Kwon, Hye Eun; Lee, Young-Mock; Kim, Heung Dong; Kang, Seong-Woong
Purpose Mitochondrial disease (MD) and Duchenne muscular dystrophy (DMD) are often associated with cardiomyopathy, but the myocardial variability has not been isolated to a specific characteristic. We evaluated the left ventricular (LV) mass by echocardiography to identify the general distribution and functional changes of the myocardium in patients with MD or DMD. Methods We retrospectively evaluated the echocardiographic data of 90 children with MD and 42 with DMD. Using two-dimensional echocardiography, including time-motion (M) mode and Doppler measurements, we estimated the LV mass, ratio of early to late mitral filling velocities (E/A), ratio of early mitral filling velocity to early diastolic mitral annular velocity (E/Ea), stroke volume, and cardiac output. A "z score" was generated using the lambda-mu-sigma method to standardize the LV mass with respect to body size. Results The LV mass-for-height z scores were significantly below normal in children with MD (-1.02▒1.52, P<0.001) or DMD (-0.82▒1.61, P=0.002), as were the LV mass-for-lean body-mass z scores. The body mass index (BMI)-for-age z scores were far below normal and were directly proportional to the LV mass-for-height z scores in both patients with MD (R=0.377, P<0.001) and those with DMD (R=0.330, P=0.033). The LV mass-for-height z score correlated positively with the stroke volume index (R=0.462, P<0.001) and cardiac index (R=0.358, P<0.001). Conclusion LV myocardial atrophy is present in patients with MD and those with DMD and may be closely associated with low BMI. The insufficient LV mass for body size might indicate deterioration of systolic function in these patients. PMID:25045366
Autonomic dysfunction: a driving force for myocardial fibrosis in young Duchenne muscular dystrophy patients?
Thomas, Tamara O; Jefferies, John L; Lorts, Angela; Anderson, Jeffrey B; Gao, Zhiqian; Benson, D Woodrow; Hor, Kan N; Cripe, Linda H; Urbina, Elaine M
Cardiac manifestations of Duchenne muscular dystrophy (DMD) include progressive cardiac dysfunction and an elevated resting heart rate (HR). We hypothesized this elevated HR reflects autonomic dysfunction that can be identified by heart rate variability (HRV) analyses which will be associated with myocardial fibrosis by cardiac magnetic resonance imaging (cMR). DMD patients (Ná=á74) and controls (Ná=á17) had time and frequency domain HRV analyses calculated via Holter monitoring. Cardiac magnetic resonance imaging was performed on DMD cases only. ? (2) test, T test, ANOVA, and logistic regression were used to perform comparisons between groups. A p value of <0.05 was used for statistical significance. DMD cases had higher resting average HR than controls (99.4á▒á8.9, 85.4á+á6.2, pá<á0.001). Among HRV variables, decreases were seen in the following: standard deviation of R to R intervals, the percent RR intervals differing by >50áms from previous RR interval, the root-meansquare of successive differences of RR intervals, the standard deviation of the mean R to R segment (SDANN), low frequency, and high frequency domain, all p values 0.001. Maximum HR and SDANN most significantly associated with positive LGE on cMR (pá=á0.008, pá=á0.016). DMD cases on beta blocker had an average HR lower than those not on beta blocker (pá=á0.009), but with no difference in HRV analysis. DMD patients have reduced HRV and therefore autonomic dysfunction prior to the onset of heart failure which is associated with myocardial fibrosis. PMID:25399404
Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: A safe alternative to tracheostomy
McKim, Douglas A; Griller, Nadia; LeBlanc, Carole; Woolnough, Andrew; King, Judy
BACKGROUND: Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative. METHODS: The authorsĺ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported. RESULTS: The mean (▒ SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8▒3.5 years and 0.90▒0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8▒3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years). CONCLUSIONS: Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone. PMID:23457679
Nutritional status evaluation in patients affected by bethlem myopathy and ullrich congenital muscular dystrophy.
Toni, Silvia; Morandi, Riccardo; Busacchi, Marcello; Tardini, Lucia; Merlini, Luciano; Battistini, Nino Carlo; Pellegrini, Massimo
Collagen VI mutations lead to disabling myopathies like Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). We have investigated the nutritional and metabolic status of one UCMD and seven BM patients (five female, three male, mean age 31?▒?9?years) in order to find a potential metabolic target for nutritional intervention. For this study, we used standard anthropometric tools, such as BMI evaluation and body circumference measurements. All results were compared to dual-energy X-ray absorptiometry (DXA), considered the "gold standard" method. Energy intake of each patient was evaluated through longitudinal methods (7-day food diary) while resting energy expenditure (REE) was predicted using specific equations and measured by indirect calorimetry. Clinical evaluation included general and nutritional blood and urine laboratory analyses and quantitative muscle strength measurement by hand-held dynamometry. BM and UCMD patients showed an altered body composition, characterized by low free fat mass (FFM) and high fat mass (FM), allowing us to classify them as sarcopenic, and all but one as sarcopenic-obese. Another main result was the negative correlation between REE/FFM ratio (basal energy expenditure per kilograms of fat-free mass) and the severity of the disease, as defined by the muscle megascore (correlation coefficient -0.955, P-value <0.001). We postulate that the increase of the REE/FFM ratio in relation to the severity of the disease may be due to an altered and pathophysiological loss of energetic efficiency at the expense of skeletal muscle. We show that a specific metabolic disequilibrium is related to the severity of the disease, which may represent a target for a nutritional intervention in these patients. PMID:25477818
Nutritional Status Evaluation in Patients Affected by Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy
Toni, Silvia; Morandi, Riccardo; Busacchi, Marcello; Tardini, Lucia; Merlini, Luciano; Battistini, Nino Carlo; Pellegrini, Massimo
Collagen VI mutations lead to disabling myopathies like Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). We have investigated the nutritional and metabolic status of one UCMD and seven BM patients (five female, three male, mean age 31?▒?9?years) in order to find a potential metabolic target for nutritional intervention. For this study, we used standard anthropometric tools, such as BMI evaluation and body circumference measurements. All results were compared to dual-energy X-ray absorptiometry (DXA), considered the ôgold standardö method. Energy intake of each patient was evaluated through longitudinal methods (7-day food diary) while resting energy expenditure (REE) was predicted using specific equations and measured by indirect calorimetry. Clinical evaluation included general and nutritional blood and urine laboratory analyses and quantitative muscle strength measurement by hand-held dynamometry. BM and UCMD patients showed an altered body composition, characterized by low free fat mass (FFM) and high fat mass (FM), allowing us to classify them as sarcopenic, and all but one as sarcopenic-obese. Another main result was the negative correlation between REE/FFM ratio (basal energy expenditure per kilograms of fat-free mass) and the severity of the disease, as defined by the muscle megascore (correlation coefficient ?0.955, P-value <0.001). We postulate that the increase of the REE/FFM ratio in relation to the severity of the disease may be due to an altered and pathophysiological loss of energetic efficiency at the expense of skeletal muscle. We show that a specific metabolic disequilibrium is related to the severity of the disease, which may represent a target for a nutritional intervention in these patients. PMID:25477818
Clinical Predictors of Conduction Disease Progression in Type I Myotonic Muscular Dystrophy
Nazarian, Saman; Wagner, Kathryn R.; Caffo, Brian S.; Tomaselli, Gordon F.
Background Patients with type I myotonic muscular dystrophy (DM1) are at risk for sudden death due to atrioventricular conduction block. We sought to characterize the trends and predictors of time dependent electrocardiographic (ECG) variations in patients with DM1. Methods Seventy patients with DM1 underwent standard electrocardiography at first evaluation and routine and symptom prompted follow-up. Individual variations in ECG conduction intervals were assessed using spaghetti plots. Clinical predictors of conduction disease progression were assessed using multivariate random effects regression models of panel data clustered by patient and adjusted for heart rate. Results Substantial individual variability was noted in time dependent changes in PR, QRS, and QTc intervals of patients with DM1. Changes in the QTc interval were closely associated with prolongation of the QRS interval. Age, the presence of paroxysmal atrial flutter or fibrillation, and the number of cytosine-thymine-guanine (CTG) repeats were independent positive predictors of time dependent PR and QRS prolongation during long-term follow-up. Female sex was negatively associated with PR prolongation but positively associated with QTc prolongation. Lower left ventricular ejection fraction was associated with greater QRS interval progression during long-term follow-up but was not predictive of PR interval progression. Conclusions Patients with DM1 can develop rapid changes in cardiac conduction intervals. Paroxysmal atrial flutter or fibrillation, older age, and larger CTG expansions predict greater time dependent PR and QRS interval prolongation and warrant particular attention in the arrhythmic evaluation of this high risk patient subset. PMID:20946286
Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy
Aartsma-Rus, Annemieke; Janson, Anneke AM; van Ommen, Gert-Jan B; van Deutekom, Judith CT
Background Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD). Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple exon duplications. These mutations are in principle ideal targets for this approach since the specific skipping of duplicated exons would generate original, full-length transcripts. Methods Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed. Results For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62), by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons. Conclusion The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches. PMID:17612397
Postural alignment in children with Duchenne muscular dystrophy and its relationship with balance
Baptista, Cyntia R. J. A.; Costa, Andreia A.; Pizzato, Tatiana M.; Souza, Francine B.; Mattiello-Sverzut, Ana C.
Background In Duchenne muscular dystrophy, functional deficits seem to arise from body misalignment, deconditioning, and obesity secondary to weakness and immobility. The question remains about the effects of postural deviations on the functional balance of these children. Objectives To identify and quantify postural deviations in children with DMD in comparison to non-affected children (eutrophic and overweight/obese), exploring relationships between posture and function. Method This case-control study evaluated 29 participants aged 6 to 11 years: 10 DMD (DG), 10 eutrophic (EG), and 9 overweight/obese (OG). Digital photogrammetry and SAPo program were used to measure postural alignment and the Pediatric Balance Scale (PBS) was used to measure balance. The Kruskall-Wallis and Dunn post-hoc tests were used for inter-group comparison of posture and balance. Spearman's coefficient tested the correlation between postural and balance variables. Results The horizontal pelvic alignment data indicated that the anteversion of the DG was similar to that of the OG and twice that of the EG (p<0.05). Compared to the EG, the DG and OG showed an increased forward position of the center of mass (p<0.05). There was a moderate and weak correlation between the PBS score and horizontal pelvic alignment (0.58 and 0.47-left/right). The PBS showed a weak correlation with asymmetries in the sagittal plane (-0.39). The PBS scores for the OG and EG suggest that obesity did not have a deleterious effect on balance. Conclusions The balance deficit in children with DMD was accompanied by an increased forward position of the center of mass and significant pelvic anteversion that constitutes a compensatory strategy to guarantee similar performance to the children not affected by the disease. PMID:24838810
Screening of Duchenne Muscular Dystrophy (DMD) Mutations and Investigating Its Mutational Mechanism in Chinese Patients
Chen, Chen; Ma, Hongwei; Zhang, Feng; Chen, Lu; Xing, Xuesha; Wang, Shusen; Zhang, Xue; Luo, Yang
Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43ľ55 and exon 10ľ23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements. PMID:25244321
Cricopharyngeal dilatation for the long-term treatment of dysphagia in oculopharyngeal muscular dystrophy.
Manjaly, Joseph G; Vaughan-Shaw, Peter G; Dale, Oliver T; Tyler, Susan; Corlett, Jonathan C R; Frost, Roger A
Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant, progressive degenerative muscle disorder featuring dysphagia with limited therapeutic options. The aim of this study was to evaluate the safety and efficacy of repeated endoscopic dilatation for OPMD over a 15-year period. All patients seen at our Regional Swallowing Clinic with OPMD confirmed by genetic analysis were included. Cricopharyngeal dilatation was performed as an outpatient procedure using a wire-guided 18-mm (54 Fr) Savary-Gilliard bougie with the patient under sedation. Patients were offered repeat endoscopic dilatation when symptoms recurred. Symptom severity prior to initial dilatation and at follow-up was evaluated using the Sydney Swallow Questionnaire (SSQ). Nine patients (7 female, 2 male) were included for analysis. Median total treatment period was 13áyears (rangeá=á3-15), median number of dilatations per patient was 7.2 (rangeá=á1-16), and median interval between treatments was 15ámonths (rangeá=á4.5-45). All patients recorded sustained symptom improvement. Mean SSQ score (out of 1,700) was 1,108.11 (SDá▒á272.85) prior to first dilatation and 297.78 (SDá▒á189.14) at last follow-up, representing a 73% decrease (95% CIá=á52-94) in degree of dysphagia symptoms (paired t-test, Pá=á0.0001). All mean scores for individual questions also showed significant improvement (Pá<á0.05). No adverse events were reported with all patients maintaining oral feeding at last follow-up. Repeated cricopharyngeal dilatation is a safe, effective, well-tolerated, and long-lasting treatment for dysphagia in OPMD. PMID:21805106
Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy
Jiang, Chunhui; Wen, Yefei; Kuroda, Kazuki; Hannon, Kevin; Rudnicki, Michael A.; Kuang, Shihuan
Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7+ and Myf5?) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD. PMID:24906372
An aberrant adenylate kinase isoenzyme from the serum of patients with Duchenne muscular dystrophy.
Hamada, M; Okuda, H; Oka, K; Watanabe, T; Ueda, K; Nojima, M; Kuby, S A; Manship, M; Tyler, F H; Ziter, F A
The sera from patients with human Duchenne (X-linked) progressive muscular dystrophy contain elevated adenylate kinase (ATP: AMP phosphotransferase, EC 126.96.36.199) activities, in addition to their characteristically high creatine kinase (ATP; creatine N-phosphotransferase, EC 18.104.22.168) activities. By agarose gel electrophoresis of human Duchenne dystrophic serum, the presence of an apparently normal human serum adenylate kinase together with a variant species of adenylate kinase was detected. The latter enzyme species appeared, in its mobility, to be similar to that of the normal human liver-type adenylate kinase. The presence of this aberrant liver-type adenylate kinase could also be demonstrated by characteristic (for the liver type) inhibition patterns with P1,P5-di-(adenosine-5')pentaphosphate, 5,5'-dithiobis(2-nitrobenzoate) and phosphoenolpyruvate. On the other hand, by inhibition titrations with an anti-muscle-type adenylate kinase, hemolysates from the erythrocytes of several Duchenne and Becker's dystrophics were found to contain approx. 96% muscle-type adenylate kinase and their serum approx. 97% muscle-type adenylate kinase. These same patients contained approx. 89% M-M type creatine kinase in their serum (by inhibition against anti-human muscle-type creatine kinase) indicative of the presence also of M-B plus B-B type active isoenzymes. All of these data can best be explained by the presence of a variant or mutant adenylate kinase isoenzyme in the dystrophic serum. This isoenzyme appears to resemble the liver type in its inhibition patterns with P1,P5-di(adenosine-5')pentaphosphate, 5,5'-dithiobis(2-nitrobenzoate) and phosphoenolpyruvate, and in its heat stability (compare also the agarose gel electrophoresis pattern); but structurally, it is a muscle type, or derived from a muscle type, as shown immunologically by inhibition reactions with anti-muscle-type adenylate kinase. Whether this is a fetal-type isoenzyme of adenylate kinase will require further investigation. PMID:6269633
Low bone density and bone metabolism alterations in Duchenne muscular dystrophy: response to calcium and vitamin D treatment
M. L. Bianchi; L. Morandi; E. Andreucci; S. Vai; J. Frasunkiewicz; R. Cottafava
SummaryááBoys with Duchenne muscular dystrophy often have reduced bone mass and increased fracture risk. In this prospective study\\u000a on 33 patients, calcifediol (25-OH vitamin D3) plus adjustment of dietary calcium to the recommended dose reduced bone resorption, corrected vitamin D deficiency, and\\u000a increased bone mass in about two-thirds of cases.\\u000a \\u000a \\u000a \\u000a \\u000a IntroductionááLow BMC and BMD and bone metabolism alterations are frequent
Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D)
A CarriÚ; F Piccolo; F Leturcq; C de Toma; K Azibi; C Beldjord; J M Vallat; L Merlini; T Voit; C Sewry; J A Urtizberea; N Romero; F M TomÚ; M Fardeau; Y Sunada; K P Campbell; J C Kaplan; M Jeanpierre
Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies in which the primary defect may reside in any of the genes coding for the different partners of the sarcolemmal sarcoglycan (SG) complex: the alpha-SG (LGMD2D at 17q21.2), the beta-SG (LGMD2E at 4q12), the gamma-SG (LGMD2C at 13q12), and the delta-SG (LGMD2F at 5q33). We report a series of
Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies
Bachinski, Linda L.; Baggerly, Keith A.; Neubauer, Valerie L.; Nixon, Tamara J.; Raheem, Olayinka; Sirito, Mario; Unruh, Anna K.; Zhang, Jiexin; Nagarajan, Lalitha; Timchenko, Lubov T.; Bassez, Guillaume; Eymard, Bruno; Gamez, Josep; Ashizawa, Tetsuo; Mendell, Jerry R.; Udd, Bjarne; Krahe, Ralf
The prevailing pathomechanistic paradigm for myotonic dystrophy (DM) is that aberrant expression of embryonic/fetal mRNA/protein isoforms accounts for most aspects of the pleiotropic phenotype. To identify aberrant isoforms in skeletal muscle of DM1 and DM2 patients, we performed exon-array profiling and RT-PCR validation on the largest DM sample set to date, including Duchenne, Becker and tibial muscular dystrophy (NMD) patients as disease controls, and non-disease controls. Strikingly, most expression and splicing changes in DM patients were shared with NMD controls. Comparison between DM and NMD identified almost no significant differences. We conclude that DM1 and DM2 are essentially identical for dysregulation of gene expression, and DM expression changes represent a subset of broader spectrum dystrophic changes. We found no evidence for qualitative splicing differences between DM1 and DM2. While some DM-specific splicing differences exist, most of the DM splicing differences were also seen in NMD controls. SSBP3 exon 6 missplicing was observed in all diseased muscle and led to reduced protein. We conclude there is no widespread DM-specific spliceopathy in skeletal muscle and suggest that missplicing in DM (and NMD) may not be the driving mechanism for the muscle pathology, since the same pathways show expression changes unrelated to splicing. PMID:24332166
Genomic screening for ?-sarcoglycan gene mutations: missense mutations may cause severe limb-girdle muscular dystrophy type 2E (LGMD 2E)
Carsten G. B÷nnemann; M. Rita Passos-Bueno; Elizabeth M. McNally; Mariz Vainzof; EloÝsa de Sß Moreira; Suely K. Marie; Rita C. M. Pavanello; Satoru Noguchi; Eijiro Ozawa; Mayana Zatz; Louis M. Kunkel
Autosomal recessive limb-girdle muscular dys- trophies (LGMDs) are genetically heterogeneous. A subgroup of these disorders is caused by mutations in the dystrophin-associated sarcoglycan complex. Truncating mutations in the 43 kDa ?-sarcoglycan gene (LGMD 2E) were originally identified in a sporadic case of Duchenne-like muscular dystrophy, and a common missense mutation (T151R) was identified indepen- dently in Indiana Amish pedigrees with
Laminin ?2 chain-null mutant mice by targeted disruption of the Lama2 gene: a new model of merosin (laminin 2)-deficient congenital muscular dystrophy
Yuko Miyagoe; Kazunori Hanaoka; Ikuya Nonaka; Michiko Hayasaka; Yoko Nabeshima; Kiichi Arahata; Yo-ichi Nabeshima; Shin'ichi Takeda
Using the gene targeting technique, we have generated a new mouse model of congenital muscular dystrophy (CMD), a null mutant for the laminin ?2 chain. These homozygous mice, designated dy3K\\/dy3K, are characterized by growth retardation and severe muscular dystrophic symptoms and die by 5 weeks of age. Light microscopy revealed that muscle fiber degeneration in these mice begins no later
Hoagland, Charles L.; Gilder, Helena; Shank, Robert E.
The diminished excretion of creatinine in progressive muscular dystrophy is a more striking and specific phenomenon than the excess excretion of creatine, marked though this is. While creatinuria is invariably encountered in all cases of long-standing dystrophy, the extent to which the excretion of creatinine is decreased provides a more reliable indication of the severity of the disease since an excess output of creatine may occur physiologically in normal human subjects and in many pathological conditions not known to be associated with muscle disease. In progressive muscular dystrophy the residual muscle mass, as inferred from the excretion of creatinine, provides a useful index of the state of the disease at any given time. Although there is excessive creatinuria in progressive muscular dystrophy, there is no evidence that a deprivation of methyl stores occurs through a loss of urinary creatine. The loss of methyl groups contained in the excess creatine is, under ordinary conditions of diet, almost exactly compensated for by a drop in the excretion of methyl groups in the urinary creatinine. Testosterone propionate, administered over variable periods of time, resulted in the retention of creatine both in normal male children and in male children with progressive muscular dystrophy, as shown in the normal subjects by a diminution in creatine output, and in both by an excess creatinuria for variable periods of time following withdrawal of the hormone. An increase in the excretion of creatine in progressive muscular dystrophy occurred following the administration of methyl testosterone. Neither testosterone propionate nor methyl testosterone appeared to effect any consistent change in the output or urinary creatinine. No effects on the excretion of creatine and creatinine were observed following the prolonged administration of concentrate of gonadotropic and thyrotropic principles of the hypophysis, or from the administration of desoxycorticosterone acetate to patients with progressive muscular dystrophy. Except in one case, in which marked improvement was observed following the administration of testosterone propionate, no effects on the clinical course of the patients with progressive muscular dystrophy were observed as a result of treatment by any of the various hormones employed in this study. PMID:19871467
Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin
Thanh, L.T.; Man, Nguyen Thi; Morris, G.E. [Wales Institute, Clwyd (United Kingdom)] [and others
We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.
AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy
Bortolanza, Sergia; Nonis, Alessandro; Sanvito, Francesca; Maciotta, Simona; Sitia, Giovanni; Wei, Jessica; Torrente, Yvan; Di Serio, Clelia; Chamberlain, Joel R; Gabellini, Davide
Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans. PMID:21829175
Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat
Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina
Previous work has established the existence of dystrophinľnitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx miceŚthe mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722
Effects of yoga breathing exercises on pulmonary function in patients with Duchenne muscular dystrophy: an exploratory analysis*, **
Rodrigues, Marcos Rojo; Carvalho, Celso Ricardo Fernandes; Santaella, Danilo Forghieri; Lorenzi-Filho, Geraldo; Marie, Suely Kazue Nagahashi
OBJECTIVE: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children, and children with DMD die prematurely because of respiratory failure. We sought to determine the efficacy and safety of yoga breathing exercises, as well as the effects of those exercises on respiratory function, in such children. METHODS: This was a prospective open-label study of patients with a confirmed diagnosis of DMD, recruited from among those followed at the neurology outpatient clinic of a university hospital in the city of SŃo Paulo, Brazil. Participants were taught how to perform hatha yoga breathing exercises and were instructed to perform the exercises three times a day for 10 months. RESULTS: Of the 76 patients who entered the study, 35 dropped out and 15 were unable to perform the breathing exercises, 26 having therefore completed the study (mean age, 9.5 ▒ 2.3 years; body mass index, 18.2 ▒ 3.8 kg/m2). The yoga breathing exercises resulted in a significant increase in FVC (% of predicted: 82.3 ▒ 18.6% at baseline vs. 90.3 ▒ 22.5% at 10 months later; p = 0.02) and FEV1 (% of predicted: 83.8 ▒ 16.6% at baseline vs. 90.1 ▒ 17.4% at 10 months later; p = 0.04). CONCLUSIONS: Yoga breathing exercises can improve pulmonary function in patients with DMD. PMID:24831396
Prescription pattern for orthoses in The Netherlands: use and experience in the ambulatory phase of Duchenne muscular dystrophy.
Bakker, J P; De Groot, I J; De Jong, B A; Van Tol-De Jager, M A; Lankhorst, G J
In the Netherlands ankle-foot orthoses (AFO), standing frames (SF), knee-ankle-foot orthoses (KAFO) and orthopaedic footwear are frequently prescribed for patients with Duchenne muscular dystrophy. Little is known, however, about the prescription pattern and the experience of patients. A questionnaire was sent to 25 rehabilitation physicians treating 53 patients with Duchenne muscular dystrophy. The use of orthoses and the patients' experience was measured during 1 year of follow-up. Our results show prescription of AFO 91%, of SF 61% and of KAFO 22%. Indications were limited passive dorsiflexion and Vignos classification 6. Patient-related factors were reasons to discontinue or to refrain from using orthoses. The prescribed duration for KAFO varied greatly. Patients' experience scores for SF and KAFO were high. The time that the orthoses were worn differed greatly from the recommended time. Ready-made shoes were prescribed for equinovarus during ambulation. Similarly, ready-made shoes or custom-made shoes were advised for wheelchair-dependent patients. This study shows no uniform prescription pattern for AFO, SF. KAFO and orthopaedic footwear. The prescription pattern was influenced by patient-related factors and actual use greatly differed from the recommended time. PMID:9279487
Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype.
Witting, Nanna; Duno, Morten; Vissing, John
With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy showed dystrophic changes. He had comorbidity with dystonia, slight mental retardation, low stature and neuropathy. The brother of the proband's mother came to medical attention when he was 43 years old. He complained about muscle pain. On examination, a MRC grade 4+ hip extention palsy and a discrete calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic evaluation revealed a deletion of exon 26 of the dystrophin gene in both. This is the first description of patients with a exon 26 deletion of the dystrophin gene. Assuming the proband's comorbidity is unrelated, exon 26 deletion results in a very mild phenotype. This might be of interest in planning exon skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK. PMID:22616200
The mapping of phosphoglycerate kinase, Duchenne muscular dystrophy, and clotting factor IX to the bovine X chromosome by in situ hybridizationá
Livingston, Robert James
3-phosphoglycerate and ATP. In humans, a deficiency of PGK activity causes hemolytic anemia. The PGK gene maps to Xq13 in humans and is syntenic to the bovine X chromosome (Shimuzu ef al, 1981). Duchenne muscular dystrophy the most common...
Transduction of Myogenic Cells by Retargeted Dual High-Capacity Hybrid Viral Vectors: Robust Dystrophin Synthesis in Duchenne Muscular Dystrophy Muscle Cells
Manuel A. F. V. Gonšalves; Maarten Holkers; Christophe CudrÚ-Mauroux; Gijsbert P. van Nierop; Shoshan Knańn-Shanzer; Ietje van der Velde; Dinko Valerio; Antoine A. F. de Vries
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), making it amenable to gene- or cell-based therapies. Another possible treatment entails the combination of both principles by transplantation of autologous myogenic cells after their genetic complementation. This approach requires efficient and stable transduction of these cells with recombinant DMD. Recently, we generated a dual high-capacity (hc)
Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-associated IkappaBalpha\\/Nuclear Factor kappaB Pathway Perturbation in Mice
Isabelle Richard; Carinne Roudaut; Sylvie Marchand; Stephen Baghdiguian; Muriel Herasse; Daniel Stockholm; Yasuko Ono; Laurence Suel; Nathalie Bourg; Hiroyuki Sorimachi; GÚrard Lefranc; Michel Fardeau; Alain SÚbille; Jacques S. Beckmann
Calpain 3 is known as the skeletal muscle- specific member of the calpains, a family of intracellu- lar nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are re- sponsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predomi- nantly the proximal limb muscles. To better understand the function of
Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of á-dystroglycan
Cheryl Longman; Martin Brockington; Silvia Torelli; Cecilia Jimenez-Mallebrera; Colin Kennedy; Nofal Khalil; Lucy Feng; Ravindra K. Saran; Thomas Voit; Luciano Merlini; Caroline A. Sewry; Susan C. Brown; Francesco Muntoni
The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of a-dystroglycan. Fukuyama CMD, muscle - eye - brain disease and Walker-Warburg syndrome, each asso- ciated with eye
Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome
Marcello Villanova; Eugenio Mercuri; Enrico Bertini; Patrizia Sabatelli; Lucia Morandi; Marina Mora; Caroline Sewry; Martin Brockington; Susan C Brown; Ana Ferreiro; Nadir M Maraldi; Tatsushi Toda; Pascale Guicheney; Luciano Merlini; Francesco Muntoni
We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest
Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families
Antonella Pini; Luciano Merlini; Fernando M. S. Tome┤; Martine Chevallay; Giuseppe Gobbi
We report clinical, EEG and neuroimaging findings of three patients in two Italian families with merosin-negative congenital muscular dystrophy (CMD), drug-resistant occipital epilepsy, diffuse persistent cerebral white matter changes and focal cortical dysplasia. Clinical and epilepsy histories, EEG and neuroimaging findings were very similar in all patients. Seizures started in childhood and mainly consisted of periodic spasms, a particular type
Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.
Zulian, Alessandra; Tagliavini, Francesca; Rizzo, Erika; Pellegrini, Camilla; Sardone, Francesca; Zini, Nicoletta; Maraldi, Nadir Mario; Santi, Spartaco; Faldini, Cesare; Merlini, Luciano; Petronilli, Valeria; Bernardi, Paolo; Sabatelli, Patrizia
Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI (ColVI) genes, which encode an extracellular matrix protein; yet, mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high-conductance channel, which causes a shortage in ATP production. We find that melanocytes do not produce ColVI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myopathy patients display increased size, reduced matrix density, and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in ColVI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia. PMID:25477819
Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors
Zulian, Alessandra; Tagliavini, Francesca; Rizzo, Erika; Pellegrini, Camilla; Sardone, Francesca; Zini, Nicoletta; Maraldi, Nadir Mario; Santi, Spartaco; Faldini, Cesare; Merlini, Luciano; Petronilli, Valeria; Bernardi, Paolo; Sabatelli, Patrizia
Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI (ColVI) genes, which encode an extracellular matrix protein; yet, mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high-conductance channel, which causes a shortage in ATP production. We find that melanocytes do not produce ColVI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myopathy patients display increased size, reduced matrix density, and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in ColVI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia. PMID:25477819
On the nature of the Duchenne muscular dystrophy locus: a portion of a complex of related gene clusters of recent pseudoautosomal origin?
J. P. Infante; V. A. Huszagh
The current hypothesis that the Duchenne\\/Becker muscular dystrophy locus encodes a single 2000 kb gene is analyzed. The apparent encoding efficiency, the individual and total exon\\/intron ratios, and the heterogeneity of deletions associated with the disease, which are currently interpreted as supporting the single gene hypothesis, are also consistent with the alternative hypothesis that this locus is a portion of
Correlative light optical, scanning electron, and transmission electron microscopy of skeletal muscle in muscular dystrophy and muscular atrophy: a pilot study.
Geissinger, H D; Vriend, R A; Ackerley, C A; Yamashiro, S
Biopsies of skeletal muscle from three different cases of muscular dystrophy and one case of spinal muscular atrophy that has been fixed with Karnovsky's fluid were either routinely prepared for scanning electron microscopy (SEM) or were frozen to -20 degrees C and sectioned on a steel knife in a cryostat at 5-10 micrometer. The sections were coverslipped and examined using a light microscope equipped with polarizing optics (Pol). After areas were selected, the sections were prepared for SEM and thereby examined. The tissues on the slides that had been observed with light microscopy (LM) and SEM were prepared further for transmission electron microscopy (TEM) by infiltrating them with Epon and cutting sections at approximately 100 nm on an ultramicrotome. It is shown that the stage of contraction in one pathologic myofiber may vary along its length. The following advantages may be realized by using correlative (Pol leads to SEM leads to TEM) microscopy on skeletal muscle biopsies: 1) lesions can be differentiated from "normal" surrounding tissue; 2) doubtful structures can be reexamined with the SEM and TEM; and 3) the SEM image of different states of muscle contraction can be reinterpreted in the light of the Pol or TEM image. PMID:7233587
Selenoproteins protect against avian nutritional muscular dystrophy by metabolizing peroxides and regulating redox/apoptotic signaling.
Huang, Jia-Qiang; Ren, Fa-Zheng; Jiang, Yun-Yun; Xiao, Chen; Lei, Xin Gen
Nutritional muscular dystrophy (NMD) of chicks is induced by dietary selenium (Se)/vitamin E (Vit. E) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms related to the presumed oxidative cell damage, we fed four groups of 1-day-old broiler chicks (n = 40/group) with a basal diet (BD; 10?g Se/kg; no Vit. E added, -Se -Vit. E) or the BD plus all-rac-?-tocopheryl acetate at 50mg/kg (-Se +Vit. E), Se (as sodium selenite) at 0.3mg/kg (+Se -Vit. E), or both of these nutrients (+Se +Vit. E) for 6 weeks. High incidences of NMD (93%) and mortality (36%) of the chicks were induced by the BD, starting at week 3. Dietary Se deficiency alone also induced muscle fiber rupture and coagulation necrosis in the pectoral muscle of chicks at week 3 and thereafter, with increased (P < 0.05) malondialdehyde, decreased (P < 0.05) total antioxidant capacity, and diminished (P < 0.05) glutathione peroxidase activities in the muscle. To link these oxidative damages of the muscle cells to the Se-deficiency-induced NMD, we first determined gene expression of the potential 26 selenoproteins in the muscle of the chicks at week 2 before the onset of symptoms. Compared with the +Se chicks, the -Se chicks had lower (P < 0.05) muscle mRNA levels of Gpx1, Gpx3, Gpx4, Sepp1, Selo, Selk, Selu, Selh, Selm, Sepw1, and Sep15. The -Se chicks also had decreased (P < 0.05) production of 6 selenoproteins (long-form selenoprotein P (SelP-L), GPx1, GPx4, Sep15, SelW, and SelN), but increased levels (P < 0.05) of the short-form selenoprotein P in muscle at weeks 2 and 4. Dietary Se deficiency elevated (P < 0.05) muscle p53, cleaved caspase 3, cleaved caspase 9, cyclooxygenase 2 (COX2), focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), phospho-Akt, nuclear factor-?B (NF-?B), p38 mitogen-activated protein kinase (p38 MAPK), phospho-p38 MAPK, phospho-JNK, and phospho-ERK and decreased (P < 0.05) muscle procaspase 3, procaspase 9, and NF-?B inhibitor ?. In conclusion, the downregulation of SelP-L, GPx1, GPx4, Sep15, SelW, and SelN by dietary Se deficiency might account for induced oxidative stress and the subsequent peroxidative damage of chick muscle cells via the activation of the p53/caspase 9/caspase 3, COX2/FAK/PI3K/Akt/NF-?B, and p38 MAPK/JNK/ERK signaling pathways. Metabolism of peroxides and redox regulation are likely to be the mechanisms whereby these selenoproteins prevented the onset of NMD in chicks. PMID:25668720
Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy
Pal, Rituraj; Palmieri, Michela; Loehr, James A.; Li, Shumin; Abo-Zahrah, Reem; Monroe, Tanner O.; Thakur, Poulami Basu; Sardiello, Marco; Rodney, George G.
Duchenne muscular dystrophy (DMD) is a fatal degenerative muscle disease resulting from mutations in the dystrophin gene. Increased oxidative stress and altered Ca2+ homeostasis are hallmarks of dystrophic muscle. While impaired autophagy has recently been implicated in the disease process, the mechanisms underlying the impairment have not been elucidated. Here we show that nicotinamide adenine dinucleotide phosphatase (Nox2)-induced oxidative stress impairs both autophagy and lysosome formation in mdx mice. Persistent activation of Src kinase leads to activation of the autophagy repressor mammalian target of rapamycin (mTOR) via PI3K/Akt phosphorylation. Inhibition of Nox2 or Src kinase reduces oxidative stress and partially rescues the defective autophagy and lysosome biogenesis. Genetic down regulation of Nox2 activity in the mdx mouse decreases ROS production, abrogates defective autophagy and rescues histological abnormalities and contractile impairment. Our data highlight mechanisms underlying the pathogenesis of DMD and identify NADPH oxidase and Src kinase as potential therapeutic targets. PMID:25028121
Successful Surgery for Scoliosis Supported by Pulmonary Rehabilitation in a Duchenne Muscular Dystrophy Patient With Forced Vital Capacity Below 10%
Lee, Jang Woo; Won, Yu Hui; Choi, Won Ah; Lee, Soon Kyu
Low vital capacity is a risk factor for scoliosis correction operation in Duchenne muscular dystrophy (DMD) patients, but pulmonary rehabilitation, including noninvasive intermittent positive pressure ventilator application, air stacking exercise, and assisted coughing technique, reduces the pulmonary complications and perioperative mortality risk. In this case, the patient's preoperative forced vital capacity (FVC) was 8.6% of normal predicted value in sitting position and 9.4% in supine position. He started pulmonary rehabilitation before the operation and continued right after the operation. Scoliosis correction operation was successful without any pulmonary complications, and his discomfort in sitting position was improved. If pulmonary rehabilitative support is provided properly, FVC below 10% of normal predicted value is not a contraindication of scoliosis correction operation in DMD patients. PMID:24466523
Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy
Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria
This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465
Germinal mosaicism in a sample of families with Duchenne/Becker muscular dystrophy with partial deletions in the DMD gene.
Berm˙dez-Lˇpez, Cesßrea; GarcÝa-de Teresa, Benilde; Gonzßlez-del Angel, Ariadna; Alcßntara-Ortigoza, Miguel Angel
Germinal mosaicism should be considered when estimating the recurrence risk in families with Duchenne/Becker muscular dystrophy (D/BMD). Germinal mosaicism, however, has not been assessed in Mexican families with deletions in the DMD gene. To determine the distribution of deletions in the two hot spots and the proportion of de novo and transmitted deletions, we analyzed 153 individuals with D/BMD and a DMD partial deletion and 322 of their maternal female relatives. Predilection for the distal hot spot was observed in 112 families (73%), while gene dosage analysis of female relatives of D/BMD patients identified germinal mosaicism deletions in at least 11.6% of the patients' families, thought to result from de novo mutations. Recurrence risk due to germinal mosaicism justifies carrier detection in maternal female relatives and prenatal diagnosis in mothers of individuals with apparently de novo DMD deletions. PMID:24236769
Pregnancy-Induced Amelioration of Muscular Dystrophy Phenotype in mdx Mice via Muscle Membrane Stabilization Effect of Glucocorticoid
Shimizu-Motohashi, Yuko; Asakura, Yoko; Motohashi, Norio; Belur, Nandkishore R.; Baumrucker, Michael G.; Asakura, Atsushi
Duchenne muscular dystrophy (DMD), the most common and severe type of dystrophinopathy, is an X-linked recessive genetic disease caused by the absence of dystrophin, which leads to fragility and vulnerability of the sarcolemma to mechanical stretching with increased membrane permeability. Currently, glucocorticoids such as prednisolone are the only medication available for DMD. However, molecular pathways responsible for this effect are still unclear. In addition, it remains unclear whether sex-related factors, including pregnancy and the postpartum period, affect the phenotype of dystrophinopathy. Here, we report the amelioration of muscle membrane permeability in the diaphragm muscle of pregnant and postpartum, but not in nulliparous, mdx mice, an animal model for DMD, during the physiological surge of corticosterone, the most abundant glucocorticoid in rodents. Cultures of single muscle fibers and myotubes isolated from mdx mouse diaphragm demonstrate resistance to hypo-osmotic shock when treated with corticosterone but not with estradiol or progesterone. This corticosterone-mediated resistance was diminished by an antagonist of corticosterone, indicating that the glucocorticoid-glucocorticoid receptor axis plays a role in this membrane stabilization effect on muscle. Moreover, subcutaneous injection of corticosterone into mdx mice showed decreased membrane permeability. This is the first report to demonstrate that pregnancy-related resistance to muscle fiber damage in mdx mice due to the membrane stabilization effect of corticosterone. We also propose that this membrane stabilization effect is exerted through annexin A1 up-regulation as the molecular mechanisms of glucocorticoid effects on DMD muscle. Furthermore, single muscle fiber culture studies provide a sensitive chemical screening platform for muscular dystrophies. PMID:25775477
One Year Outcome of Boys with Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development
Connolly, Anne M.; Florence, Julaine M.; Cradock, Mary M.; Eagle, Michelle; Flanigan, Kevin M.; McDonald, Craig M.; Karachunski, Peter I.; Darras, Basil T.; Bushby, Kate; Malkus, Elizabeth C.; Golumbek, Paul T.; Zaidman, Craig M.; Miller, J Philip; Mendell, Jerry R.
BACKGROUND The pathogenesis of Duchenne muscular dystrophy starts prior to birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here we report six and twelve month follow-up of two subsets of these boys. PATIENTS Nineteen boys (1.9 ▒ 0.8 years) were assessed at baseline and six months. Twelve boys (1.5 ▒ 0.8 years) were assessed at baseline, six, and twelve months. RESULTS Gross motor scores were lower at baseline compared to published controls (6.2 ▒ 1.7; normal 10 ▒ 3; p<.0001), and showed a further declining trend to 5.7 ▒ 1.7 (p =.20) at six months. Repeated measures analysis of the 12 boys followed for 12 months showed that gross motor scores, again low at baseline (6.6 ▒ 1.7; p<.0001), declined at six months (5.9 ▒ 1.8) and further at 12 months (5.3 ▒ 2.0) (p=0.11). Cognitive and language scores were lower at baseline compared to normal children (range p=.002 to p<0.0001) and did not change significantly at 6 or 12 months (range p=.89 to p=.09). Fine motor skills, also low at baseline, improved over one year (p=.05). CONCLUSION Development can reliably be measured in infants and young boys with DMD across time using the Bayley-III. Power calculations using these data show that motor development may be used as an outcome measure. PMID:24842254
Sensitive Ultrasonic Detection of Dystrophic Skeletal Muscle in Patients with Duchenne's Muscular Dystrophy using an Entropy-Based Signal Receiver
Hughes, M.S.; Marsh, J.N.; Wallace, K.D.; Donahue, T.A.; Connolly, A.M.; Lanza, G. M.; Wickline, S. A.
The dystrophinopathies comprise a group of X-linked genetic diseases that feature dystrophin deficiency. Duchenne and Becker muscular dystrophy are characterized by progressive weakness and wasting of skeletal, smooth, and/or cardiac muscle. Duchenne's Muscular Dystrophy (DMD) is the most severe dystrophinopathy, and with an incidence of 1:3500 male births. Despite understanding the structural and genetic basis for DMD, the pathogenesis and clinical basis for more severe involvement in specific skeletal muscle groups and the heart are poorly understood. Current techniques, such as strength testing, for monitoring progress of disease and therapy in DMD patients, are imprecise and physically demanding for test subjects. Ultrasound is well-suited to detect changes in structure and organization in muscle tissue in a manner that makes low demands on the patient. Therefore, we investigated the use of ultrasound to quantitatively phenotype the remodeling process in patients with DMD. Beam-formed RF data were acquired from the skeletal muscles of nine DMD and five normal subjects imaged with a clinical imaging system (HDI5000 w/7 MHz probe applied above left biceps muscle). From these data, images were reconstructed using B-mode (log of analytic signal magnitude) and information-theoretic receivers (Hf -receiver). Hf images obtained from dystrophic muscle contained extensive ômottledö regions (i.e. areas with heterogeneous image contrast) that were not readily apparent from the B-Mode images. The two dimensional autocorrelation of DMD Hf images have broader peaks than those of normal subjects, which is indicative of larger scatterer sizes, consistent with pathological changes of fibers, edema, and fatty infiltration. Comparison of the relative peak widths (Full width measured at 60% maximum) of the autocorrelation of the DMD and normal Hf images shows a quantitative difference between the two groups (p < 0.005, student two-tailed paired t-test). Consequently, these imaging techniques may prove useful for longitudinal monitoring of disease progression and therapy. PMID:17467153
From innate to adaptive immune response in muscular dystrophies and skeletal muscle regeneration: the role of lymphocytes.
Madaro, Luca; BouchÚ, Marina
Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease. PMID:25028653
An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to WalkerľWarburg syndrome (WWS) caused by a mutation in the POMT1 gene
Burcu Balci; G÷khan Uyanik; Pervin Dincer; Claudia Gross; Tobias Willer; Beril Talim; G÷knur Haliloglu; GŘlsev Kale; Ute Hehr; JŘrgen Winkler; Haluk Topalo?lu
Mutations of the protein O-mannosyltransferase (POMT1) gene affect glycosylation of ?-dystroglycan, leading to WalkerľWarburg syndrome, a lethal disorder in early life with severe congenital muscular dystrophy, and brain and eye malformations. Recently, we described a novel form of recessive limb girdle muscular dystrophy with mild mental retardation, associated with an abnormal ?-dystroglycan pattern in the muscle, suggesting a glycosylation defect.
Cib2 Binds Integrin ?7B?1D and Is Reduced in Laminin ?2 Chain-deficient Muscular Dystrophy*S?
Hńger, Mattias; Bigotti, Maria Giulia; Meszaros, Renata; Carmignac, Virginie; Holmberg, Johan; Allamand, ValÚrie; ┼kerlund, Mikael; Kalamajski, Sebastian; Brancaccio, Andrea; Mayer, Ulrike; Durbeej, Madeleine
Mutations in the gene encoding laminin ?2 chain cause congenital muscular dystrophy type 1A. In skeletal muscle, laminin ?2 chain binds at least two receptor complexes: the dystrophin-glycoprotein complex and integrin ?7?1. To gain insight into the molecular mechanisms underlying this disorder, we performed gene expression profiling of laminin ?2 chain-deficient mouse limb muscle. One of the down-regulated genes encodes a protein called Cib2 (calcium- and integrin-binding protein 2) whose expression and function is unknown. However, the closely related Cib1 has been reported to bind integrin ?IIb and may be involved in outside-in-signaling in platelets. Since Cib2 might be a novel integrin ?7?1-binding protein in muscle, we have studied Cib2 expression in the developing and adult mouse. Cib2 mRNA is mainly expressed in the developing central nervous system and in developing and adult skeletal muscle. In skeletal muscle, Cib2 colocalizes with the integrin ?7B subunit at the sarcolemma and at the neuromuscular and myotendinous junctions. Finally, we demonstrate that Cib2 is a calcium-binding protein that interacts with integrin ?7B?1D. Thus, our data suggest a role for Cib2 as a cytoplasmic effector of integrin ?7B?1D signaling in skeletal muscle. PMID:18611855
Body Composition, Muscle Strength, and Physical Function of Patients with Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy
Miscione, Maria Teresa; Bruno, Francesca; Ripamonti, Claudio; Nervuti, Giuliana; Orsini, Riccardo; Faldini, Cesare; Pellegrini, Massimo; Cocchi, Daniela; Merlini, Luciano
Objective. To determine the contributions of body mass, adiposity, and muscularity to physical function and muscle strength in adult patients with Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). Materials and Methods. Evaluation involved one UCMD and 7 BM patients. Body composition was determined by body mass index (BMI) and dual-energy-X-ray-absorptiometry (DXA), muscle strength by dynamometry, physical function by the distance walked in 6 minutes (6MWD), forced vital capacity (FVC) by a spirometer. Results. Six participants were of normal weight and 2 overweight based on BMI; all were sarcopenic based on appendicular fat free mass index (AFFMI); and 7 were sarcopenic obese based on AFFMI and % fat mass. Average muscle strength was reduced below 50% of normal. The 6MWD was in BM patients 30% less than normal. FVC was reduced in 4 of the BM patients. Muscle strength had a good correlation with the physical function variables. Correlation between muscle strength and BMI was poor; it was very high with AFFMI. AFFMI was the best single explicator of muscle strength and physical function. Conclusion. Muscle mass determined by DXA explains most of the variability of the measures of muscle strength and physical function in patients with BM and UCMD. PMID:24163611
[A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG)8 repeat expansion in the PAPBN1 gene].
Tokutake, Takayoshi; Ikeuchi, Takeshi; Tanaka, Keiko; Onodera, Osamu; Nishizawa, Masatoyo
We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1; PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG)8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent. PMID:16022469
Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy
Introduction Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD. Methods Here, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice. Results Analysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1?/?Rag1?/? mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the therapeutic collagen VI protein missing in the mutant mice. Conclusions Overall, our findings suggest that stem cell therapy can potentially provide a new avenue for the treatment of COL6 CMD and other muscular disorders and injuries. PMID:24522088
Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy deficient in adhalin.
Higuchi, I; Yamada, H; Fukunaga, H; Iwaki, H; Okubo, R; Nakagawa, M; Osame, M; Roberds, S L; Shimizu, T; Campbell, K P
Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (alpha-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability. Images PMID:8040315
Distal mdx muscle groups exhibiting up-regulation of utrophin and rescue of dystrophin-associated glycoproteins exemplify a protected phenotype in muscular dystrophy
NASA Astrophysics Data System (ADS)
Dowling, Paul; Culligan, Kevin; Ohlendieck, Kay
Unique unaffected skeletal muscle fibres, unlike necrotic torso and limb muscles, may pave the way for a more detailed understanding of the molecular pathogenesis of inherited neuromuscular disorders and help to develop new treatment strategies for muscular dystrophies. The sparing of extraocular muscle in Duchenne muscular dystrophy is mostly attributed to the special protective properties of extremely fast-twitching small-diameter fibres, but here we show that distal muscles also represent a particular phenotype that is more resistant to necrosis. Immunoblot analysis of membranes isolated from the well established dystrophic animal model mdx shows that, in contrast to dystrophic limb muscles, the toe musculature exhibits an up-regulation of the autosomal dystrophin homologue utrophin and a concomitant rescue of dystrophin-associated glycoproteins. Thus distal mdx muscle groups provide a cellular system that naturally avoids myofibre degeneration which might be useful in the search for naturally occurring compensatory mechanisms in inherited skeletal muscle diseases.
Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study.
Andersen, Grete; ěrngreen, Mette C; Preisler, Nicolai; Jeppesen, Tina D; Krag, Thomas O; Hauerslev, Simon; van Hall, Gerrit; Vissing, John
In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 ▒ 11 yr (18-52), body mass index: 22 ▒ 3 kg/m(2) (16-26)] and 8 healthy matched controls [3 women and 5 men, age 33 ▒ 13 years (19-54), body mass index: 23 ▒ 3 kg/m(2) (19-27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ▒ 1 ?mol phenylalanine/min) vs. rest (8 ▒ 1 ?mol phenylalanine/min, P = 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P = 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions. PMID:25411362
Quantitative Southern blot analysis in the dystrophin gene of Japanese patients with Duchenne or Becker muscular dystrophy: a high frequency of duplications
Y Hiraishi; S Kato; T Ishihara; T Takano
Eighty-four unrelated patients with Duchenne or Becker muscular dystrophy in Japan were studied by quantitative Southern blot analysis with dystrophin cDNA probes. We found partial deletions and duplications in 47 (56%) and 12 (14%) cases respectively by HindIII digestion. The duplications were confirmed by BglII digestion and densitometric scanning. The frequency of duplications in this study is significantly higher than
A new locus on 3p23ľp25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H
Luigi Bisceglia; Stefano Zoccolella; Alessandra Torraco; Maria Rosaria Piemontese; Rosa Dell'Aglio; Angela Amati; Patrizia De Bonis; Lucia Artuso; Massimiliano Copetti; Filippo Maria Santorelli; Luigi Serlenga; Leopoldo Zelante; Enrico Bertini; Vittoria Petruzzella
Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic girdles. We clinically examined 19 members in a four-generation Italian family with autosomal-dominant LGMD. A total of 11 subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented
Interactions with M-band Titin and Calpain 3 Link Myospryn (CMYA5) to Tibial and Limb-girdle Muscular Dystrophies*
Sarparanta, Jaakko; Blandin, GaŰlle; Charton, Karine; Vihola, Anna; Marchand, Sylvie; Milic, Astrid; Hackman, Peter; Ehler, Elisabeth; Richard, Isabelle; Udd, Bjarne
Mutations in the C terminus of titin, situated at the M-band of the striated muscle sarcomere, cause tibial muscular dystrophy (TMD) and limb-girdle muscular dystrophy (LGMD) type 2J. Mutations in the protease calpain 3 (CAPN3), in turn, lead to LGMD2A, and secondary CAPN3 deficiency in LGMD2J suggests that the pathomechanisms of the diseases are linked. Yeast two-hybrid screens carried out to elucidate the molecular pathways of TMD/LGMD2J and LGMD2A resulted in the identification of myospryn (CMYA5, cardiomyopathy-associated 5) as a binding partner for both M-band titin and CAPN3. Additional yeast two-hybrid and coimmunoprecipitation studies confirmed both interactions. The interaction of myospryn and M-band titin was supported by localization of endogenous and transfected myospryn at the M-band level. Coexpression studies showed that myospryn is a proteolytic substrate for CAPN3 and suggested that myospryn may protect CAPN3 from autolysis. Myospryn is a muscle-specific protein of the tripartite motif superfamily, reported to function in vesicular trafficking and protein kinase A signaling and implicated in the pathogenesis of Duchenne muscular dystrophy. The novel interactions indicate a role for myospryn in the sarcomeric M-band and may be relevant for the molecular pathomechanisms of TMD/LGMD2J and LGMD2A. PMID:20634290
Physical training in boys with Duchenne Muscular Dystrophy: the protocol of the No Use is Disuse study
Background "Use it or lose it" is a well known saying which is applicable to boys with Duchenne Muscular Dystrophy (DMD). Besides the direct effects of the muscular dystrophy, the increasing effort to perform activities, the fear of falling and the use of personal aids indirectly impair leg and arm functions as a result of disuse. Physical training could oppose this secondary physical deterioration. The No Use is Disuse (NUD) study is the first study in human subjects with DMD that will examine whether a low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD and, study 2 "Functional training with arm support for boys with DMD who have been confined to a wheelchair for several years". This paper describes the hypotheses and methods of the NUD study. Methods Study 1 is an explorative randomized controlled trial with multiple baseline measurements. Thirty boys with a DNA-established diagnosis of DMD will be included. The intervention consists of a six-months physical training during which boys train their legs and arms with active and/or assisted cycling training equipment. The primary study outcomes are muscle endurance and functional abilities, assessed with a Six-Minute Bicycle Test and the Motor Function Measure. Study 2 has a within-group repeated measurements design and will include ten boys with DMD who have already been confined to a wheelchair for several years. The six-months physical training program consists of 1) a computer-assisted training and 2) a functional training with an arm support. The primary study outcome is functional abilities of the upper extremity, assessed with the Action Research Arm Test. Discussion The NUD study will fill part of the gap in the current knowledge about the possible effects of training in boys with DMD and will increase insight into what type of exercise should be recommended to boys with DMD. The study will finish at the end of 2010 and results are expected in 2011. Trial registration The Netherlands National Trial Register1631 PMID:20691042
Co-administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy.
Pereira, Juliano Alves; Marques, Maria Julia; Santo Neto, Humberto
The standard therapy used in the treatment of Duchenne muscle dystrophy (DMD) is corticoids, such as deflazacort and prednisone. However, they have limited therapeutic value, and their combination with drugs already in use to treat other human diseases could potentially increase corticoid outcomes in DMD. In the present study, we evaluated whether a combined therapy of the corticoid deflazacort with doxycycline could result in greater improvement in mdx dystrophy than deflazacort alone. Deflazacort alone or deflazacort/doxycycline were administered for 36ádays (starting on postnatal day 0) in drinking water. Histopathological, biochemical (creatine kinase), functional (forelimb muscle grip strength and fatigue) parameters and inflammatory markers (MMP-9, TNF-?, NF-kB) were evaluated in biceps brachii and diaphragm muscles of the mdx mice. The combined therapy was superior in improving the dystrophic phenotype compared to monotherapy. The primary results were observed in attenuating muscle fatigue, decreasing muscle total calcium and inflammatory markers and increasing ?-dystroglycan, a main component of the dystrophin-protein complex. Furthermore, the combined therapy was effective in preventing the loss of body mass observed with deflazacort alone at this very early stage of therapy. The present study offers preclinical data to support further studies with deflazacort/doxycycline combined therapy in DMD clinical trials. PMID:25959722
Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy
S Benedetti; E Bertini; S Iannaccone; C Angelini; M Trisciani; D Toniolo; B Sferrazza; P Carrera; G Comi; M Ferrari; A Quattrini; S C Previtali
The coexistence of neurogenic and myogenic features in scapuloperoneal syndrome is rarely ascribed to a single gene. Defects in the nuclear envelope protein lamin A\\/C, encoded by the LMNA gene, have been shown to be associated with a variety of disorders affecting mainly the muscular and adipose tissues and, more recently, with autosomal recessive CharcotľMarieľTooth type 2 neuropathy. This report
New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing.
Oliveira, Jorge; NegrŃo, LuÝs; Fineza, Isabel; Taipa, Ricardo; Melo-Pires, Manuel; Fortuna, Ana Maria; Gonšalves, Ana Rita; Froufe, Hugo; Egas, ConceišŃo; Santos, Rosßrio; Sousa, Mßrio
Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis. PMID:25740612
Preclinical studies on intestinal administration of antisense oligonucleotides as a model for oral delivery for treatment of duchenne muscular dystrophy.
van Putten, Maaike; Young, Courtney; van den Berg, Sjoerd; Pronk, Amanda; Hulsker, Margriet; Karnaoukh, Tatyana G; Vermue, Rick; van Dijk, Ko Willems; de Kimpe, Sjef; Aartsma-Rus, Annemieke
Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-? expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2'-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2'-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate. PMID:25405468
Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy.
Pant, Meghna; Sopariwala, Danesh H; Bal, Naresh C; Lowe, Jeovanna; DelfÝn, Dawn A; Rafael-Fortney, Jill; Periasamy, Muthu
The utrophin-dystrophin deficient (DKO) mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients. PMID:25859846
Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy.
Betts, Corinne A; Saleh, Amer F; Carr, Carolyn A; Muses, Sofia; Wells, Kim E; Hammond, Suzan M; Godfrey, Caroline; McClorey, Graham; Woffindale, Caroline; Clarke, Kieran; Wells, Dominic J; Gait, Michael J; Wood, Matthew J A
Duchenne muscular dystrophy (DMD) is caused by absence of the integral structural protein, dystrophin, which renders muscle fibres susceptible to injury and degeneration. This ultimately results in cardiorespiratory dysfunction, which is the predominant cause of death in DMD patients, and highlights the importance of therapeutic targeting of the cardiorespiratory system. While there is some evidence to suggest that restoring dystrophin in the diaphragm improves both respiratory and cardiac function, the role of the diaphragm is not well understood. Here using exon skipping oligonucleotides we predominantly restored dystrophin in the diaphragm and assessed cardiac function by MRI. This approach reduced diaphragmatic pathophysiology and markedly improved diaphragm function but did not improve cardiac function or pathophysiology, with or without exercise. Interestingly, exercise resulted in a reduction of dystrophin protein and exon skipping in the diaphragm. This suggests that treatment regimens may require modification in more active patients. In conclusion, whilst the diaphragm is an important respiratory muscle, it is likely that dystrophin needs to be restored in other tissues, including multiple accessory respiratory muscles, and of course the heart itself for appropriate therapeutic outcomes. This supports the requirement of a body-wide therapy to treat DMD. PMID:26113184
Paradoxical weight loss with extra energy expenditure at brown adipose tissue in adolescent patients with Duchenne muscular dystrophy.
Satomura, S; Yokota, I; Tatara, K; Naito, E; Ito, M; Kuroda, Y
We examined the energy expenditure in patients with Duchenne muscular dystrophy(DMD) to evaluate the cause of the paradoxical weight loss observed in large numbers of adolescent patients before any obvious impairment of their swallowing function. In the morning, resting energy expenditure (REE)/m(2) was almost the same as that in normal controls despite a reduction in fat-free mass (FFM); thus, REE/m(2)/FFM was significantly increased in patients (median, 21.2 kcal/m(2)/FFM kg; range, 17.7 to 44.2, P =.012). A thermographic examination in the morning showed an obvious elevation of the body surface temperature on the back. This phenomenon was consistent with a paradoxical fall in the low frequency (LF)/high frequency (HF) ratio at night analyzed using the inter-RR spectrum by 24-hour electrocardiogram, which indicated relative activation of the sympathetic nervous system. The urinary secretion of norepinephrine at night was also significantly greater in patients (median, 0.119 microg/kg/h; range, 0.061 to 0.219, P =.011). These results suggest that paradoxical activation of the sympathetic nervous system may accelerate the production of heat in brown adipose tissue (BAT) and increase the level of energy consumption in patients, and that adolescent DMD patients may require greater caloric intake than expected to maintain body weight, which is important to improve the prognosis of their respiratory function. PMID:11586490
Dexmedetomidine-ketamine sedation during bone marrow aspirate and biopsy in a patient with duchenne muscular dystrophy
Rozmiarek, Andrew; Corridore, Marco; Tobias, Joseph D.
Sedation during invasive procedures not only provides appropriate humanitarian care for patients, but also facilitates the completion of invasive procedures. Although generally safe and effective, adverse effects may occur especially in patients with co-morbid diseases. We present the successful use of a combination of dexmedetomidine and ketamine to provide sedation and analgesia in a 21-year-old patient with Duchenne muscular dystrophy (DMD) undergoing bone marrow aspiration and biopsy. Co-morbidities included both depressed myocardial function and impaired respiratory function. Dexmedetomidine was administered as a loading dose of 1 ?g/kg over 5 min followed by an infusion of 1 ?g/kg/h. Ketamine (20 mg) was administered along with the dexmedetomidine loading dose. An additional 10 mg of ketamine was administered to treat the pain experienced during the placement of the local anesthetic agent prior to the procedure. No clinically significant hemodynamic or respiratory changes were noted. The patient tolerated the procedure well and was discharged home. A review of previously published reports of dexmedetomidine and ketamine for procedural sedation are reviewed. PMID:21804807
Becker Muscular Dystrophy (BMD) caused by duplication of exons 3-6 of the dystrophin gene presenting as dilated cardiomyopathy
Tsai, A.C.; Allingham-Hawkins, D.J.; Becker, L. [Univ. of Toronto, Ontario (Canada)] [and others
X-linked dilated cardiomyopathy (XLCM) is a progressive myocardial disease presenting with congestive heart failure in teenage males without clinical signs of skeletal myopathy. Tight linkage of XLCM to the DMD locus has been demonstrated; it has been suggested that, at least in some families, XLCM is a {open_quotes}dystrophinopathy.{close_quotes} We report a 14-year-old boy who presented with acute heart failure due to dilated cardiomyopathy. He had no history of muscle weakness, but physical examination revealed pseudohypertrophy of the calf muscles. He subsequently received a heart transplantation. Family history was negative. Serum CK level at the time of diagnosis was 10,416. Myocardial biopsy showed no evidence of carditis. Dystrophin staining of cardiac and skeletal muscle with anti-sera to COOH and NH{sub 2}termini showed a patchy distribution of positivity suggestive of Becker muscular dystrophy. Analysis of 18 of the 79 dystrophin exons detected a duplication that included exons 3-6. The proband`s mother has an elevated serum CK and was confirmed to be a carrier of the same duplication. A mutation in the muscle promotor region of the dystrophin gene has been implicated in the etiology of SLCM. However, Towbin et al. (1991) argued that other 5{prime} mutations in the dystrophin gene could cause selective cardiomyopathy. The findings in our patient support the latter hypothesis. This suggests that there are multiple regions in the dystrophin gene which, when disrupted, can cause isolated dilated cardiomyopathy.
Comprehensive Mutation Analysis for Congenital Muscular Dystrophy: A Clinical PCR-Based Enrichment and Next-Generation Sequencing Panel
Rhodenizer, Devin; Bhide, Shruti; Littlejohn, Martin Robert; Keong, Lisa Mari; Rutkowski, Anne; Sparks, Susan; Bonnemann, Carsten; Hegde, Madhuri
The congenital muscular dystrophies (CMDs) comprise a heterogeneous group of heritable muscle disorders with often difficult to interpret muscle pathology, making them challenging to diagnose. Serial Sanger sequencing of suspected CMD genes, while the current molecular diagnostic method of choice, can be slow and expensive. A comprehensive panel test for simultaneous screening of mutations in all known CMD-associated genes would be a more effective diagnostic strategy. Thus, the CMDs are a model disorder group for development and validation of next-generation sequencing (NGS) strategies for diagnostic and clinical care applications. Using a highly multiplexed PCR-based target enrichment method (RainDance) in conjunction with NGS, we performed mutation detection in all CMD genes of 26 samples and compared the results with Sanger sequencing. The RainDance NGS panel showed great consistency in coverage depth, on-target efficiency, versatility of mutation detection, and genotype concordance with Sanger sequencing, demonstrating the test's appropriateness for clinical use. Compared to single tests, a higher diagnostic yield was observed by panel implementation. The panel's limitation is the amplification failure of select gene-specific exons which require Sanger sequencing for test completion. Successful validation and application of the CMD NGS panel to improve the diagnostic yield in a clinical laboratory was shown. PMID:23326386
Wild-Type Mouse Models to Screen Antisense Oligonucleotides for Exon-Skipping Efficacy in Duchenne Muscular Dystrophy
Cao, Limin; Han, Gang; Gu, Ben; Yin, HaiFang
A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD), a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO)-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs. PMID:25365558
The Effect of 6-Thioguanine on Alternative Splicing and Antisense-Mediated Exon Skipping Treatment for Duchenne Muscular Dystrophy
Verhaart, Ingrid E. C.; Aartsma-Rus, Annemieke
The severe muscle wasting disorder Duchenne muscular dystrophy (DMD) is caused by genetic defects in the DMD gene, leading to a complete absence of dystrophin protein. Of the therapeutic approaches addressing the underlying genetic defect, exon skipping through antisense oligonucleotides (AONs) is the closest to clinical application. Several strategies to improve the efficiency of this approach are currently being investigated, such as the use of small chemical compounds that improve AONmediated exon skipping levels. Recently, enhanced exon skipping in combination with a guanine analogue, 6-thioguanine (6TG) was reported for phosphorodiamidate morpholino oligomers (PMO). Here the effect of 6TG on the exon skipping efficacy of 2ĺ-O-methyl phosphorothioate RNA (2OMePS) and PMO AONs in vitro and in vivo was further evaluated, as well as the effect of 6TG by itself. Results confirm an increase of exon skipping levels in vitro, however, in contrast to the previous report, no effect was observed in vivo. Importantly, 6TG treatment in vitro resulted in numerous additional DMD exon skipping events. This, in combination with the known cytotoxic effects of 6TG after incorporation in DNA, warrants reconsidering of the use of 6TG as enhancer of AON efficiency in DMD, were chronic treatment will be required. PMID:23259153
Dexmedetomidine-ketamine sedation during upper gastrointestinal endoscopy and biopsy in a patient with Duchenne muscular dystrophy and egg allergy
Raman, Vidya; Yacob, Desale; Tobias, Joseph D
Sedation during invasive procedures provides appropriate humanitarian care as well as facilitating the completion of procedure. Although generally safe and effective, adverse effects may occur especially in patients with co-morbid diseases. In many cases, given its rapid onset and offset, propofol is chosen to provide sedation during various invasive procedures. We present a nine-year-old, 45 kg child with Duchenne muscular dystrophy (DMD) who presented for esophagogastroduodenoscopy (EGD). Given the egg allergy, which was a relative contraindication to the use of propofol, and the potential risk of malignant hyperthermia due to DMD, a combination of dexmedetomidine and ketamine was used for procedural sedation. Dexmedetomidine was administered as a loading dose of 1 ?g/kg along with a single bolus dose of ketamine (1 mg/kg). This was followed by a dexmedetomidine infusion at 0.5 ?g/kg/hour. The patient tolerated the procedure well and was discharged to home. Previous reports regarding the use of dexmedetomidine and ketamine for procedural sedation are reviewed and the potential efficacy of this combination is discussed. PMID:22624101
Cerebellar-Dependent Associative Learning Is Preserved in Duchenne Muscular Dystrophy: A Study Using Delay Eyeblink Conditioning
Schara, Ulrike; Busse, Melanie; Timmann, Dagmar; Gerwig, Marcus
Objective Besides progressive muscle weakness cognitive deficits have been reported in patients with Duchenne muscular dystrophy (DMD). Cerebellar dysfunction has been proposed to explain cognitive deficits at least in part. In animal models of DMD disturbed Purkinje cell function has been shown following loss of dystrophin. Furthermore there is increasing evidence that the lateral cerebellum contributes to cognitive processing. In the present study cerebellar-dependent delay eyeblink conditioning, a form of associative learning, was used to assess cerebellar function in DMD children. Methods Delay eyeblink conditioning was examined in eight genetically defined male patients with DMD and in ten age-matched control subjects. Acquisition, timing and extinction of conditioned eyeblink responses (CR) were assessed during a single conditioning session. Results Both groups showed a significant increase of CRs during the course of learning (block effect p < 0.001). CR acquisition was not impaired in DMD patients (mean total CR incidence 37.4 ▒ 17.6%) as compared to control subjects (36.2 ▒ 17.3%; group effect p = 0.89; group by block effect p = 0.38; ANOVA with repeated measures). In addition, CR timing and extinction was not different from controls. Conclusions Delay eyeblink conditioning was preserved in the present DMD patients. Because eyeblink conditioning depends on the integrity of the intermediate cerebellum, this older part of the cerebellum may be relatively preserved in DMD. The present findings agree with animal model data showing that the newer, lateral cerebellum is primarily affected in DMD. PMID:25973604
Quantitative Magnetic Resonance Imaging in Limb-Girdle Muscular Dystrophy 2I: A Multinational Cross-Sectional Study
Coombs, Anna; Sveen, Marie-Louise; Andersen, Soren; Stojkovic, Tanya; Eagle, Michelle; Mayhew, Anna; de Sousa, Paulo Loureiro; Dewar, Liz; Morrow, Jasper M.; Sinclair, Christopher D. J.; Thornton, John S.; Bushby, Kate; Lochmuller, Hanns; Hanna, Michael G.; Hogrel, Jean-Yves; Carlier, Pierre G.; Vissing, John; Straub, Volker
We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p?=?0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I. PMID:24587344
Capillary electrophoresis for analysis of deletion and duplication in exon 44-55 of Duchenne muscular dystrophy gene.
Chen, Chung-An; Chang, Ming-Yuh; Chang, Tung-Ming; Jong, Yuh-Jyh; Wu, Shou-Mei
In this study, a genotyping CGE method was established for analysis of Duchenne muscular dystrophy (DMD) gene deletions and duplications in exon 44-55. A total of 12 DMD exons (exon 44-55) and 2 internal standard gene fragments were simultaneously amplified by using a universal multiplex PCR (UMPCR) and determined by CGE. The conditions of UMPCR and CGE were optimized, including the kinds of polymerase, temperatures in UMPCR, separation matrix, separation temperature, and voltage. Finally, the separation was performed by 1.2% poly(ethylene oxide) in 1Î TBE buffer at -6 kV and 25░C. After validation, our results showed the peak patterns for differentiation of genetic deletion or duplication in 27 DMD patients and normal subjects, according to the peak height ratios by comparison of two internal standard peaks. Among the 27 subjects, 23 cases are deletion type and four are duplication type. The data of two patients analyzed by this CGE-PCR method were different from that of multiplex ligation dependent probe amplification method, and the sequencing results demonstrated that our results were correct. This UMPCR-CGE method was considered better than the multiplex ligation dependent probe amplification method. Furthermore, this method can be used for eugenics in clinical applications. PMID:23818053
Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
van Putten, Maaike; Young, Courtney; van den Berg, Sjoerd; Pronk, Amanda; Hulsker, Margriet; Karnaoukh, Tatyana G; Vermue, Rick; van Dijk, Ko Willems; de Kimpe, Sjef; Aartsma-Rus, Annemieke
Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-? expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2?-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2?-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate. PMID:25405468
A Long ncRNA Links Copy Number Variation to a Polycomb/Trithorax Epigenetic Switch in FSHD Muscular Dystrophy
Cabianca, DaphneáS.; Casa, Valentina; Bodega, Beatrice; Xynos, Alexandros; Ginelli, Enrico; Tanaka, Yujiro; Gabellini, Davide
Summary Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and thatáD4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease. PMID:22541069
[Induced pluripotent stem (iPS) cell-based cell therapy for muscular dystrophy: current progress and future prospects].
Nishiyama, Takashi; Takeda, Shin'ichi
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by mutations in the dystrophin gene. There is currently no effective treatment for DMD. Muscle satellite cells are tissue-specific stem cells found in the skeletal muscle; these cells play a central role in postnatal muscle growth and regeneration, and are, therefore, a potential source for stem cell therapy for DMD. However, transplantation of satellite cell-derived myoblasts has not yet been successful in humans. Patient-specific induced pluripotent stem (iPS) cells are expected to be a source for autologous cell transplantation therapy for DMD, because iPS cells can proliferate vigorously in vitro and can differentiate into multiple cell lineages both in vitro and in vivo. Here, we discuss the strategies to generate muscle stem cells from iPS cells. So far, the most promising method for generating muscle stem cells from iPS cells is the conditional overexpression of Pax3 or Pax7 in the differentiating mouse embryoid bodies. However, induction methods for human iPS cells have not yet been developed. Thus, iPS cells are expected to serve as an in vitro disease model system, which will enable us to determine the pathology of muscle diseases and develop pharmaceutical treatments. PMID:22223500
Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy.
Ousterout, David G; Kabadi, Ami M; Thakore, Pratiksha I; Majoros, William H; Reddy, Timothy E; Gersbach, Charles A
The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, we use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). We design single or multiplexed sgRNAs to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45-55 and introducing shifts within exons or deleting one or more exons. Following gene editing in DMD patient myoblasts, dystrophin expression is restored in vitro. Human dystrophin is also detected in vivo after transplantation of genetically corrected patient cells into immunodeficient mice. Importantly, the unique multiplex gene-editing capabilities of the CRISPR/Cas9 system facilitate the generation of a single large deletion that can correct up to 62% of DMD mutations. PMID:25692716
Heat shock protein families 70 and 90 in Duchenne muscular dystrophy and inflammatory myopathy: balancing muscle protection and destruction.
Paepe, Boel De; Creus, Kim K; Weis, Joachim; Bleecker, Jan L De
Heat shock proteins are important factors in skeletal muscle physiology and stress response. We examined the effects of chronic inflammation on the distribution of heat shock protein families 70 and 90 using immunofluorescence and Western blotting, in muscle biopsies from 33 idiopathic inflammatory myopathy patients [aged 26-66 (dermatomyositis), 17-78 (polymyositis) and 57-80 (sporadic inclusion body myositis) years], and seven Duchenne muscular dystrophy patients (aged 3-19 years). Our results reveal the multifaceted role played by chaperones in inflammatory muscle tissue. On the one hand, regenerating, atrophic and vacuolated muscle fibers displayed upregulation of both protein families. Higher levels of chaperones in challenged fibers point to the myocyte's attempt to restore and regenerate. On the other hand, heat shock proteins of the 90 family were strongly upregulated in macrophages and cytotoxic T-cells actively invading nonnecrotic muscle fibers of sporadic inclusion body myositis and polymyositis, probably conferring enhanced myocytotoxic capacity. Our data provide positive arguments for exploring heat shock protein 90-based therapy in inflammatory muscle disease. PMID:21855341
Treatment and complications in flaccid neuromuscular scoliosis (Duchenne muscular dystrophy and spinal muscular atrophy) with posterior-only pedicle screw instrumentation
Modi, Hitesh N.; Hong, Jae-Young; Cho, Jae-Woo; Park, Jong-Hoon; Yang, Jae-Hyuk
Literature has described treatment of flaccid neuromuscular scoliosis using different instrumentation; however, only one article has been published using posterior-only pedicle screw fixation. Complications using pedicle screws in paralytic neuromuscular scoliosis has not been described before. To present results and complications with posterior-only pedicle screws, a retrospective study was carried out in 27 consecutive patients with flaccid neuromuscular scoliosis (Duchenne muscular dystrophy and spinal muscular atrophy), who were operated between 2002 and 2006 using posterior-only pedicle screw instrumentation. Immediate postoperative and final follow-up results were compared using t test for Cobb angle, pelvic obliquity, thoracic kyphosis and lumbar lordosis. Perioperative and postoperative complications were noted from the hospital records of each patient. Complications, not described in literature, were discussed in detail. Average follow-up was 32.2ámonths. Preoperative, immediate postoperative and final follow-up Cobb angle were 79.8░, 30.2░ (63.3% correction, pá<á0.0001) and 31.9░, respectively; and pelvic obliquity was 18.3░, 8.9░ (52% correction, pá<á0.0001) and 8.9░. Postoperative thoracic kyphosis remained unchanged from 27.6░ to 19.9░ (pá=á0.376); while lumbar lordosis improved significantly from +15.6░ to ?22.4░ lordosis (pá=á0.0002). Most patients had major to moderate improvement in postoperative functional and ambulatory status compared to the preoperative status. Thirteen (48.1%) perioperative complications were noted with five major complications (four respiratory in the form of hemothorax or respiratory failure that required ventilator support and one death) and eight minor complications (three UTI, two atelectasis, two neurological and one ileus). Postoperatively, we noted complications, such as coccygodynia with subluxation in 7, back sore on the convex side in 4 and dislodging of rod distally in 1 patient making a total of 12 (44.4%) postoperative complications. Of 12 postoperative complications, 6 (50%) required secondary procedure. We conclude that although flaccid neuromuscular scoliosis can be well corrected with posterior-only pedicle screw, there is a high rate of associated complications. PMID:19885687
Menstrual Blood-derived Cells Confer Human Dystrophin Expression in the Murine Model of Duchenne Muscular Dystrophy via Cell Fusion and Myogenic Transdifferentiation
Cui, Chang-Hao; Uyama, Taro; Miyado, Kenji; Terai, Masanori; Kyo, Satoru; Kiyono, Tohru
Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative endometrial progenitor obtained from endometrial tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined menstrual bloodľderived cells to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of menstrual bloodľderived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that endometrial progenitor cells and menstrual bloodľderived cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial progenitor cells and menstrual bloodľderived cells can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo. PMID:17314403
Use of epitope libraries to identify exon-specific monoclonal antibodies for characterization of altered dystrophins in muscular dystrophy
Nguyen thi Man; Morris, G.E. (North East Wales Inst., Clwyd (United Kingdom))
The majority of mutations in Xp21-linked muscular dystrophy (MD) can be identified by PCR or Southern blotting, as deletions or duplications of groups of exons in the dystrophin gene, but it is not always possible to predict how much altered dystrophin, if any, will be produced. Use of exon-specific monoclonal antibodies (mAbs) on muscle biopsies from MD patients can, in principle, provide information on both the amount of altered dystrophin produced and, when dystrophin is present, the nature of the genetic deletion or point mutation. For this purpose, mAbs which recognize regions of dystrophin encoded by known exons and whose binding is unaffected by the absence of adjacent exons are required. To map mAbs to specific exons, random [open quotes]libraries[close quotes] of expressed dystrophin fragments were created by cloning DNAseI digestion fragments of a 4.3-kb dystrophin cDNA into a pTEX expression vector. The libraries were then used to locate the epitopes recognized by 48 mAbs to fragments of 25--60 amino acids within the 1,434-amino-acid dystrophin fragment used to produce the antibodies. This is sufficiently detailed to allow further refinement by using synthetic peptides and, in many cases, to identify the exon in the DMD (Duchenne MD) gene which encodes the epitope. To illustrate their use in dystrophin analysis, a Duchenne patient with a frameshift deletion of exons 42 and 43 makes a truncated dystrophin encoded by exons 1--41, and the authors now show that this can be detected in the sarcolemma by mAbs up to and including those specific for exon 41 epitopes but not by mAbs specific for exon 43 or later epitopes. 38 refs., 2 figs., 4 tabs.
Low Intensity, High Frequency Vibration Training to Improve Musculoskeletal Function in a Mouse Model of Duchenne Muscular Dystrophy
Novotny, Susan A.; Mader, Tara L.; Greising, Angela G.; Lin, Angela S.; Guldberg, Robert E.; Warren, Gordon L.; Lowe, Dawn A.
The objective of the study was to determine if low intensity, high frequency vibration training impacted the musculoskeletal system in a mouse model of Duchenne muscular dystrophy, relative to healthy mice. Three-week old wildtype (n?=?26) and mdx mice (n?=?22) were randomized to non-vibrated or vibrated (45 Hz and 0.6 g, 15 min/d, 5 d/wk) groups. In vivo and ex vivo contractile function of the anterior crural and extensor digitorum longus muscles, respectively, were assessed following 8 wks of vibration. Mdx mice were injected 5 and 1 days prior to sacrifice with Calcein and Xylenol, respectively. Muscles were prepared for histological and triglyceride analyses and subcutaneous and visceral fat pads were excised and weighed. Tibial bones were dissected and analyzed by micro-computed tomography for trabecular morphometry at the metaphysis, and cortical geometry and density at the mid-diaphysis. Three-point bending tests were used to assess cortical bone mechanical properties and a subset of tibiae was processed for dynamic histomorphometry. Vibration training for 8 wks did not alter trabecular morphometry, dynamic histomorphometry, cortical geometry, or mechanical properties (P?0.34). Vibration did not alter any measure of muscle contractile function (P?0.12); however the preservation of muscle function and morphology in mdx mice indicates vibration is not deleterious to muscle lacking dystrophin. Vibrated mice had smaller subcutaneous fat pads (P?=?0.03) and higher intramuscular triglyceride concentrations (P?=?0.03). These data suggest that vibration training at 45 Hz and 0.6 g did not significantly impact the tibial bone and the surrounding musculature, but may influence fat distribution in mice. PMID:25121503
Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging.
Tandon, Animesh; Jefferies, John L; Villa, Chet R; Hor, Kan N; Wong, Brenda L; Ware, Stephanie M; Gao, Zhiqian; Towbin, Jeffrey A; Mazur, Wojciech; Fleck, Robert J; Sticka, Joshua J; Benson, D Woodrow; Taylor, Michael D
Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies. PMID:25702278
Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis
Chartier, Aymeric; Klein, Pierre; Pierson, StÚphanie; Barbezier, Nicolas; Gidaro, Teresa; Casas, Franšois; Carberry, Steven; Dowling, Paul; Maynadier, Laurie; Bellec, MaŰlle; Oloko, Martine; Jardel, Claude; Moritz, Bodo; Dickson, George; Mouly, Vincent; Ohlendieck, Kay; Butler-Browne, Gillian; Trollet, Capucine; Simonelig, Martine
Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction. PMID:25816335
MLPA based detection of mutations in the dystrophin gene of 180 Polish families with Duchenne/Becker muscular dystrophy.
Zimowski, Janusz G; Massalska, Diana; Holding, Mariola; Jadczak, Sylwia; Fidzia?ska, El?bieta; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Kami?ska, Anna; Zaremba, Jacek
Duchenne/Becker muscular dystrophy (DMD/BMD) is a recessive, X-linked disorder caused by a mutation in the dystrophin gene. Deletions account for approximately 60-65% of mutations, duplications for 5-10%. The remaining cases are mainly point mutations. According to Monaco theory clinical form of the disease depends on maintaining or disrupting the reading frame. The purpose of the study was to determine frequency and location of deletions and duplications in the dystrophin gene, to determine the compliance between maintaining/disrupting the reading frame and clinical form of the disease and to check the effectiveness of MLPA (multiplex ligation-dependent probe amplification) in the detection of these mutations in hemizygous patients and heterozygous female carriers. The material is composed of combined results of molecular diagnosis carried out in years 2009-2012 in 180 unrelated patients referred with the diagnosis of DMD/BMD tested by use of MLPA. We identified 110 deletions, 22 duplication (in one patient two different duplications were detected) and 2 point mutations. Deletions involved mainly exons 45-54 and 3-21, whereas most duplications involved exons 3-18. The compliance with Monaco theory was 95% for deletions and 76% for duplications. Most of mutations in the dystrophin gene were localized in the hot spots - different for deletions and duplications. MLPA enabled their quick identification, exact localization and determination whether or not they maintained or disrupted the reading frame. MLPA was also effective in detection of deletions and duplications in female carriers. PMID:25482253
NIM811, a cyclophilin inhibitor without immunosuppressive activity, is beneficial in collagen VI congenital muscular dystrophy models.
Zulian, Alessandra; Rizzo, Erika; Schiavone, Marco; Palma, Elena; Tagliavini, Francesca; Blaauw, Bert; Merlini, Luciano; Maraldi, Nadir Mario; Sabatelli, Patrizia; Braghetta, Paola; Bonaldo, Paolo; Argenton, Francesco; Bernardi, Paolo
Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are inherited muscle diseases due to mutations in the genes encoding the extracellular matrix protein collagen (Col) VI. Opening of the cyclosporin A-sensitive mitochondrial permeability transition pore (PTP) is a causative event in disease pathogenesis, and a potential target for therapy. Here, we have tested the effect of N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclophilin inhibitor, in a zebrafish model of ColVI myopathy obtained by deletion of the N-terminal region of the ColVI ?1 triple helical domain, a common mutation of UCMD. Treatment with antisense morpholino sequences targeting col6a1 exon 9 at the 1-4 cell stage (within 1 h post fertilization, hpf) caused severe ultrastructural and motor abnormalities as assessed by electron and fluorescence microscopy, birefringence, spontaneous coiling events and touch-evoked responses measured at 24-48 hpf. Structural and functional abnormalities were largely prevented when NIM811--which proved significantly more effective than cyclosporin A--was administered at 21 hpf, while FK506 was ineffective. Beneficial effects of NIM811 were also detected (i) in primary muscle-derived cell cultures from UCMD and BM patients, where the typical mitochondrial alterations and depolarizing response to rotenone and oligomycin were significantly reduced; and (ii) in the Col6a1(-/-) myopathic mouse model, where apoptosis was prevented and muscle strength was increased. Since the PTP of zebrafish shares its key regulatory features with the mammalian pore, our results suggest that early treatment with NIM811 should be tested as a potential therapy for UCMD and BM. PMID:24852368
The Dietary Supplement Protandim« Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice
Qureshi, Muhammad Muddasir; McClure, Warren C.; Arevalo, Nicole L.; Rabon, Rick E.; Mohr, Benjamin; Bose, Swapan K.; McCord, Joe M.; Tseng, Brian S.
Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim« is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim« provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim«-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim« chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim«, a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim« group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim«-treated mice. Protandim« increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim« showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim« did not significantly alter motor function nor histological criteria. PMID:20740052
The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice.
Qureshi, Muhammad Muddasir; McClure, Warren C; Arevalo, Nicole L; Rabon, Rick E; Mohr, Benjamin; Bose, Swapan K; McCord, Joe M; Tseng, Brian S
Therapeutic options for Duchenne muscular dystrophy (DMD), the most common and lethal neuromuscular disorder in children, remain elusive. Oxidative damage is implicated as a pertinent factor involved in its pathogenesis. Protandim((R)) is an over-the-counter supplement with the ability to induce antioxidant enzymes. In this study we investigated whether Protandim((R)) provided benefit using surrogate markers and functional measures in the dystrophin-deficient (mdx)mouse model of DMD. Male 3-week-old mdx mice were randomized into two treatment groups: control (receiving standard rodent chow) and Protandim((R))-supplemented standard rodent chow. The diets were continued for 6-week and 6-month studies. The endpoints included the oxidative stress marker thiobarbituric acid-reactive substances (TBARS), plasma osteopontin (OPN), plasma paraoxonase (PON1) activity, H&E histology, gadolinium-enhanced magnetic resonance imaging (MRI) of leg muscle and motor functional measurements. The Protandim((R)) chow diet in mdx mice for 6 months was safe and well tolerated. After 6 months of Protandim((R)), a 48% average decrease in plasma TBARS was seen; 0.92 nmol/mg protein in controls versus 0.48 nmol/mg protein in the Protandim((R)) group (p = .006). At 6 months, plasma OPN was decreased by 57% (p = .001) in the Protandim((R))-treated mice. Protandim((R)) increased the plasma antioxidant enzyme PON1 activity by 35% (p = .018). After 6 months, the mdx mice with Protandim((R)) showed 38% less MRI signal abnormality (p = .07) than mice on control diet. In this 6-month mdx mouse study, Protandim((R)) did not significantly alter motor function nor histological criteria. PMID:20740052
Phase 2a Study of Ataluren-Mediated Dystrophin Production in Patients with Nonsense Mutation Duchenne Muscular Dystrophy
Finkel, Richard S.; Flanigan, Kevin M.; Wong, Brenda; B÷nnemann, Carsten; Sampson, Jacinda; Sweeney, H. Lee; Reha, Allen; Northcutt, Valerie J.; Elfring, Gary; Barth, Jay; Peltz, Stuart W.
Background Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins. Methods This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n?=?6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n?=?20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n?=?12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint. Findings Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated. Interpretation Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD. Trial Registration ClinicalTrials.gov NCT00264888 PMID:24349052
The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy.
Mu, Xiaodong; Tang, Ying; Lu, Aiping; Takayama, Koji; Usas, Arvydas; Wang, Bing; Weiss, Kurt; Huard, Johnny
Although it has been speculated that stem cell depletion plays a role in the rapid progression of the muscle histopathology associated with Duchenne Muscular Dystrophy (DMD), the molecular and cellular mechanisms responsible for stem cell depletion remain poorly understood. The rapid depletion of muscle stem cells has not been observed in the dystrophin-deficient model of DMD (mdx mouse), which may explain the relatively mild dystrophic phenotype observed in this animal model. In contrast, we have observed a rapid occurrence of stem cell depletion in the dystrophin/utrophin double knockout (dKO) mouse model, which exhibits histopathological features that more closely recapitulate the phenotype observed in DMD patients compared with the mdx mouse. Notch signaling has been found to be a key regulator of stem cell self-renewal and myogenesis in normal skeletal muscle; however, little is known about the role that Notch plays in the development of the dystrophic histopathology associated with DMD. Our results revealed an over-activation of Notch in the skeletal muscles of dKO mice, which correlated with sustained inflammation, impaired muscle regeneration and the rapid depletion and senescence of the muscle progenitor cells (MPCs, i.e. Pax7+ cells). Consequently, the repression of Notch in the skeletal muscle of dKO mice delayed/reduced the depletion and senescence of MPCs, and restored the myogenesis capacity while reducing inflammation and fibrosis. We suggest that the down-regulation of Notch could represent a viable approach to reduce the dystrophic histopathologies associated with DMD. PMID:25678553
Retinal telangiectasis detected during a vision screening examination in a child with hearing loss led to the diagnosis of facioscapulohumeral muscular dystrophy.
Lee, Gregory D; Chen, Vicki M; Barnes, Alexander C; Goldman, Darin R; Duker, Jay S
A 2-year-old girl with congenital sensorineural hearing loss was found to have retinal exudation and subretinal fluid in her left eye. Further investigation revealed leaking retinal telangiectasias in her left eye and extensive areas of peripheral retinal nonperfusion in both eyes. A clinical diagnosis of facioscapulohumeral muscular dystrophy (FSHD) was confirmed by genetic testing. The patient was followed with serial intraoperative optical coherence tomography (OCT) scans, which demonstrated subretinal fluid in the macula and its subsequent resolution after treatment. She underwent 6 rounds of panretinal photocoagulation and 2 injections of intravitreal bevacizumab, which resolved the subretinal fluid and exudates. PMID:24924285
Late-Onset Muscle Dystrophy: Oculopharyngoesophageal Variety
Lewis, Irwin
Oculopharyngeal muscular dystrophy is a localized or restricted variety of muscular dystrophy, characterized by bilateral ptosis, myopathic facies, external ophthalmoplegia and dysphagia. A patient with this unusual myopathy is described and detailed esophageal motility studies are presented that provide conclusive evidence of both striated and smooth muscle involvement. Because these unusual localized forms of muscular dystrophy exist and may be of late onset, previous rigid concepts concerning the dystrophies should be discarded. ImagesFig. 1Fig. 5Fig. 6 PMID:5940325
Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy
Chalkiadaki, Angeliki; Igarashi, Masaki; Nasamu, Armiyaw Sebastian; Knezevic, Jovana; Guarente, Leonard
SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1?, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1? targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases. PMID:25032964
14.1 T whole body MRI for detection of mesoangioblast stem cells in a murine model of Duchenne muscular dystrophy.
Odintsov, Boris; Chun, Ju Lan; Mulligan, James A; Berry, Suzanne E
Noninvasive imaging procedures will be important for stem cell therapy for muscular dystrophy (MD). Mesoangioblasts regenerate muscle in animal models of muscular dystrophy. In this study, superparamagnetic iron oxide nanoparticles were used to visualize mesoangioblasts in vivo with MRI. Mesoangioblasts incorporated superparamagnetic iron oxide without transfection reagents, and cell differentiation was not negatively impacted. A custom-built radiofrequency coil with an adjustable field of view and 14.1 T magnet were used for whole-body MRI of mice. High-resolution images of mesoangioblasts in skeletal and cardiac muscle of Mdx mice were obtained following local delivery. Labeled cells were verified by Prussian blue staining and dystrophin expression, indicating that the wild-type mesoangioblasts survived and differentiated in muscle. Iron-labeled cells were detected with MRI in vivo 6 months following intracardiac injection but were determined to be activated macrophages. Iron-labeled cells were not detected by MRI following systemic delivery but were present in skeletal and cardiac muscle, visualized by Prussian blue staining. Systemically delivered mesoangioblasts were detected in lungs by Prussian blue staining and DiI but not by MRI in our study. MRI may be useful for short-term tracking of mesoangioblasts delivered locally but not for long-term monitoring or detection after systemic delivery. PMID:22086733
A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics
Al-Zaidy, Samiah A; Malik, Vinod; Kneile, Kelley; Rosales, Xiomara Q; Gomez, Ana Maria; Lewis, Sarah; Hashimoto, Sayaka; Gastier-Foster, Julie; Kang, Peter; Darras, Basil; Kunkel, Louis; Carlo, Jose; Sahenk, Zarife; Moore, Steven A; Pyatt, Robert; Mendell, Jerry R
Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of ?-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability. PMID:25802879
Long-term engraftment of multipotent mesenchymal stromal cells that differentiate to form myogenic cells in dogs with Duchenne muscular dystrophy.
Nitahara-Kasahara, Yuko; Hayashita-Kinoh, Hiromi; Ohshima-Hosoyama, Sachiko; Okada, Hironori; Wada-Maeda, Michiko; Nakamura, Akinori; Okada, Takashi; Takeda, Shin'ichi
Duchenne muscular dystrophy (DMD) is an incurable genetic disease with early mortality. Multipotent mesenchymal stromal cells (MSCs) are of interest because of their ability to differentiate to form myogenic cells in situ. In the present study, methods were developed to expand cultures of MSCs and to promote the myogenic differentiation of these cells, which were then used in a new approach for the treatment of DMD. MSC cultures enriched in CD271(+) cells grew better than CD271-depleted cultures. The transduction of CD271(+) MSCs with MyoD caused myogenic differentiation in vitro and the formation of myotubes expressing late myogenic markers. CD271(+) MSCs in the myogenic cell lineage transplanted into dog leukocyte antigen (DLA)-identical dogs formed clusters of muscle-like tissue. Intra-arterial injection of the CD271(+) MSCs resulted in engraftment at the site of the cardiotoxin (CTX)-injured muscle. Dogs affected by X-linked muscular dystrophy in Japan (CXMD(J)) treated with an intramuscular injection of CD271(+) MSCs similarly developed muscle-like tissue within 8-12 weeks in the absence of immunosuppression. In the newly formed tissues, developmental myosin heavy chain (dMyHC) and dystrophin were upregulated. These findings demonstrate that a cell transplantation strategy using CD271(+) MSCs may offer a promising treatment approach for patients with DMD. PMID:21934652
McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W
Introduction: An international clinical trial enrolled 174 ambulatory males ?5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rateľdetermined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357ľ368, 2013 PMID:23674289
Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy
Lin, Bo; Li, Yang; Han, Lu; Kaplan, Aaron D.; Ao, Ying; Kalra, Spandan; Bett, Glenna C. L.; Rasmusson, Randall L.; Denning, Chris; Yang, Lei
ABSTRACT Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca2+, mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca2+ level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients. PMID:25791035
Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.
Meilleur, Katherine G; Jain, Minal S; Hynan, Linda S; Shieh, Ching-Yi; Kim, Eunice; Waite, Melissa; McGuire, Michelle; Fiorini, Courtney; Glanzman, Allan M; Main, Marion; Rose, Kristy; Duong, Tina; Bendixen, Roxanna; Linton, Melody M; Arveson, Irene C; Nichols, Carmel; Yang, Kelly; Fischbeck, Kenneth H; Wagner, Kathryn R; North, Kathryn; Mankodi, Ami; Grunseich, Christopher; Hartnett, Elizabeth J; Smith, Michaele; Donkervoort, Sandra; Schindler, Alice; Kokkinis, Angela; Leach, Meganne; Foley, A Reghan; Collins, James; Muntoni, Francesco; Rutkowski, Anne; B÷nnemann, Carsten G
Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes. PMID:25307854
Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: Local or systemic?
Kerkis, Irina; Ambrosio, Carlos E; Kerkis, Alexandre; Martins, Daniele S; Zucconi, Eder; Fonseca, Simone AS; Cabral, Rosa M; Maranduba, Carlos MC; Gaiad, Thais P; Morini, Adriana C; Vieira, Natassia M; Brolio, Marina P; Sant'Anna, Osvaldo A; Miglino, Maria A; Zatz, Mayana
Background The golden retriever muscular dystrophy (GRMD) dogs represent the best available animal model for therapeutic trials aiming at the future treatment of human Duchenne muscular dystrophy (DMD). We have obtained a rare litter of six GRMD dogs (3 males and 3 females) born from an affected male and a carrier female which were submitted to a therapeutic trial with adult human stem cells to investigate their capacity to engraft into dogs muscles by local as compared to systemic injection without any immunosuppression. Methods Human Immature Dental Pulp Stem Cells (hIDPSC) were transplanted into 4 littermate dogs aged 28 to 40 days by either arterial or muscular injections. Two non-injected dogs were kept as controls. Clinical translation effects were analyzed since immune reactions by blood exams and physical scores capacity of each dog. Samples from biopsies were checked by immunohistochemistry (dystrophin markers) and FISH for human probes. Results and Discussion We analyzed the cells' ability in respect to migrate, engraftment, and myogenic potential, and the expression of human dystrophin in affected muscles. Additionally, the efficiency of single and consecutive early transplantation was compared. Chimeric muscle fibers were detected by immunofluorescence and fluorescent in situ hybridisation (FISH) using human antibodies and X and Y DNA probes. No signs of immune rejection were observed and these results suggested that hIDPSC cell transplantation may be done without immunosuppression. We showed that hIDPSC presented significant engraftment in GRMD dog muscles, although human dystrophin expression was modest and limited to several muscle fibers. Better clinical condition was also observed in the dog, which received monthly arterial injections and is still clinically stable at 25 months of age. Conclusion Our data suggested that systemic multiple deliveries seemed more effective than local injections. These findings open important avenues for further researches. PMID:18598348
Alternative isoform regulation in myotonic dystrophy
Wang, Eric T. (Eric Tzy-shi)
Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, affecting more than 1 in 8000 individuals globally. The symptoms of DM are multi-systemic and include myotonia, severe muscle wasting, ...
Optical coherence tomography can assess skeletal muscle tissue from mouse models of muscular dystrophy by parametric imaging of the attenuation coefficient
Klyen, Blake R.; Scolaro, Loretta; Shavlakadze, Tea; Grounds, Miranda D.; Sampson, David D.
We present the assessment of ex vivo mouse muscle tissue by quantitative parametric imaging of the near-infrared attenuation coefficient Át using optical coherence tomography. The resulting values of the local total attenuation coefficient Át (mean ▒ standard error) from necrotic lesions in the dystrophic skeletal muscle tissue of mdx mice are higher (9.6 ▒ 0.3 mm?1) than regions from the same tissue containing only necrotic myofibers (7.0 ▒ 0.6 mm?1), and significantly higher than values from intact myofibers, whether from an adjacent region of the same sample (4.8 ▒ 0.3 mm?1) or from healthy tissue of the wild-type C57 mouse (3.9 ▒ 0.2 mm?1) used as a control. Our results suggest that the attenuation coefficient could be used as a quantitative means to identify necrotic lesions and assess skeletal muscle tissue in mouse models of human Duchenne muscular dystrophy. PMID:24761302
A Sensitive, Reproducible and Objective Immunofluorescence Analysis Method of Dystrophin in Individual Fibers in Samples from Patients with Duchenne Muscular Dystrophy
Beekman, Chantal; Sipkens, Jessica A.; Testerink, Janwillem; Giannakopoulos, Stavros; Kreuger, Dyonne; van Deutekom, Judith C.; Campion, Giles V.; de Kimpe, Sjef J.; Lourbakos, Afrodite
Duchenne muscular dystrophy (DMD) is characterized by the absence or reduced levels of dystrophin expression on the inner surface of the sarcolemmal membrane of muscle fibers. Clinical development of therapeutic approaches aiming to increase dystrophin levels requires sensitive and reproducible measurement of differences in dystrophin expression in muscle biopsies of treated patients with DMD. This, however, poses a technical challenge due to intra- and inter-donor variance in the occurrence of revertant fibers and low trace dystrophin expression throughout the biopsies. We have developed an immunofluorescence and semi-automated image analysis method that measures the sarcolemmal dystrophin intensity per individual fiber for the entire fiber population in a muscle biopsy. Cross-sections of muscle co-stained for dystrophin and spectrin have been imaged by confocal microscopy, and image analysis was performed using Definiens software. Dystrophin intensity has been measured in the sarcolemmal mask of spectrin for each individual muscle fiber and multiple membrane intensity parameters (mean, maximum, quantiles per fiber) were calculated. A histogram can depict the distribution of dystrophin intensities for the fiber population in the biopsy. This method was tested by measuring dystrophin in DMD, Becker muscular dystrophy, and healthy muscle samples. Analysis of duplicate or quadruplicate sections of DMD biopsies on the same or multiple days, by different operators, or using different antibodies, was shown to be objective and reproducible (inter-assay precision, CV 2ľ17% and intra-assay precision, CV 2ľ10%). Moreover, the method was sufficiently sensitive to detect consistently small differences in dystrophin between two biopsies from a patient with DMD before and after treatment with an investigational compound. PMID:25244123
A sensitive, reproducible and objective immunofluorescence analysis method of dystrophin in individual fibers in samples from patients with duchenne muscular dystrophy.
Beekman, Chantal; Sipkens, Jessica A; Testerink, Janwillem; Giannakopoulos, Stavros; Kreuger, Dyonne; van Deutekom, Judith C; Campion, Giles V; de Kimpe, Sjef J; Lourbakos, Afrodite
Duchenne muscular dystrophy (DMD) is characterized by the absence or reduced levels of dystrophin expression on the inner surface of the sarcolemmal membrane of muscle fibers. Clinical development of therapeutic approaches aiming to increase dystrophin levels requires sensitive and reproducible measurement of differences in dystrophin expression in muscle biopsies of treated patients with DMD. This, however, poses a technical challenge due to intra- and inter-donor variance in the occurrence of revertant fibers and low trace dystrophin expression throughout the biopsies. We have developed an immunofluorescence and semi-automated image analysis method that measures the sarcolemmal dystrophin intensity per individual fiber for the entire fiber population in a muscle biopsy. Cross-sections of muscle co-stained for dystrophin and spectrin have been imaged by confocal microscopy, and image analysis was performed using Definiens software. Dystrophin intensity has been measured in the sarcolemmal mask of spectrin for each individual muscle fiber and multiple membrane intensity parameters (mean, maximum, quantiles per fiber) were calculated. A histogram can depict the distribution of dystrophin intensities for the fiber population in the biopsy. This method was tested by measuring dystrophin in DMD, Becker muscular dystrophy, and healthy muscle samples. Analysis of duplicate or quadruplicate sections of DMD biopsies on the same or multiple days, by different operators, or using different antibodies, was shown to be objective and reproducible (inter-assay precision, CV 2-17% and intra-assay precision, CV 2-10%). Moreover, the method was sufficiently sensitive to detect consistently small differences in dystrophin between two biopsies from a patient with DMD before and after treatment with an investigational compound. PMID:25244123
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the ?M?2 leukocyte integrin receptor
Vidal, Berta; Ardite, Esther; Suelves, M˛nica; Ruiz-Bonilla, Vanessa; JanuÚ, Anna; Flick, Matthew J.; Degen, Jay L.; Serrano, Antonio L.; Mu˝oz-Cßnoves, Pura
In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin ?M?2-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fib?390-396A) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the ?M?2 binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/?M?2 blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-?M?2 interactions may provide a novel strategy for DMD treatment. PMID:22381526
... it is the second leading cause of hereditary neuromuscular disease, after Duchenne muscular dystrophy . Most of the ... out if there is: A family history of neuromuscular disease Floppy (flaccid) muscles No deep tendon reflexes ...
Genetics of laminin ?2 chain (or merosin) deficient congenital muscular dystrophy: from identification of mutations to prenatal diagnosis
Pascale Guicheney; Nicolas Vignier; Anne Helbling-Leclerc; Marja Nissinen; Xu Zhang; Corrinne Cruaud; Jean-Claude Lambert; Christian Richelme; Haluk Topaloglu; Luciano Merlini; Annie Barois; Ketty Schwartz; Fernando M. S. TomÚ; Karl Tryggvason; Michel Fardeau
Congenital muscular dystropies (CMD) are a clinically and genetically heterogeneous group of muscle disorders, with autosomal recessive inheritance. Absence of the laminin ?2 chain in the skeletal muscle of patients with classical CMD has permitted the identification of a subgroup, referred to as Ĺmerosin-deficient CMD or laminin ?2 chain deficient CMDĺ. We first identified a nonsense and a splice site
A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene
Paris-Sud XI, UniversitÚ de
A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular. This article is published with open access at Springerlink.com Abstract Autism spectrum disorder is a genetically com- plex and clinically heterogeneous neurodevelopmental disorder. A recent study by the Autism
Correction of Dystrophin Expression in Cells From Duchenne Muscular Dystrophy Patients Through Genomic Excision of Exon 51 by Zinc Finger Nucleases
Ousterout, David G; Kabadi, Ami M; Thakore, Pratiksha I; Perez-Pinera, Pablo; Brown, Matthew T; Majoros, William H; Reddy, Timothy E; Gersbach, Charles A
Duchenne muscular dystrophy (DMD) is caused by genetic mutations that result in the absence of dystrophin protein expression. Oligonucleotide-induced exon skipping can restore the dystrophin reading frame and protein production. However, this requires continuous drug administration and may not generate complete skipping of the targeted exon. In this study, we apply genome editing with zinc finger nucleases (ZFNs) to permanently remove essential splicing sequences in exon 51 of the dystrophin gene and thereby exclude exon 51 from the resulting dystrophin transcript. This approach can restore the dystrophin reading frame in ~13% of DMD patient mutations. Transfection of two ZFNs targeted to sites flanking the exon 51 splice acceptor into DMD patient myoblasts led to deletion of this genomic sequence. A clonal population was isolated with this deletion and following differentiation we confirmed loss of exon 51 from the dystrophin mRNA transcript and restoration of dystrophin protein expression. Furthermore, transplantation of corrected cells into immunodeficient mice resulted in human dystrophin expression localized to the sarcolemmal membrane. Finally, we quantified ZFN toxicity in human cells and mutagenesis at predicted off-target sites. This study demonstrates a powerful method to restore the dystrophin reading frame and protein expression by permanently deleting exons. PMID:25492562
Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort.
GutiÚrrez-Rivas, E; Bautista, J; VÝlchez, J J; Muelas, N; DÝaz-Manera, J; Illa, I; MartÝnez-Arroyo, A; OlivÚ, M; Sanz, I; Arpa, J; Fernßndez-Torrˇn, R; Lˇpez de Munßin, A; JimÚnez, L; Solera, J; Lukacs, Z
We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DBS) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fluorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and in 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T?>?G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis. PMID:25998610
Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements
Vohra, Ravneet S.; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C.; Sweeney, H. Lee; Walter, Glenn A.; Vandenborne, Krista
Introduction The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Methods Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Results Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Discussion Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD. PMID:26103164
Nucleocytoplasmic shuttling of the Duchenne muscular dystrophy gene product dystrophin Dp71d is dependent on the importin ?/? and CRM1 nuclear transporters and microtubule motor dynein.
Sußrez-Sßnchez, R; Aguilar, A; Wagstaff, K M; Velez, G; Azuara-Medina, P M; Gomez, P; Vßsquez-Limeta, A; Hernßndez-Hernßndez, O; Lieu, K G; Jans, D A; Cisneros, B
Even though the Duchenne muscular dystrophy (DMD) gene product Dystrophin Dp71d is involved in various key cellular processes through its role as a scaffold for structural and signalling proteins at the plasma membrane as well as the nuclear envelope, its subcellular trafficking is poorly understood. Here we map the nuclear import and export signals of Dp71d by truncation and point mutant analysis, showing for the first time that Dp71d shuttles between the nucleus and cytoplasm mediated by the conventional nuclear transporters, importin (IMP) ?/? and the exportin CRM1. Binding was confirmed in cells using pull-downs, while in vitro binding assays showed direct, high affinity (apparent dissociation coefficient of c. 0.25nM) binding of Dp71d to IMP?/?. Interestingly, treatment of cells with the microtubule depolymerizing reagent nocodazole or the dynein inhibitor EHNA both decreased Dp71d nuclear localization, implying that Dp71d nuclear import may be facilitated by microtubules and the motor protein dynein. The role of Dp71d in the nucleus appears to relate in part to interaction with the nuclear envelope protein emerin, and maintenance of the integrity of the nuclear architecture. The clear implication is that Dp71d's previously unrecognised nuclear transport properties likely contribute to various, important physiological roles. PMID:24486332
Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9.
Li, Hongmei Lisa; Fujimoto, Naoko; Sasakawa, Noriko; Shirai, Saya; Ohkame, Tokiko; Sakuma, Tetsushi; Tanaka, Michihiro; Amano, Naoki; Watanabe, Akira; Sakurai, Hidetoshi; Yamamoto, Takashi; Yamanaka, Shinya; Hotta, Akitsu
Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach. We further investigated the genomic integrity by karyotyping, copy number variation array, and exome sequencing to identify clones with a minimal mutation load. Finally, we differentiated the corrected iPSCs toward skeletal muscle cells and successfully detected the expression of full-length dystrophin protein. These results provide an important framework for developing iPSC-based gene therapy for genetic disorders using programmable nucleases. PMID:25434822
Mcdonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine M; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart
Introduction: Duchenne muscular dystrophy (DMD) subjects ?5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Results: Baseline age (?7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (?6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. Conclusion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. PMID:23681930
Systemic Delivery of Allogenic Muscle Stem Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs
Rouger, Karl; Larcher, Thibaut; Dubreil, Laurence; Deschamps, Jack-Yves; Le Guiner, Caroline; Jouvion, Gregory; Delorme, Bruno; Lieubeau, Blandine; Carlus, Marine; Fornasari, Benoţt; Theret, Marine; Orlando, Priscilla; Ledevin, Mireille; Zuber, CÚline; Leroux, Isabelle; Deleau, StÚphane; Guigand, Lydie; Testault, Isabelle; Le Rumeur, Elisabeth; Fiszman, Marc; ChÚrel, Yan
Duchenne muscular dystrophy (DMD) is a genetic progressive muscle disease resulting from the lack of dystrophin and without effective treatment. Adult stem cell populations have given new impetus to cell-based therapy of neuromuscular diseases. One of them, muscle-derived stem cells, isolated based on delayed adhesion properties, contributes to injured muscle repair. However, these data were collected in dystrophic mice that exhibit a relatively mild tissue phenotype and clinical features of DMD patients. Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog's clinical status. These results demonstrate that MuStem cells could provide an attractive therapeutic avenue for DMD patients. PMID:21924229
Intra-amniotic rAAV-mediated microdystrophin gene transfer improves canine X-linked muscular dystrophy and may induce immune tolerance.
Hayashita-Kinoh, Hiromi; Yugeta, Naoko; Okada, Hironori; Nitahara-Kasahara, Yuko; Chiyo, Tomoko; Okada, Takashi; Takeda, Shin'ichi
Duchenne muscular dystrophy (DMD) is a severe congenital disease due to mutations in the dystrophin gene. Supplementation of dystrophin using recombinant adenoassociated virus vector has promise as a treatment of DMD, although therapeutic benefit of the truncated dystrophin still remains to be elucidated. Besides, host immune responses against the vector as well as transgene products have been denoted in the clinical gene therapy studies. Here, we transduced dystrophic dogs fetuses to investigate the therapeutic effects of an AAV vector expressing microdystrophin under conditions of immune tolerance. rAAV-CMV-microdystrophin and a rAAV-CAG-luciferase were injected into the amniotic fluid surrounding fetuses. We also reinjected rAAV9-CMV-microdystrophin into the jugular vein of an infant dystrophic dog to induce systemic expression of microdystrophin. Gait and cardiac function significantly improved in the rAAV-microdystrophin-injected dystrophic dog, suggesting that an adequate treatment of rAAV-microdystrophin with immune modulation induces successful long-term transgene expression to analyze improved dystrophic phenotype. PMID:25586688
Characterization of 65 Epitope-Specific Dystrophin Monoclonal Antibodies in Canine and Murine Models of Duchenne Muscular Dystrophy by Immunostaining and Western Blot
Shin, Jin-Hong; Yue, Yongping; Morris, Glenn E.; McIntosh, Mark A.; Duan, Dongsheng
Epitope-specific monoclonal antibodies can provide unique insights for studying cellular proteins. Dystrophin is one of the largest cytoskeleton proteins encoded by 79 exons. The absence of dystrophin results in Duchenne muscular dystrophy (DMD). Over the last two decades, dozens of exon-specific human dystrophin monoclonal antibodies have been developed and successfully used for DMD diagnosis. Unfortunately, the majority of these antibodies have not been thoroughly characterized in dystrophin-deficient dogs, an outstanding large animal model for translational research. To fill the gap, we performed a comprehensive study on 65 dystrophin monoclonal antibodies in normal and dystrophic dogs (heart and skeletal muscle) by immunofluorescence staining and western blot. For comparison, we also included striated muscles from normal BL10 and dystrophin-null mdx mice. Our analysis revealed distinctive species, tissue and assay-dependent recognition patterns of different antibodies. Importantly, we identified 15 antibodies that can consistently detect full-length canine dystrophin in both immunostaining and western blot. Our results will serve as an important reference for studying DMD in the canine model. PMID:24516626
Characterization of 65 epitope-specific dystrophin monoclonal antibodies in canine and murine models of duchenne muscular dystrophy by immunostaining and western blot.
Kodippili, Kasun; Vince, Lauren; Shin, Jin-Hong; Yue, Yongping; Morris, Glenn E; McIntosh, Mark A; Duan, Dongsheng
Epitope-specific monoclonal antibodies can provide unique insights for studying cellular proteins. Dystrophin is one of the largest cytoskeleton proteins encoded by 79 exons. The absence of dystrophin results in Duchenne muscular dystrophy (DMD). Over the last two decades, dozens of exon-specific human dystrophin monoclonal antibodies have been developed and successfully used for DMD diagnosis. Unfortunately, the majority of these antibodies have not been thoroughly characterized in dystrophin-deficient dogs, an outstanding large animal model for translational research. To fill the gap, we performed a comprehensive study on 65 dystrophin monoclonal antibodies in normal and dystrophic dogs (heart and skeletal muscle) by immunofluorescence staining and western blot. For comparison, we also included striated muscles from normal BL10 and dystrophin-null mdx mice. Our analysis revealed distinctive species, tissue and assay-dependent recognition patterns of different antibodies. Importantly, we identified 15 antibodies that can consistently detect full-length canine dystrophin in both immunostaining and western blot. Our results will serve as an important reference for studying DMD in the canine model. PMID:24516626
A 230kb cosmid walk in the Duchenne muscular dystrophy gene: detection of a conserved sequence and of a possible deletion prone region.
Heilig, R; Lemaire, C; Mandel, J L
A 230 kb genomic region from the Duchenne muscular dystrophy gene has been cloned in a cosmid walk, using an improved vector and by screening the same unamplified library for all steps. The region cloned surrounds the translocation breakpoint characterized by Worton et al and Ray et al, and overlaps by 70 kb the Pert region cloned by Monaco et al. We have identified a region of strong sequence conservation in mammals and chicken, and comparison of the homologous sequences in chicken and man has indicated the presence of two putative protein coding exons. Comparison with the sequence recently published by Koenig et al shows that only one is present in the Duchenne cDNA, and this raises the question of the functional significance of the other conserved sequence. Single copy probes and whole cosmids generated during this work have been used to analyse the corresponding region in Duchenne patients. Of five independant patients shown to be deleted for a probe 30 kb in 3' of the translocation breakpoint, three have the 5' endpoint of the deletion within a region of less than 20 kb, 100 kb away from the probe used to ascertain the deletion. This might suggest the presence of a region where deletions occur preferentially. PMID:2825128
Facioscapulohumeral dystrophy and scapuloperoneal syndromes
Richard W. Orrell
Facioscapulohumeral dystrophy (FSHD) is the third most common muscular dystrophy. It is named for its characteristic involvement of the muscles of the face and upper arm. It is present worldwide, with a prevalence of around 4 per 100000 and an incidence of about 1 in 20000. Overall lifespan is not affected significantly. The scapuloperoneal syndrome is a rarer presentation that
Squarzoni, S; Sabatelli, P; Capanni, C; Petrini, S; Ognibene, A; Toniolo, D; Cobianchi, F; Zauli, G; Bassini, A; Baracca, A; Guarnieri, C; Merlini, L; Maraldi, N M
Emerin is an almost ubiquitous protein which is abnormal in X-linked Emery-Dreifuss muscular dystrophy (EMD), a syndrome characterized by muscle weakness, joint contractures and cardiac arrhythmia. Emerin is localized in the cells at the nuclear rim and its function is still unknown. In some models, emerin has also been described in the cytoplasm; however, its presence outside the nucleus is still matter of debate. We report the presence of emerin in circulating normal human platelets and its absence in platelets from X-linked EMD patients. Since platelets are cytoplasmic fragments derived from megakaryocytes, the presence of emerin in platelets confirms cytoplasmic localization of this protein, probably related to specific functions. We found also that emerin is present in the cytoplasm of megakaryocytes, while it is absent in circulating granulocytes. PMID:10965799
Emerin Caps the Pointed End of Actin Filaments: Evidence for an Actin Cortical Network at the Nuclear Inner Membrane
X-linked Emery-Dreifuss muscular dystrophy is caused by loss of emerin, a LEM-domain protein of the nuclear inner membrane. To better understand emerin function, we used affinity chromatography to purify emerin-binding proteins from nuclear extracts of HeLa cells. Complexes that included actin, ?II-spectrin and additional proteins, bound specifically to emerin. Actin polymerization assays in the presence or absence of gelsolin or capping protein showed that emerin binds and stabilizes the pointed end of actin filaments, increasing the actin polymerization rate 4- to 12-fold. We propose that emerin contributes to the formation of an actin-based cortical network at the nuclear inner membrane, conceptually analogous to the actin cortical network at the plasma membrane. Thus, in addition to disrupting transcription factors that bind emerin, loss of emerin may destabilize nuclear envelope architecture by weakening a nuclear actin network. PMID:15328537
MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice.
Wu, Rimao; Li, Hu; Zhai, Lili; Zou, Xiaoting; Meng, Jiao; Zhong, Ran; Li, Changyin; Wang, Haixia; Zhang, Yong; Zhu, Dahai
Skeletal muscle stem cells, called satellite cells, are a quiescent heterogeneous population. Their heterogeneity is influenced by Pax7, a well-defined transcriptional regulator of satellite cell functions that defines two subpopulations: Pax7(Hi) and Pax7(Lo). However, the mechanisms by which these subpopulations are established and maintained during myogenesis are not completely understood. Here we show that miR-431, which is predominantly expressed in the skeletal muscle, mediates satellite cell heterogeneity by fine-tuning Pax7 levels during muscle development and regeneration. In miR-431 transgenic mice, the Pax7(Lo) subpopulation is enriched, enhances myogenic differentiation and accelerates muscle regeneration. Notably, miR-431 attenuates the muscular dystrophic phenotype in mdx mice and may be a potential therapeutic target in muscular diseases. miR-431 transgenic mice are a unique genetic model for investigating the cellular features and biological functions of Pax7(Lo) satellite cells during muscle development and regeneration. PMID:26151913
Incidence and risk factors for post-operative complications after scoliosis surgery in patients with Duchenne muscular dystrophy : a comparison with other neuromuscular conditions.
Duckworth, A D; Mitchell, M J; Tsirikos, A I
We report the incidence of and risk factors for complications after scoliosis surgery in patients with Duchenne muscular dystrophy (DMD) and compare them with those of other neuromuscular conditions. We identified 110 (64 males, 46 females) consecutive patients with a neuromuscular disorder who underwent correction of the scoliosis at a mean age of 14 years (7 to 19) and had a minimum two-year follow-up. We recorded demographic and peri-operative data, including complications and re-operations. There were 60 patients with cerebral palsy (54.5%) and 26 with DMD (23.6%). The overall complication rate was 22% (24 patients), the most common of which were deep wound infection (9, 8.1%), gastrointestinal complications (5, 4.5%) and hepatotoxicity (4, 3.6%). The complication rate was higher in patients with DMD (10/26, 38.5%) than in those with other neuromuscular conditions (14/84, 16.7% (p = 0.019). All hepatotoxicity occurred in patients with DMD (p = 0.003), who also had an increased rate of deep wound infection (19% vs 5%) (p = 0.033). In the DMD group, no peri-operative factors were significantly associated with the rate of overall complications or deep wound infection. Increased intra-operative blood loss was associated with hepatotoxicity (p = 0.036). In our series, correction of a neuromuscular scoliosis had an acceptable rate of complications: patients with DMD had an increased overall rate compared with those with other neuromuscular conditions. These included deep wound infection and hepatotoxicity. Hepatotoxicity was unique to DMD patients, and we recommend peri-operative vigilance after correction of a scoliosis in this group. PMID:24986949
Distinct roles of TRAF6 at early and late stages of muscle pathology in the mdx model of Duchenne muscular dystrophy.
Hindi, Sajedah M; Sato, Shuichi; Choi, Yongwon; Kumar, Ashok
Duchenne muscular dystrophy (DMD) is a lethal genetic disorder caused by loss of functional dystrophin protein. Accumulating evidence suggests that the deficiency of dystrophin leads to aberrant activation of many signaling pathways which contribute to disease progression. However, the proximal signaling events leading to the activation of various pathological cascades in dystrophic muscle remain less clear. TNF receptor-associated factor 6 (TRAF6) is an adaptor protein which acts as a signaling intermediate for several receptor-mediated signaling events leading to the context-dependent activation of a number of signaling pathways. TRAF6 is also an E3 ubiquitin ligase and an important regulator of autophagy. However, the role of TRAF6 in pathogenesis of DMD remains unknown. Here, we demonstrate that the levels and activity of TRAF6 are increased in skeletal muscle of mdx (a mouse model of DMD) mice. Targeted deletion of TRAF6 improves muscle strength and reduces fiber necrosis, infiltration of macrophages and the activation of proinflammatory transcription factor nuclear factor-kappa B (NF-?B) in 7-week-old mdx mice. Ablation of TRAF6 also increases satellite cells proliferation and myofiber regeneration in young mdx mice. Intriguingly, ablation of TRAF6 exacerbates muscle injury and increases fibrosis in 9-month-old mdx mice. TRAF6 inhibition reduces the markers of autophagy and Akt signaling in dystrophic muscle of mdx mice. Collectively, our study suggests that while the inhibition of TRAF6 improves muscle structure and function in young mdx mice, its continued inhibition causes more severe myopathy at later stages of disease progression potentially through repressing autophagy. PMID:24163132
Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy.
Janssen, Paul M L; Murray, Jason D; Schill, Kevin E; Rastogi, Neha; Schultz, Eric J; Tran, Tam; Raman, Subha V; Rafael-Fortney, Jill A
Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology. PMID:24551095
Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy
Asai, Akihiro; Sahani, Nita; Kaneki, Masao; Ouchi, Yasuyoshi; Martyn, J.A. Jeevendra; Yasuhara, Shingo Egusa
Background Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage. Methodology/Principal Findings In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a ôtwo-hitö mechanism in the pathogenesis of this disease. Conclusions/Significance Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the ôtwo-hitö mechanism in this disease was documented. Significantly, the vasoactive drug tadalafil, a phosphodiesterase 5 inhibitor, administered to mdx mice ameliorated muscle damage. PMID:17726536
Online Self-Report Data for Duchenne Muscular Dystrophy Confirms Natural History and Can Be Used to Assess for Therapeutic Benefits
Wang, Richard T.; Silverstein Fadlon, Cheri A.; Ulm, J. Wes; Jankovic, Ivana; Eskin, Ascia; Lu, Ake; Rangel Miller, Vanessa; Cantor, Rita M.; Li, Ning; Elashoff, Robert; Martin, Anne S.; Peay, Holly L.; Halnon, Nancy; Nelson, Stanley F.
To assess the utility of online patient self-report outcomes in a rare disease, we attempted to observe the effects of corticosteroids in delaying age at fulltime wheelchair use in Duchenne muscular dystrophy (DMD) using data from 1,057 males from DuchenneConnect, an online registry. Data collected were compared to prior natural history data in regard to age at diagnosis, mutation spectrum, and age at loss of ambulation. Because registrants reported differences in steroid and other medication usage, as well as age and ambulation status, we could explore these data for correlations with age at loss of ambulation. Using multivariate analysis, current steroid usage was the most significant and largest independent predictor of improved wheelchair-free survival. Thus, these online self-report data were sufficient to retrospectively observe that current steroid use by patients with DMD is associated with a delay in loss of ambulation. Comparing commonly used steroid drugs, deflazacort prolonged ambulation longer than prednisone (median 14 years and 13 years, respectively). Further, use of Vitamin D and Coenzyme Q10, insurance status, and age at diagnosis after 4 years were also significant, but smaller, independent predictors of longer wheelchair-free survival. Nine other common supplements were also individually tested but had lower study power. This study demonstrates the utility of DuchenneConnect data to observe therapeutic differences, and highlights needs for improvement in quality and quantity of patient-report data, which may allow exploration of drug/therapeutic practice combinations impractical to study in clinical trial settings. Further, with the low barrier to participation, we anticipate substantial growth in the dataset in the coming years. PMID:25635234
Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes.
Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai; Hu, Ji-Wei; Ouyang, Pin
Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity. PMID:24309110
A novel point mutation (G-1 to T) in a 5' splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker muscular dystrophy.
Hagiwara, Y.; Nishio, H.; Kitoh, Y.; Takeshima, Y.; Narita, N.; Wada, H.; Yokoyama, M.; Nakamura, H.; Matsuo, M.
The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. We now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5' splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5' splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G-1-to-T mutation at the 5' splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. Images Figure 2 Figure 5 PMID:8279470
Immunocytochemical detection of emerin within the nuclear matrix
S Squarzoni; P Sabatelli; A Ognibene; D Toniolo; L Cartegni; F Cobianchi; S Petrini; L Merlini; N. M Maraldi
Emerin, the protein whose production is altered in the X-linked form of EmeryľDreifuss muscular distrophy, has been hypothesized to be associated with the nuclear matrix on the basis of biochemical studies. In addition, immunocytochemical data reported its localization at the nuclear periphery, on the nuclear lamina, in sections of several normal tissues. We investigated the association of emerin with the
Duchenne and Becker Muscular Dystrophies
... for DMD or BMD. (See page 7.) Braces, standing frames and wheelchairs Braces, also called orthoses , support the ankle and ... to stand. Some wheelchairs will tilt into a standing position. Sooner or later, all boys with DMD need wheelchairs. Many at first use wheelchairs at school or ...
Learning about Duchenne Muscular Dystrophy
... age 12, most boys are confined to a wheelchair. Bones develop abnormally, causing skeletal deformities of the ... described below) . If untreated, the affected boys become wheelchair dependent before age 13 years. A muscle biopsy ( ...
Muscular Dystrophy: Hope Through Research
... without support, and some affected children may never learn to walk. There are three groups of congenital ... of contractures. Individuals with a weakened diaphragm can learn coughing and deep breathing exercises that are designed ...
Relationship between the climbing up and climbing down stairs domain scores on the FES-DMD, the score on the Vignos Scale, age and timed performance of functional activities in boys with Duchenne muscular dystrophy
Fernandes, Lilian A. Y.; Caromano, Fßtima A.; Assis, Silvana M. B.; Hukuda, Michele E.; Voos, Mariana C.; Carvalho, Eduardo V.
BACKGROUND: Knowing the potential for and limitations of information generated using different evaluation instruments favors the development of more accurate functional diagnoses and therapeutic decision-making. OBJECTIVE: To investigate the relationship between the number of compensatory movements when climbing up and going down stairs, age, functional classification and time taken to perform a tested activity (TA) of going up and down stairs in boys with Duchenne muscular dystrophy (DMD). METHOD: A bank of movies featuring 30 boys with DMD performing functional activities was evaluated. Compensatory movements were assessed using the climbing up and going down stairs domain of the Functional Evaluation Scale for Duchenne Muscular Dystrophy (FES-DMD); age in years; functional classification using the Vignos Scale (VS), and TA using a timer. Statistical analyses were performed using the Spearman correlation test. RESULTS: There is a moderate relationship between the climbing up stairs domain of the FES-DMD and age (r=0.53, p=0.004) and strong relationships with VS (r=0.72, p=0.001) and TA for this task (r=0.83, p<0.001). There were weak relationships between the going down stairs domain of the FES-DMD-going down stairs with age (r=0.40, p=0.032), VS (r=0.65, p=0.002) and TA for this task (r=0.40, p=0.034). CONCLUSION: These findings indicate that the evaluation of compensatory movements used when climbing up stairs can provide more relevant information about the evolution of the disease, although the activity of going down stairs should be investigated, with the aim of enriching guidance and strengthening accident prevention. Data from the FES-DMD, age, VS and TA can be used in a complementary way to formulate functional diagnoses. Longitudinal studies and with broader age groups may supplement this information. PMID:25590443
Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy.
Nik-Ahd, Farnoosh; Bertoni, Carmen
Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. PMID:24753122
Pulsed-field gel electrophoresis of the D4F104S1 locus reveals the size and the parental origin of the facioscapulohumeral muscular dystrophy (FSHD)-associated deletions
Wijmenga, C.; Deutekom, J.C.T. van; Padberg, G.W.; Van Ommen, G.J.B.; Hofker, M.H.; Frants, R.R. (Leiden Univ. (Netherlands)); Hewitt, J.E. (Univ. of Manchester (United Kingdom))
Recently, probe p13E-11 (D4F104S1) was shown to identify de novo DNA rearrangements, which are associated with the development of facioscapulohumeral muscular dystrophy (FSHD). These rearrangements are likely to become instrumental in cloning the FSHD gene itself. Analysis by pulsed-field gel electrophoresis demonstrates that p13E-11 recognizes two highly polymorphic loci, with HindIII restriction fragments ranging in size from about 30 to 320 kb. Haplotype analysis unambiguously assigned one of the two loci to chromosome 4q35. The detection of identical NotI or NruI fragments with both CEB8 (D4F35S1) and p13E-11 demonstrated that the DNA rearrangements are deletions that are restricted to the HindIII fragments detectable by p13E-11. In two cases, the sizes of the deletion could be established and were found to be 25 and 85 kb in length, respectively. So far, the authors have been able to define the parental origin of the mutation in seven different patients and have found that in five cases the maternal allele was involved. 22 refs., 4 figs., 1 tab.
Muscle-specific expression of insulin-like growth factor 1 improves outcome in Lama2Dy-w mice, a model for congenital muscular dystrophy type 1A
Kumar, Ajay; Yamauchi, Jenny; Girgenrath, Tanya; Girgenrath, Mahasweta
MDC1A, the second most prevalent form of congenital muscular dystrophy, results from laminin-?2 chain deficiency. This disease is characterized by extensive muscle wasting that results in extremely weak skeletal muscles. A large percentage of children with MDC1A are faced with respiratory as well as ambulatory difficulties. We investigated the effects of overexpressing insulin-like growth factor-1 (IGF-1) as a potential therapeutic target for the disease in the Lama2Dy-w mouse, a model that closely resembles human MDC1A. IGF-1 transgenic Lama2Dy-w mice showed increased survivability, body weight and muscle weight. In addition, these mice showed better ability to stand up on their hind limbs: a typical exploratory behavior seen in healthy mice. Histology and immunohistochemistry analyses revealed increased regenerative capacity and proliferation in IGF-1 transgenic Lama2Dy-w muscles. Western blot analysis showed increased phosphorylation of Akt and ERK1/2, both known to enhance myogenesis. Additionally, we saw increases in the expression of the regeneration markers MyoD, myogenin and embryonic myosin (myosin heavy chain 3, MYH3). We conclude that overexpression of IGF-1 in Lama2Dy-w mice increases lifespan and improves their overall wellbeing mainly through the restoration of impaired muscle regeneration, as fibrosis or inflammation was not impacted by IGF-1 in this disease model. Our results demonstrate that IGF-1 has a promising therapeutic potential in the treatment of MDC1A. PMID:21441569
Membrane abnormalities and Ca homeostasis in muscles of the mdx mouse, an animal model of the Duchenne muscular dystrophy: a review.
Gillis, J M
Muscles of the mdx mouse lack dystrophin, a cytoskeletal protein. Mdx fibres exhibit an increased fragility to hypo-osmotic shock and to forced lengthening, an abnormal opening time of stretch-sensitive calcium channels. The question of a chronic elevated [Ca2+]i value is a matter of controversy. We have analysed Ca homeostasis in smooth and skeletal muscles from the adult mdx mouse. The wall of the vas deferens was loaded with the fluorescent Ca indicator Fura-2-AM (cell-diffusible). Resting [Ca2+]i was measured after changes of the electrochemical potential for Ca2+ and after KCl or electrical stimulations. In no instance was a difference observed between these and similar muscles from control mice. Single striated fibres were isolated by collagenase treatment of the flexor digitorum brevis muscle and loaded with Fura-2-AM. The value of resting [Ca2+]i was measured using an in situ calibration procedure which took account of Ca buffering by Fura-2. A chronic increase of cytosolic Ca2+ was not confirmed. The expression of the intracellular Ca-binding protein, parvalbumin, was measured. It increased by about threefold in fast mdx muscles (tibialis anterior) but remained undetectable in the soleus. It is hypothesized that parvalbumin helps to maintain [Ca2+]i within normal values. This hypothesis will be discussed in connection with dystrophy phenotypes in mutant dogs and in human patients. PMID:8729700
Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 3. Differential diagnosis and prognosis.
Nicholson, L V; Johnson, M A; Bushby, K M; Gardner-Medwin, D; Curtis, A; Ginjaar, I B; den Dunnen, J T; Welch, J L; Butler, T J; Bakker, E
This report is the third part of a trilogy from a multidisciplinary study which was undertaken to investigate gene and protein expression in a large cohort of patients with well defined and diverse clinical phenotypes. The aim of part 3 was to review which of the analytical techniques that we had used would be the most useful for differential diagnosis, and which would provide the most accurate indication of disease severity. Careful clinical appraisal is very important and every DMD patient was correctly diagnosed on this basis. In contrast, half of the sporadic BMD patients and all of the sporadic female patients had received different tentative diagnoses based on clinical assessments alone. Sequential observations of quantitative parameters (such as the time taken to run a fixed distance) were found to be useful clinical indicators for prognosis. Intellectual problems might modify the impression of physical ability in patients presenting at a young age. Histopathological assessment was accurate for DMD but differentiation between BMD and other disorders was more difficult, as was the identification of manifesting carriers. Our data on a small number of women with symptoms of muscle disease indicate that abnormal patterns of dystrophin labelling on sections may be an effective way of differentiating between female patients with a form of limb girdle dystrophy and those carrying a defective Xp21 gene. Dystrophin gene analysis detects deletions/duplications in 50 to 90% of male patients and is the most effective non-invasive technique for diagnosis. Quantitative Western blotting, however, would differentiate between all Xp21 and non-Xp21 male patients. In this study we found a clear relationship between increased dystrophin abundance (determined by densitometric analysis of blots) and clinical condition, with a correlation between dystrophin abundance and the age at loss of independent mobility among boys with DMD and intermediate D/BMD. This indicates that blotting is the most sensitive and accurate technique for diagnosis and prognosis. Images PMID:8411069
Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 1. Trends across the clinical groups.
Nicholson, L V; Johnson, M A; Bushby, K M; Gardner-Medwin, D; Curtis, A; Ginjaar, I B; den Dunnen, J T; Welch, J L; Butler, T J; Bakker, E
This multidisciplinary study was undertaken to record the variation in gene and protein expression in a large cohort of patients with well defined clinical phenotypes. The patients, whose ages ranged from 4 years to 66 years, spanned a wide range of disease severity. They represented the first 100 patients who had been examined in Newcastle, had undergone a muscle biopsy, and provided a blood sample for DNA analysis. The study had three aims: to observe any trends in the analyses across the clinical groups, to correlate gene and protein expression in individual patients, and to use the data collected to assess the relative usefulness of different techniques in the diagnosis and prognosis of patients with Duchenne and Becker dystrophy (DMD/BMD). In part 1, we describe the clinical assessment of the patients and the trends that were observed across the cohort. The patients were divided into seven groups. Group 1 had severe DMD (n = 21), group 2 had milder DMD (n = 20), group 3 were intermediate D/BMD patients (n = 9), group 4 had severe BMD (n = 5), and group 5 were more typical BMD patients (n = 31). Some patients were too young to be classified (n = 7) and a group of all the female patients were also classified separately (n = 7). The number of DMD and BMD patients was about equal, in accord with disease prevalence in the north of England, but an unusually high proportion were sporadic cases. Dystrophin labelling (performed with up to three antibodies) on both blots and sections increased gradually across the clinical groups. All histopathological indices, except the proportion of fat in biopsy sections, showed clear trends across the groups. Images PMID:8411067
Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice
Domenighetti, Andrea A.; Chu, Pao-Hsien; Wu, Tongbin; Sheikh, Farah; Gokhin, David S.; Guo, Ling T.; Cui, Ziyou; Peter, Angela K.; Christodoulou, Danos C.; Parfenov, Michael G.; Gorham, Joshua M.; Li, Daniel Y.; Banerjee, Indroneal; Lai, Xianyin; Witzmann, Frank A.; Seidman, Christine E.; Seidman, Jonathan G.; Gomes, Aldrin V.; Shelton, G. Diane; Lieber, Richard L.; Chen, Ju
Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and EmeryľDreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-of-function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations. PMID:23975679
Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland
Tiina Suominen; Linda L Bachinski; Satu Auvinen; Peter Hackman; Keith A Baggerly; Corrado Angelini; Leena Peltonen; Ralf Krahe; Bjarne Udd
Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1\\/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of
Muscular Dystrophy Association Programs and Services
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What Are the Treatments for Muscular Dystrophy?
... 2 . Eventually, many MD patients require assisted ventilation. Speech Therapy MD patients who experience weakness in the ... from learning to slow the pace of their speech by pausing more between breaths 3 and by ...
Genetics Home Reference: Fukuyama congenital muscular dystrophy
... the brain, this protein helps direct the movement (migration) of nerve cells (neurons) during early development. The ... skeletal muscles. Defective ?-dystroglycan also affects the migration of neurons during the early development of the ...
Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)
... least expenditure of energy. In some cases a wheelchair, electric wheelchair or electric scooter with elevating seat may be ... person with FSHD spends sitting at a computer, standing, walking, climbing stairs, getting into and out of ...
Genetics Home Reference: Oculopharyngeal muscular dystrophy
... cause the PABPN1 protein to form clumps within muscle cells that accumulate because they cannot be broken down. ... are thought to impair the normal functioning of muscle cells and eventually cause cell death. The progressive loss ...
Myotonic dystrophy as a cause of colonic pseudoobstruction: not just another constipated child
Glaser, Andrea M; Johnston, Jennifer H; Gleason, Wallace A; Rhoads, J Marc
Key Clinical Message Muscular dystrophy has been traditionally associated with common gastrointestinal symptoms such as reflux, constipation, and dysphasia. In myotonic dystrophy, there are rare reports of chronic intestinal pseudoobstruction (CIPOS). We herein present a case of CIPOS requiring colectomy and with good results. PMID:26185641
Barrier-to-autointegration factor-like (BAF-L): A proposed regulator of BAF
Tifft, Kathryn E. [Department of Cell Biology, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205 (United States); Segura-Totten, Miriam [Department of Science and Technology, Universidad Metropolitana, Ave. Ana G. Mendez, San Juan, PR 00928 (United States); Lee, Kenneth K. [Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110 (United States); Wilson, Katherine L. [Department of Cell Biology, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205 (United States)]. E-mail: firstname.lastname@example.com
Barrier-to-autointegration factor (BAF) is an essential chromatin protein conserved in metazoans. BAF has roles in nuclear assembly, chromatin organization, gene expression, and gonad development and is exploited by retroviruses. BAF forms stable dimers that bind nonspecifically to dsDNA and specifically to LEM-domain proteins (e.g., LAP2{beta}, emerin, MAN1), homeodomain transcription factors, histones, and lamin A. We characterized a protein named BAF-Like (BAF-L) that in humans is 40% identical to BAF. Overexpression studies in HeLa cells show that BAF-L, like BAF, is a predominantly nuclear protein. Recombinant BAF-L forms stable homodimers and heterodimerizes with BAF in vitro and also interacts with BAF in vivo. BAF-L does not bind significantly to DNA, LAP2{beta}, or emerin but can form ternary complexes in vitro with BAF plus DNA, or BAF plus LAP2{beta}. Levels of BAF-L mRNA were high in pancreas and testis, suggesting functions in the germline. BAF-L mRNA was detectable at low levels in eleven other tissues and undetectable in heart and skeletal muscle which are specifically affected by Emery-Dreifuss muscular dystrophy, a disease caused by mutations in either emerin or lamin A. We propose that BAF-L regulates BAF function via heterodimerization and might thereby influence tissue-specific roles of BAF.
Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction.
Arimura, Sumimasa; Okada, Takashi; Tezuka, Tohru; Chiyo, Tomoko; Kasahara, Yuko; Yoshimura, Toshiro; Motomura, Masakatsu; Yoshida, Nobuaki; Beeson, David; Takeda, Shin'ichi; Yamanashi, Yuji
The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders. PMID:25237101
Aggresome-Autophagy Involvement in a Sarcopenic Patient with Rigid Spine Syndrome and a p.C150R Mutation in FHL1 Gene.
Sabatelli, Patrizia; Castagnaro, Silvia; Tagliavini, Francesca; Chrisam, Martina; Sardone, Francesca; Demay, Laurence; Richard, Pascale; Santi, Spartaco; Maraldi, Nadir M; Merlini, Luciano; Sandri, Marco; Bonaldo, Paolo
The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresome-autophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation. PMID:25191266
AggresomeľAutophagy Involvement in a Sarcopenic Patient with Rigid Spine Syndrome and a p.C150R Mutation in FHL1 Gene
Sabatelli, Patrizia; Castagnaro, Silvia; Tagliavini, Francesca; Chrisam, Martina; Sardone, Francesca; Demay, Laurence; Richard, Pascale; Santi, Spartaco; Maraldi, Nadir M.; Merlini, Luciano; Sandri, Marco; Bonaldo, Paolo
The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and EmeryľDreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresomeľautophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation. PMID:25191266
Cell nuclei spin in the absence of lamin b1.
Ji, Julie Y; Lee, Richard T; Vergnes, Laurent; Fong, Loren G; Stewart, Colin L; Reue, Karen; Young, Stephen G; Zhang, Qiuping; Shanahan, Catherine M; Lammerding, Jan
Mutations of the nuclear lamins cause a wide range of human diseases, including Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome. Defects in A-type lamins reduce nuclear structural integrity and affect transcriptional regulation, but few data exist on the biological role of B-type lamins. To assess the functional importance of lamin B1, we examined nuclear dynamics in fibroblasts from Lmnb1(Delta/Delta) and wild-type littermate embryos by time-lapse videomicroscopy. Here, we report that Lmnb1(Delta/Delta) cells displayed striking nuclear rotation, with approximately 90% of Lmnb1(Delta/Delta) nuclei rotating at least 90 degrees during an 8-h period. The rotation involved the nuclear interior as well as the nuclear envelope. The rotation of nuclei required an intact cytoskeletal network and was eliminated by expressing lamin B1 in cells. Nuclear rotation could also be abolished by expressing larger nesprin isoforms with long spectrin repeats. These findings demonstrate that lamin B1 serves a fundamental role within the nuclear envelope: anchoring the nucleus to the cytoskeleton. PMID:17488709
Prelamin A is involved in early steps of muscle differentiation
Capanni, Cristina; Del Coco, Rosalba; Squarzoni, Stefano; Columbaro, Marta; Mattioli, Elisabetta [IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna (Italy); Camozzi, Daria [Laboratory of Cell Biology Istituto Ortopedico Rizzoli, Bologna (Italy); Rocchi, Anna; Scotlandi, Katia [Laboratory of Oncological Research, Istituto Ortopedico Rizzoli, Bologna (Italy); Maraldi, Nadir [IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna (Italy); Laboratory of Cell Biology Istituto Ortopedico Rizzoli, Bologna (Italy); Foisner, Roland [Max F. Perutz Laboratories, Medical University of Vienna, Vienna (Austria); Lattanzi, Giovanna [IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna (Italy)], E-mail: email@example.com
Lamin A is a nuclear lamina constituent implicated in a number of human disorders including Emery-Dreifuss muscular dystrophy. Since increasing evidence suggests a role of the lamin A precursor in nuclear functions, we investigated the processing of prelamin A during differentiation of C2C12 mouse myoblasts. We show that both protein levels and cellular localization of prelamin A are modulated during myoblast activation. Similar changes of lamin A-binding proteins emerin and LAP2{alpha} were observed. Furthermore, prelamin A was found in a complex with LAP2{alpha} in differentiating myoblasts. Prelamin A accumulation in cycling myoblasts by expressing unprocessable mutants affected LAP2{alpha} and PCNA amount and increased caveolin 3 mRNA and protein levels, while accumulation of prelamin A in differentiated muscle cells following treatment with a farnesyl transferase inhibitor appeared to inhibit caveolin 3 expression. Our data provide evidence for a critical role of the lamin A precursor in the early steps of muscle cell differentiation.
Myotonic Dystrophy: RNA Pathogenesis Comes into Focus
Ranum, Laura P. W.; Day, John W.
Myotonic dystrophy (DM)Śthe most common form of muscular dystrophy in adults, affecting 1/8,000 individualsŚis a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3? untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases. PMID:15065017
Using a Handheld to Help People with NeuroMuscular Disorders
Brad A. Myers; Sunny Yang; Brian Yeung; Jeffrey Nichols; Robert Miller
People with Muscular Dystrophy and certain other muscular and nervous system disorders lose their gross motor control while retaining fine motor control. The result is that they often lose the ability to move their wrists and arms and so their ability to operate a mouse and keyboard deteriorates over time. However, they can often still use their fingers to control
Whole exome sequencing identifies a novel EMD mutation in a Chinese family with dilated cardiomyopathy
Background Variants in the emerin gene (EMD) were implicated in X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD), characterized by early-onset contractures of tendons, progressive muscular weakness and cardiomyopathy. To date, 223 mutations have been reported in EMD gene and the majority of them caused a predominant skeletal muscular phenotype. In this study, we identified a novel deletion mutation in EMD exon 1, which results in almost a complete loss of emerin protein in a large Chinese family. However, the patients suffered severe dilated cardiomyopathy (DCM) but very mild skeletal muscle disorder. Case presentation Whole exome sequencing (WES) and linkage analysis were performed to identify the underlying mutation in a Chinese DCM family spanning five generations. A missense variation in the GPR50 gene was found co-segregated with the disease phenotype, whereas no functional alteration was detected in the variant GPR50 protein. When analyzing the failure sequences in the exome sequencing data, a novel deletion mutation (c.26_39delATACCGAGCTGACC) in EMD exon 1, was identified in this family. Different from the typical clinical features caused by most reported EMD mutations, patients in our study presented very mild skeletal muscle degeneration that had not been diagnosed until the mutation was found. Conclusion We described a family with rare clinical presentations caused by a novel EMD deletion mutation. Our findings broaden the heterogeneous spectrum of phenotypes attributed to EMD mutations and provide new insight to explain the genotype-phenotype correlations between EMD mutations and EDMD symptoms. PMID:24997722
Histological Landmarks in Corneal Dystrophy: Pathology of Corneal Dystrophies
Geeta K. Vemuganti; Varsha M. Rathi; Somasheila I. Murthy
Corneal dystrophies are bilateral, progressive, genetically determined noninflammatory diseases restricted to the cornea. These are characterized by deposition of nonnative protein or other material, both intracellular and extracellular, within the corneal layers. Dystrophies are classified based on the anatomical location of the lesions as: anterior corneal dystrophies (affecting the epithelium and extending into the superficial stroma), stromal dystrophies (which involve
Nesprins: tissue-specific expression of epsilon and other short isoforms.
Duong, Nguyen Thuy; Morris, Glenn E; Lam, Le Thanh; Zhang, Qiuping; Sewry, Caroline A; Shanahan, Catherine M; Holt, Ian
Nesprin-1-giant and nesprin-2-giant regulate nuclear positioning by the interaction of their C-terminal KASH domains with nuclear membrane SUN proteins and their N-terminal calponin-homology domains with cytoskeletal actin. A number of short isoforms lacking the actin-binding domains are produced by internal promotion. We have evaluated the significance of these shorter isoforms using quantitative RT-PCR and western blotting with site-specific monoclonal antibodies. Within a complete map of nesprin isoforms, we describe two novel nesprin-2 epsilon isoforms for the first time. Epsilon isoforms are similar in size and structure to nesprin-1-alpha. Expression of nesprin isoforms was highly tissue-dependent. Nesprin-2-epsilon-1 was found in early embryonic cells, while nesprin-2-epsilon-2 was present in heart and other adult tissues, but not skeletal muscle. Some cell lines lack shorter isoforms and express only one of the two nesprin genes, suggesting that either of the giant nesprins is sufficient for basic cell functions. For the first time, localisation of endogenous nesprin away from the nuclear membrane was shown in cells where removal of the KASH domain by alternative splicing occurs. By distinguishing between degradation products and true isoforms on western blots, it was found that previously-described beta and gamma isoforms are expressed either at only low levels or with a limited tissue distribution. Two of the shortest alpha isoforms, nesprin-1-alpha-2 and nesprin-2-alpha-1, were found almost exclusively in cardiac and skeletal muscle and a highly conserved and alternatively-spliced exon, available in both nesprin genes, was always included in these tissues. These "muscle-specific" isoforms are thought to form a complex with emerin and lamin A/C at the inner nuclear membrane and mutations in all three proteins cause Emery-Dreifuss muscular dystrophy and/or inherited dilated cardiomyopathy, disorders in which only skeletal muscle and/or heart are affected. PMID:24718612
Both lamin A and lamin C mutations cause lamina instability as well as loss of internal nuclear lamin organization
Broers, Jos L.V. [Department of Molecular Cell Biology, Box 17, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, PO Box 616, NL-6200 MD Maastricht (Netherlands) and Department of Biomedical Engineering, Biomechanics and Tissue Engineering Eindhoven University of Technology (Netherlands)]. E-mail: email@example.com; Kuijpers, H.J.H. [Department of Molecular Cell Biology, Box 17, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, PO Box 616, NL-6200 MD Maastricht (Netherlands); Oestlund, C. [Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10027 (United States); Worman, H.J. [Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10027 (United States); Endert, J. [Department of Molecular Cell Biology, Box 17, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, PO Box 616, NL-6200 MD Maastricht (Netherlands); Ramaekers, F.C.S. [Department of Molecular Cell Biology, Box 17, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, PO Box 616, NL-6200 MD Maastricht (Netherlands)
We have applied the fluorescence loss of intensity after photobleaching (FLIP) technique to study the molecular dynamics and organization of nuclear lamin proteins in cell lines stably transfected with green fluorescent protein (GFP)-tagged A-type lamin cDNA. Normal lamin A and C proteins show abundant decoration of the inner layer of the nuclear membrane, the nuclear lamina, and a generally diffuse localization in the nuclear interior. Bleaching studies revealed that, while the GFP-tagged lamins in the lamina were virtually immobile, the intranuclear fraction of these molecules was partially mobile. Intranuclear lamin C was significantly more mobile than intranuclear lamina A. In search of a structural cause for the variety of inherited diseases caused by A-type lamin mutations, we have studied the molecular organization of GFP-tagged lamin A and lamin C mutants R453W and R386K, found in Emery-Dreifuss muscular dystrophy (EDMD), and lamin A and lamin C mutant R482W, found in patients with Dunnigan-type familial partial lipodystrophy (FPLD). In all mutants, a prominent increase in lamin mobility was observed, indicating loss of structural stability of lamin polymers, both at the perinuclear lamina and in the intranuclear lamin organization. While the lamin rod domain mutant showed overall increased mobility, the tail domain mutants showed mainly intranuclear destabilization, possibly as a result of loss of interaction with chromatin. Decreased stability of lamin mutant polymers was confirmed by flow cytometric analyses and immunoblotting of nuclear extracts. Our findings suggest a loss of function of A-type lamin mutant proteins in the organization of intranuclear chromatin and predict the loss of gene regulatory function in laminopathies.
Neuromuscular function in limb girdle dystrophy.
Belanger, A Y; McComas, A J
The contractile properties of ankle dorsiflexor and plantarflexor muscles in 20 patients with limb girdle muscular dystrophy have been compared with those in matched controls. Twitch and voluntary torques were significantly smaller in the patient population and in nine patients it was impossible to record a twitch from tibialis anterior, a dorsiflexor muscle studied in detail. The disease process evidently ran a more rapid course in tibialis anterior than in plantarflexor muscles and this susceptibility was related to some aspect of the muscle other than its fibre type composition. Surviving fibres in dorsiflexor and plantarflexor muscles did not reveal evidence of excitation-contraction uncoupling; they exhibited normal post-activation potentiation and fatigue properties. Some patients were initially incapable of exciting their motor units maximally during voluntary contractions. A finding of possible pathogenetic significance was that one patient, with prominent calves, developed exceptionally large voluntary torque in his plantarflexor muscles. PMID:4087001
Genetics Home Reference: Infantile neuroaxonal dystrophy
... to the symptoms of infantile neuroaxonal dystrophy is unknown. How common is infantile neuroaxonal dystrophy? Infantile neuroaxonal ... a very rare disorder. Its specific incidence is unknown. What genes are related to infantile neuroaxonal dystrophy? ...
Edward Meryon (1809-1880) and muscular dystrophy.
Emery, A E; Emery, M L
Edward Meryon was an English physician of Huguenot stock. He studied medicine at University College, London, and his chief appointments were at St Thomas's Hospital and the London Infirmary for Epilepsy and Paralysis. In a communication to the Royal Medical and Chirurgical Society in December 1851, which was published in the Transactions of the Society the following year, he described in detail eight boys in three families with a disease later to be associated with the name of Duchenne. He was particularly impressed by the predilection for males and its familial nature. He appears to have been the first physician to make a systematic study of the disorder some years before Duchenne. Images PMID:8326496
Altered biomechanical properties of large arteries in muscular dystrophy
Dye, Wendy Watson
to detect any vascular alterations that occur as a result of a defective DGC. Acute biaxial biomechanical data were obtained through pressure-diameter and axial force-length tests on common carotid arteries of mdx, sgcd-/-, and wild-type mice in the active...
Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.
Meyer, Alain; Lannes, BÚatrice; Carapito, RaphaŰl; Bahram, Seiamak; Echaniz-Laguna, Andoni; Geny, Bernard; Sibilia, Jean; Gottenberg, Jacques Eric
Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8?kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2. PMID:25443993
Brillouin spectroscopy reveals changes in muscular viscoelasticity in Drosophila POMT mutants
NASA Astrophysics Data System (ADS)
Meng, Zhaokai; Baker, Ryan; Panin, Vladislav M.; Yakovlev, Vladislav V.
Muscular dystrophy (MD) is a group of muscle diseases that induce weakness in skeletal muscle and cause progressive muscle degeneration. The muscular mechanical properties (i.e., viscoelasticity), however, have not been thoroughly examined before and after MD. On the other hand, Brillouin spectroscopy (BS) provides a non-invasive approach to probing the local sound speed within a small volume. Moreover, recent advances in background-free Brillouin spectroscopy enable investigators to imaging not only transparent samples, but also turbid ones. In this study, we investigated the mechanical properties of muscles while employing Drosophila model of dystroglycanopathies, human congenital muscular dystrophies resulting from abnormal glycosylation of alphadystroglycan. Specifically, we analyzed larval abdominal muscles of Drosophila with mutations in protein Omannosyltransferase (POMT) genes. As a comparison, we have also examined muscular tissues dissected from wildtype Drosophila. The Brillouin spectra were obtained by a background free VIPA (virtually imaged phased array) spectrometer described in the previous report. As a reference, the Raman spectra were also acquired for each test. Our current results indicated that POMT defects cause changes in muscle elasticity, which suggests that muscular dystrophy conditions may be also associated with abnormalities in muscle elastic properties.
Cancer-related genes in the transcription signature of facioscapulohumeral dystrophy myoblasts and myotubes
Dmitriev, Petr; Kairov, Ulykbek; Robert, Thomas; Barat, Ana; Lazar, Vladimir; Carnac, Gilles; Laoudj-Chenivesse, Dalila; Vassetzky, Yegor S
Muscular dystrophy is a condition potentially predisposing for cancer; however, currently, only Myotonic dystrophy patients are known to have a higher risk of cancer. Here, we have searched for a link between facioscapulohumeral dystrophy (FSHD) and cancer by comparing published transcriptome signatures of FSHD and various malignant tumours and have found a significant enrichment of cancer-related genes among the genes differentially expressed in FSHD. The analysis has shown that gene expression profiles of FSHD myoblasts and myotubes resemble that of Ewing's sarcoma more than that of other cancer types tested. This is the first study demonstrating a similarity between FSHD and cancer cell expression profiles, a finding that might indicate the existence of a common step in the pathogenesis of these two diseases. PMID:24341522
Italian guidelines for molecular analysis in myotonic dystrophies.
Botta, A; Bonifazi, E; Vallo, L; Gennarelli, M; GarrŔ, C; Salehi, L; Iraci, R; Sansone, V; Meola, G; Novelli, G
Myotonic dystrophies, the most common form of adult muscular dystrophy, comprise at least two forms, clinically and genetically heterogeneous. Myotonic dystrophy type 1 and type 2 are both caused by unstable repetitions in untranslated gene regions: a [CTG]n expansion in the 3' region of the DMPK gene on chromosome 19q13 (DM1) and [CCTG]n tetranucleotide repeat located in the first intron of the ZNF9 gene on chromosome 3q21 (DM2). DM clinical features are caused by a gain of functions RNA mechanism in which the CUG and CCUG repeats alter nuclear functions, including alternative splicing of shared genes. Southern blot and/or polymerase chain reaction PCR-based approaches allow the detection of DM mutations in almost 100% of cases, however, the expansion size and the elevated grade of somatic instability make molecular testing for DM a diagnostic challenge. The increased use of DNA testing for DM generates many questions regarding the indications and interpretations of the test which require standardized methods, routinely available in molecular genetic laboratories. Here, we propose Guidelines for the molecular diagnosis of DM1 and DM2 approved by the Italian Ministry of Health in 2005 (Piano Nazionale Linee Guida, PNLG). Best practice for DM molecular analysis in diagnostic application, presymptomatic and prenatal testing, using direct and indirect approaches are described, with particular attention focused on ethical, legal and social issues. Overviews of materials used in the molecular diagnosis, as well as internet resources, are also included. PMID:17039977
CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy.
Morales, MarÝa Gabriela; Cabello-Verrugio, Claudio; Santander, Cristian; Cabrera, Daniel; Goldschmeding, Roel; Brandan, Enrique
Muscular dystrophies are diseases characterized by muscle weakness together with cycles of degeneration and regeneration of muscle fibres, resulting in a progressive decrease of muscle mass, diminished muscle force generation and an increase in fibrosis. Fibrotic disorders are the endpoint of many chronic diseases in different tissues, where accumulation of the extracellular matrix (ECM) occurs. Connective tissue growth factor CTGF/CCN2, which is over-expressed in muscular dystrophies, plays a major role in many progressive scarring conditions. To test the hypothesis that CTGF might not only contribute conversion of already damaged muscle into scar tissue, but that it could by itself also directly contribute to skeletal muscle deterioration, we evaluated the effect of CTGF over-expression in tibialis anterior muscle of wild-type mice, using an adenovirus containing the CTGF mouse sequence (Ad-mCTGF). CTGF over-expression induced extensive skeletal muscle damage, which was followed by a massive regeneration of the damaged muscle, as evidenced by increased embryonic myosin and fibres with centrally located nuclei. It also induced strong fibrosis with increased levels of fibronectin, collagen, decorin and ?-smooth muscle actin (?-SMA). Moreover, CTGF over-expression caused a decrease of the specific isometric contractile force. Strikingly, when CTGF over-expression stopped, the entire phenotype proved to be reversible, in parallel with normalization of CTGF levels. Thus, CTGF not merely acts downstream of muscle injury but also contributes directly to the deterioration of skeletal muscle phenotype and function. Moreover, normalization of expression levels led to spontaneous reversal of the CTGF-induced phenotype and to full recovery of muscle structure. These observations underscore the importance of CTGF in the pathophysiology of muscular dystrophies and suggest that targeting CTGF might have significant potential in the development of novel therapies for Duchenne muscular dystrophy and related diseases. PMID:21826667
NSDL National Science Digital Library
Ms. Jeni
What do the muscular and skeletal systems do? Identify structures and functions of the muscular and skeletal systems of the human body. (S3.6) You are going to watch a Movie of muscular system. I'm going to hand out a worksheet and you need to write three facts that you have learned from the video in the spaces provided and then fill out the chart about the three types of muscles. Now you are going to do a ...
Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland.
Suominen, Tiina; Bachinski, Linda L; Auvinen, Satu; Hackman, Peter; Baggerly, Keith A; Angelini, Corrado; Peltonen, Leena; Krahe, Ralf; Udd, Bjarne
Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n = 93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value = 0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population. PMID:21364698
Spinal muscular atrophy in childhood
A. Moosa; V. Dubowitz
A coarse tremor was noted in 13 children suffering from the childhood form of spinal muscular atrophy. Tremor has not been seen in any other condition producing proximal muscle weakness in childhood, and its presence should therefore suggest the diagnosis of spinal muscular atrophy.In addition, the feet of patients with spinal muscular atrophy tended to evert, whereas in Duchenne muscular
Confocal Microscopy of Corneal Dystrophies
Shukla, Anita N.; Cruzat, Andrea; Hamrah, Pedram
In vivo confocal microscopy (IVCM) of the cornea is becoming an indispensable tool in the cellular study of corneal physiology and disease. This technique offers non-invasive imaging of the living cornea with images comparable to that of ex vivo histology. The ability to provide high-resolution images of all layers in the living cornea has resulted in new discoveries of corneal pathology at the cellular level. The IVCM analysis of corneal dystrophies is of importance to clinicians, as current methods of diagnosis involve slit-lamp characteristics, genetic analysis, and invasive biopsy. IVCM is helpful in evaluating the morphological characteristics of corneal dystrophies at the histological level and may be helpful in diagnosis, determination of progression, and understanding the pathophysiology of disease. The purpose of this review is to describe the principles, applications, and clinical correlation of IVCM in the study of corneal dystrophies. PMID:23163262
The molecular mechanisms involved in the genetic instability of the CCTG. CAGG repeats associated with myotonic dystrophy type 2
Dere, Ruhee J.
. Kaytan Amrute for always being there for me, and cheering me on when the going got tough. viii LIST OF ABBREVIATIONS HNPCC hereditary nonpolyposis colorectal carcinoma TRS trinucleotide repeat sequence FRAXA Fragile X syndrome DM1... myotonic dystrophy type 1 FRDA Friedreich?s ataxia HD Huntington?s disease HDL2 Huntington disease-like 2 SCA spinocerebellar ataxia DRPLA dentatorubral-pallidoluysian atrophy / Haw River syndrome SBMA spinal and bulbar muscular atrophy...
Myotonic Dystrophy in Ancient Egypt
Giacomo Cattaino; Laura Vicario
Amenhotep IV, better known as Akhenaton, the heretical pharaoh, was a king of the New Kingdom of Ancient Egypt. Statues and reliefs of him show an unhealthy man whose body has abnormal features. By studying the pictures of Akhenaton (the mummy has not yet been found), we conclude that he may have been affected by myotonic dystrophy (MD). Moreover, the
Macular corneal dystrophy in Iceland
F Jonasson; J H Johannsson; A Garner; N S C Rice
This study includes the fourteen Icelanders who had penetrating keratoplasty for macular corneal dystrophy during 1974 through 1988, and a further five patients whose deterioration of vision has so far not led to surgery. The clinical presentation, mode of inheritance and the course of the disease were similar to those seen in other studies. The genealogical part of this study
[Aggravation of hypoxemia in supine position in myotonic dystrophy].
Horikawa, H; Takahashi, K; Yoshinaka, H; Mano, Y; Takayanagi, T
Myotonic dystrophy (MyD) involves a variety of systems. Respiratory disorders are common, namely elevation of diaphragm, alveolar hypoventilation, aspiration pneumonia and sleep apnea. We evaluated respiratory involvement. The subjects were 11 patients with MyD. Also 6 patients with limb girdle muscular dystrophy (LG) were examined to be compared with MyD. Both groups had the similar activities of daily living. All of them never complained of dyspnea. Arterial blood gas studies were performed in supine position and standing position. A new evidence was found that hypoxemia was aggravated and alveolar-arterial oxygen pressure difference was increased in supine position in MyD. Next, pulmonary function tests were done in supine position and sitting position. Functional residual capacity (FRC) were more reduced in supine position in MyD compared with LG. The value to subtract closing capacity from FRC was negative in supine position in MyD, showing closing phenomenon. We propose the mechanism of the aggravation of hypoxemia may be the following. The reduction of FRC caused by respiratory muscle involvement brings out the closing phenomenon. Abnormal uneven distribution of ventilation-perfusion ratio happens and then hypoxemia is worsened in supine position in MyD. PMID:1297547
Misregulation of Alternative Splicing Causes Pathogenesis in Myotonic Dystrophy
Muge Kuyumcu-Martinez, N.; Cooper, Thomas A.
Myotonic dystrophy (DM), the most common form of adult onset muscular dystrophy, affects skeletal muscle, heart, and the central nervous system (CNS). Mortality results primarily from muscle wasting and cardiac arrhythmias. There are two forms of the disease: DM 1 and DM 2. DM 1, which constitutes 98% of cases, is caused by a CTG expansion in the 3? untranslated region (UTR) of the DMPK gene. DM 2 is caused by a CCTG expansion in the first intron of the ZNF9 gene. RNA containing CUG- or CCUG-expanded repeats are transcribed but are retained in the nucleus in foci. Disease pathogenesis results primarily from a gain of function of the expanded RNAs, which alter developmentally regulated alternative splicing as well as pathways of muscle differentiation. The toxic RNA has been implicated in sequestration of splicing regulators and transcription factors thereby causing specific symptoms of the disease. Here we review the proposed mechanisms for the toxic effects of the expanded repeats and discuss the molecular mechanisms of splicing misregulation and disease pathogenesis. PMID:17076268
DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model
Berul, Charles I.; Maguire, Colin T.; Aronovitz, Mark J.; Greenwood, Jessica; Miller, Carol; Gehrmann, Josef; Housman, David; Mendelsohn, Michael E.; Reddy, Sita
Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPKľ/ľ mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (AľV) block. Our results demonstrate that the AľV node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/ľ mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy. PMID:10021468
Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice
Oana, Kosuke; Oma, Yoko; Suo, Satoshi; Takahashi, Masanori P.; Nishino, Ichizo; Takeda, Shin'ichi; Ishiura, Shoichi
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults and as yet no cure for DM1. Here, we report the potential of manumycin A for a novel DM1 therapeutic reagent. DM1 is caused by expansion of CTG repeat. Mutant transcripts containing expanded CUG repeats lead to aberrant regulation of alternative splicing. Myotonia (delayed muscle relaxation) is the most commonly observed symptom in DM1 patients and is caused by aberrant splicing of the skeletal muscle chloride channel (CLCN1) gene. Identification of small-molecule compounds that correct aberrant splicing in DM1 is attracting much attention as a way of improving understanding of the mechanism of DM1 pathology and improving treatment of DM1 patients. In this study, we generated a reporter screening system and searched for small-molecule compounds. We found that manumycin A corrects aberrant splicing of Clcn1 in cell and mouse models of DM1. PMID:23828222
DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy
Geng, Linda N.; Yao, Zizhen; Snider, Lauren; Fong, Abraham P.; Cech, Jennifer N.; Young, Janet M; van der Maarel, Silvere M.; Ruzzo, Walter L.; Gentleman, Robert C.; Tawil, Rabi; Tapscott, Stephen J.
Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. PMID:22209328
Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail
Simon, Dan N; Zastrow, Michael S
Nuclear intermediate filament networks formed by A- and B-type lamins are major components of the nucleoskeleton. Lamins have growing links to human physiology and disease including Emery-Dreifuss muscular dystrophy (EDMD), lipodystrophy, cardiomyopathy, neuropathy, cerebellar disorders and segmental accelerated Ĺagingĺ syndromes. How lamins interact with other nucleoskeletal components, and even the identities of these other components, are open questions. Previous studies suggested lamins might bind actin. We report that the recombinant C-terminal tail domain of human A- and B-type lamins binds directly to purified actin in high-speed pelleting assays. This interaction maps to a conserved Actin Binding site (AB-1) comprising lamin A residues 461ľ536 in the Ig-fold domain, which are 54% identical in lamin B1. Two EDMD-causing missense mutations (R527P and L530P) in lamin A that are predicted to disrupt the Ig-fold, each reduced F-actin binding by ?66%, whereas the surface-exposed lipodystrophy-causing R482Q mutation had no significant effect. The lamin A tail was unique among lamins in having a second actin-binding site (AB-2). This second site was mapped to lamin A tail residues 564ľ608, based on actin-binding results for the lamin C tail and internal deletions in the lamin A tail that cause Hutchinson-Gilford Progeria Syndrome (?35, ?50) or restrictive dermopathy (?90). Supporting the presence of two actin-binding sites, recombinant precursor (unmodified) and mature lamin A tails (not C or B1 tails) each bundled F-actin in vitro: furthermore F-actin bundling was reduced 25ľ40% by the R527P, L530P, ?35 and ?50 mutations, and was abolished by ?90. Unexpectedly, the mature lamin A tail bound F-actin significantly more efficiently than did the prelamin A tail; this suggested unmodified residues 647ľ664, unique to prelamin A, might auto-inhibit binding to actin (and potentially other partners). These biochemical results suggest direct mechanisms by which lamins, particularly lamin A, might impact the concentration of free actin in the nucleus or pathways including transcription, nuclear export, chromatin remodeling, chromatin movement and nuclear assembly that require nuclear myosin 1c and polymerizable actin. PMID:21327074
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy.
Kisand, Kai; Peterson, Pńrt
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. This review focuses on the clinical and immunological features of APECED, summarizes the current knowledge on the function of AIRE and discusses the importance of autoantibodies in disease diagnosis and prognosis. Additionally, we review the outcome of recent immunomodulatory treatments in APECED patients. PMID:26141571
Petur Ludvigsson; Elias Olafsson; W. Allen Hauser
Spinal muscular atrophy (SMA) is among the commonest degenerative disorders of the nervous system in childhood. This is an inherited autosomal recessive disease which results in premature death of anterior horn cells of the spinal cord and is manifested by progressive weakness and atrophy of skeletal muscles. Few studies have looked at the frequency of the disease in a defined
Corneal dystrophy in the dog and cat.
Cooley, P L; Dice, P F
Two types of epithelial dystrophy have been described in dogs, one each in the Boxer and Shetland Sheepdog breeds, both of which can be associated with corneal erosions. Medical therapy is recommended when erosions or tear film abnormalities are present. Stromal dystrophies documented in dogs appear to be a primary lipid deposition in various layers of the stroma, depending on the breed. Stromal dystrophies seldom lead to loss of vision, but vision loss has been observed in middle aged Airedale Terriers and aged Siberian Huskies. Treatment is usually unnecessary. The dog demonstrates two types of endothelial dystrophy, one of which (posterior polymorphous dystrophy in the American Cocker Spaniel) does not lead to corneal edema. Endothelial dystrophy observed in the Boston Terrier, Chihuahua, and other breeds is associated with progressive corneal edema, which can lead to bullous keratopathy and corneal erosions. Stromal and endothelial dystrophies, both of which are associated with rapid progression of corneal edema, occur rarely in the cat. Treatment of dystrophies with progressive corneal edema is symptomatic and palliative. PMID:2194353
K. Talbot
Spinal muscular atrophy is a common cause of disability in childhood and is characterized by weakness and wasting of voluntary\\u000a muscle. It is frequently fatal. The gene for this disorder has been identified as the SMN gene and is part of a highly complex\\u000a duplicated region of chromosome 5 that is subject to a high rate of gene deletion and
Susan T. Iannaccone; Stephen A. Smith; Louise R. Simard
Spinal muscular atrophy is a common genetic disease of the motor neuron (frequency of eight cases per 100,000 live births)\\u000a with a high mortality during infancy and no known treatment. Death is caused by severe and progressive restrictive lung disease.\\u000a New information regarding the nature and function of the SMN protein and the availability of new pharmacologic agents now\\u000a make
Muscular system in polychaetes (Annelida)
Alexander B. Tzetlin; Anna V. Filippova
The structure of the polychaete muscular system is reviewed. The muscular system comprises the muscles of the body wall, the\\u000a musculature of the parapodial complex and the muscle system of the dissepiments and mesenteries. Various types of organisation\\u000a of the longitudinal and circular components of the muscular body wall are distinguished. In Opheliidae, Polygordiidae, Protodrilidae,\\u000a Spionidae, Oweniidae, Aphroditidae, Acoetidae (=Polyodontidae),
Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2
Nakayama, Takahiro; Nakamura, Harumasa; Oya, Yasushi; Kimura, Takashi; Imahuku, Ichiro; Ohno, Kinji; Nishino, Ichizo; Abe, Koji; Matsuura, Tohru
Myotonic dystrophy type 2 (DM2) is more common than DM1 in Europe and is considered a rare cause of myotonic dystrophies in Asia. Its clinical course is also milder with more phenotypic variability than DM1. We herein describe the first known Asian family (three affected siblings) with DM2 based on clinical and genetic analyses. Notably, two of the affected siblings were previously diagnosed with limb-girdle muscular dystrophy. Myotonia (the inability of the muscle to relax) was absent or only faintly present in these individuals. The third sibling had grip myotonia and is the first known Asian DM2 patient. The three DM2 siblings share several systemic characteristics, including late-onset, proximal-dominant muscle weakness, diabetes, cataracts and asthma. Repeat-primed PCR across the DM2 repeat revealed a characteristic ladder pattern of a CCTG expansion in all siblings. Southern blotting analysis identified the presence of 3400 repeats. Further DM2 studies in Asian populations are needed to define the clinical presentation of Asian DM2 and as yet unidentified phenotypic differences from Caucasian patients. PMID:24430576
Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy.
Morales, Maria Gabriela; Gutierrez, Jaime; Cabello-Verrugio, Claudio; Cabrera, Daniel; Lipson, Kenneth E; Goldschmeding, Roel; Brandan, Enrique
In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-? (TGF-?), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD. PMID:23904456
Docetaxel-induced nail dystrophy.
Nicolopoulos, Jenny; Howard, Anne
A 73-year-old man with metastatic prostate cancer treated with weekly docetaxel chemotherapy for 5 months developed an acute nail dystrophy restricted to the fingernails. This was characterized by onycholysis, subungual haemorrhage and acute paronychia, progressing to a subungual abscess of the right index finger. Nail bed hyperaemia and haemosiderin-like nail bed discoloration were present. Nail plate avulsion was performed to decompress the acutely painful subungual abscess. The right thumb, middle finger and left index finger demonstrated early, proximal white subungual collections of pus obscuring the lunula (onychophosis). Central nail plate fenestrations with a surgical drill led to exudation of purulent material. Cultures of the subungual abscess material yielded mixed organisms, possibly related to administration of flucloxacillin for 1 week prior to presentation. The patient completed a further two courses of docetaxel without sequelae, and the nail dystrophy appears to be resolving. Docetaxel-induced nail changes are a common adverse effect, occurring in 30-40% of patients. Mild changes do not usually warrant the discontinuation of treatment. PMID:12423438
Genetics Home Reference: Congenital stromal corneal dystrophy
... associated with additional eye abnormalities, including "lazy eye" (amblyopia), eyes that do not look in the same ... definitions help with understanding congenital stromal corneal dystrophy? amblyopia ; autosomal ; autosomal dominant ; cell ; collagen ; congenital ; cornea ; gene ; ...
Genetics Home Reference: Fuchs endothelial dystrophy
... dystrophy is rare, although the exact prevalence is unknown. For reasons that are unclear, women are affected ... the late-onset form of the disorder are unknown. Read more about the COL8A2 gene. See a ...
Genetics Home Reference: Vitelliform macular dystrophy
... faces. Vitelliform macular dystrophy causes a fatty yellow pigment (lipofuscin) to build up in cells underlying the ... structures in these cells that contain light-sensing pigments. It is unclear why PRPH2 mutations affect only ...
Genetics Home Reference: Meesmann corneal dystrophy
... Registry: Meesman's corneal dystrophy Merck Manual Home Health Handbook: Tests for Eye Disorders: The Eye Examination You ... management of genetic conditions is available in the Handbook. Read more about genetic testing , particularly the difference ...
Differential diagnosis of Schnyder corneal dystrophy.
Weiss, Jayne S; Khemichian, Arbi J
Schnyder corneal dystrophy (SCD) is a rare corneal dystrophy characterized by abnormally increased deposition of cholesterol and phospholipids in the cornea leading to progressive vision loss. SCD is inherited as an autosomal dominant trait with high penetrance and has been mapped to the UBIAD1 gene on chromosome 1p36.3. Although 2/3 of SCD patients also have systemic hypercholesterolemia, the incidence of hypercholesterolemia is also increased in unaffected members of SCD pedigrees. Consequently, SCD is thought to result from a local metabolic defect in the cornea. The corneal findings in SCD are very predictable depending on the age of the individual, with initial central corneal haze and/or crystals, subsequent appearance of arcus lipoides in the third decade and formation of midperipheral haze in the late fourth decade. Because only 50% of affected patients have corneal crystals, the International Committee for Classification of Corneal Dystrophies recently changed the original name of this dystrophy from Schnyder crystalline corneal dystrophy to Schnyder corneal dystrophy. Diagnosis of affected individuals without crystalline deposits is often delayed and these individuals are frequently misdiagnosed. The differential diagnosis of the SCD patient includes other diseases with crystalline deposits such as cystinosis, tyrosinemia, Bietti crystalline dystrophy, hyperuricemia/gout, multiple myeloma, monoclonal gammopathy, infectious crystalline keratopathy, and Dieffenbachia keratitis. Depositions from drugs such as gold in chrysiasis, chlorpromazine, chloroquine, and clofazamine can also result in corneal deposits and are different from SCD. Diseases of systemic lipid metabolism that cause corneal opacification, such as lecithin-cholesterol acyltransferase deficiency, fish eye disease and Tangier disease, should also be considered although these are autosomal recessive disorders. PMID:21540632
Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy
Chisato Nakada; Yoshiyuki Tsukamoto; Akira Oka; Ikuya Nonaka; Kenzo Sato; Shigeo Mori; Hisao Ito; Masatsugu Moriyama
Objectives: Ankyrin-repeated protein with PEST and a proline-rich region (ARPP) is a recently identified protein with 4 ankyrin-repeated motifs in its central portion. Type 1 myofibers of skeletal muscle express high levels of ARPP. Recently, we have found that ARPP expression was induced in mouse denervated skeletal muscle. This led us to hypothesize that ARPP expression might be induced in