{'fraction_non_alphanumeric': 0.013467336683417085, 'fraction_numerical': 0.004221105527638191, 'mean_word_length': 5.453955901426719, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Barth syndrome and the many fascinating aspects of cardiolipin

Barth syndrome, the only known Mendelian disorder of cardiolipin biosynthesis, is caused by pathogenic variants in the TAFAZZIN gene (previously TAZ, G4.5) which codes for the acyltransferase responsible for cardiolipin remodeling. Following the description of Barth syndrome by Dr. Peter Barth in 1983 as an X-linked disorder involving cardiomyopathy, skeletal myopathy, and neutropenia, it took until the year 2000 until Vreken et al discovered the defective synthesis and remodeling of cardiolipin without any abnormalities in other phospholipid major classes. This key finding raised the interest of many researchers and set the stage for a range of new studies which included resolution of the question of the exact enzymatic role of the transferase in the synthesis of cardiolipin, a mitochondrial lipid composed of two phosphatidyl groups linked to a glycerol backbone and four acyl side chains. Furthermore, it sparked studies to identify the underlying mechanisms behind the clinical signs and symptoms including cardiomyopathy, which is a major issue for individuals with Barth syndrome, by making use of different model systems including a Barth syndrome mouse. Since much progress has been made in the field of Barth syndrome, we decided to put a Special Issue of our Journal together documenting the many fascinating aspects of Barth syndrome and to this end, we have invited key experts in the field to contribute to this Special Issue. This themed issue of the Journal of Inherited Metabolic Disease kicks off with a contribution by Erik Lontok et al in which the important role of the Barth Syndrome Foundation is described. Next, the clinical presentation and natural history of Barth syndrome are discussed by Taylor et al. This is important for patient management and to devise endpoints especially for new and emerging therapies, which are underway. This is followed up by a contribution from Thompson et al which provides an update on the current and future treatment approaches for Barth syndrome which includes description of two recently performed clinical trials. Subsequently, Vaz et al describe an improved, reversed phase-UHPLC method for the analysis of cardiolipins which not only allows accurate determination of the monolysocardiolipin/cardiolipin-ratio but also generates a complete cardiolipin spectrum allowing the interrogation of the cardiolipin fatty acid composition, which greatly enhances the diagnostic reliability of the assay. This is especially important in the current era of genetic testing where functional tests are needed to validate the genetic findings to confirm or refute pathogenicity, especially in case of new genetic variants. Following earlier work from the same group of Keller and coworkers, Oemer et al provide data to show that the molecular composition of cardiolipin is very much dependent on the surrounding lipid environment as concluded from experiments in cultured cells but also in the mouse which may provide an explanation for the large differences in cardiolipin species between tissues. The next paper in this issue by Schlame et al is focused on the physical properties, biosynthesis, membrane assembly, and functional role of cardiolipin. Furthermore, these authors discuss their intriguing hypothesis that cardiolipin plays a crucial role in the spatial organization of the oxidative phosphorylation (OXPHOS) system by boosting the close packing of OXPHOS complexes within the mitochondrial inner membrane thereby inducing the capacity to generate ATP formation via this system. This is obviously of great significance given the exercise intolerance of individuals with Barth syndrome. Our current understanding of Barth syndrome and the consequences of defective cardiolipin formation and remodeling has greatly benefited from studies in the yeast Saccharomyces cerevisiae, as pioneered by Greenberg and coworkers. The paper by Ji and Greenberg discusses these findings with special emphasis on the effects on other metabolic pathways including oxidative phosphorylation, pyruvate dehydrogenase, and the citric acid cycle but also oxidative stress, as well as iron and calcium homeostasis. The different experimental models which have been established to study the pathophysiology of defects in cardiolipin formation and remodeling caused by mutations in TAFAZZIN are discussed by Pu. Key features of each of the different model systems ranging from yeast to fruit fly, zebrafish, mice, and induced pluripotent stem cells, and their relevance to Barth syndrome are discussed. The next paper in line by Dudek and Maack deals with the mechano-energetic aspects of Barth syndrome induced by the impairment in cardiolipin synthesis and remodeling. Special attention is paid to calcium which plays a central role during excitation-contraction with calcium released from the sarcoplasmic reticulum driving sarcomere DOI: 10.1002/jimd.12460