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Clinical and genetic aspects of Charcot-Marie- Tooth disease subtypes

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies and is both genetically and clinically heterogeneous, with variable inheritance modes. With regard to clinical and genetic aspects, CMT is divided into several subtypes, including CMT1, CMT2, CMT3, CMT4, CMT5, CMT6, X-linked CMT, and intermediate CMT. Up to date, more than 90 causative genes for CMT have been identified. Furthermore, previous animal studies reported some molecules to have therapeutic effects on specific CMT subtypes, depending on the underlying genetic cause. Therefore, accurate genetic diagnosis is of crucial importance when performing customized therapy. Finally, recent investigations on induced pluripotent stem cells expanded the possibility of both patient-specific cell therapy and drug discovery. The current review focuses on the latest classification updates for accurate CMT diagnosis.


INTRODUCTION
Charcot-Marie-Tooth disease (CMT) is the most common form of inherited peripheral neuropathy, with a prevalence of one in 2,500 people [1]. CMT patients usually present muscle atrophy, sensory loss, foot deformities, and areflexia [2,3]. However, CMT is a clinically and genetically heterogeneous disease, and some subtypes reveal unusual clinical features, including pyramidal features, vocal cord paralysis, hearing loss, or optic atrophy [4]. Furthermore, CMT is divided into three categories based on its pathology, namely demyelinating, axonal, and intermediate neuropathy [5,6]. Intermediate CMT neuropathy was reported to be characterized by both demyelination and axonal degeneration in peripheral nerve biopsies [7]. Demyelinating and axonal CMT neuropathy can be generally distinguished by assessing the median motor nerve conduction velocity (NCV), which is lower and higher than 38 m/sec, respectively [5,6]. Intermediate neuropathy usually ranges from 30 to 40 m/sec [7]. As more than 90 causative genes for CMT were found up to date, this disease is categorized into numerous subtypes [8][9][10]. In this review, the latest updates on the CMT subtypes and their clinical and genetic aspects were described, including Charcot-Marie-Tooth disease type 1 (CMT1), type 2 (CMT2), type 3 (CMT3), type 4 (CMT4), type 5 (CMT5), type 6 (CMT6), X-linked CMT (CMTX), and intermediate CMT.

CMT1A
CMT1A is caused by a duplication of the PMP22 gene, which encodes the PMP22, or a mutation in such a gene. The inheritance is autosomal dominant [11,12]. PMP22, a 22 KDa protein, constitutes 2% to 5% of the peripheral nervous system  MPZ is the major structural protein of myelin [13,14]. CMT1B accounts for less than 5% of the CMT cases and develops before the age of 20, mainly starting from patients' feet and legs. However, upper limb involvement also occurs, usually at later stages. CMT1B is clinically and genetically heteroge-neous and its progression is characterized by a slow, insidious onset. Distal limb muscle weakness, muscle atrophy, steppage gait, and foot drop are the main symptoms. Additionally, cold-induced muscle cramps, distal sensory impairment, hyporeflexia, and areflexia may be also observed.
Similarly, pes cavus, hammer toes, foot deformities, and, in some cases, claw hand deformities, are found. Furthermore, kyphoscoliosis of the spine and either Adie pupils or tonically dilated pupils may appear in some patients. In this subtype, the motor NCV is also reduced and hypertrophic nerve changes may occur. Finally, while onion bulb formation and segmental demyelination/remyelination are observed through nerve biopsy, the number of myelinated fibers decreases and some patients experience myelin outfoldings.

CMT1C
CMT1C is caused by a heterozygous mutation in the LITAF gene (also referred to as SIMPLE) on chromosome 16p13 [15]. The inheritance is autosomal dominant. The LITAF gene was first identified as a regulator of the TNFα gene expression and its product is an early endosomal membrane protein enriched in peripheral nerves and Schwann cells. CMT1C develops mainly during childhood and is genetically heterogeneous. It is characterized by pes cavus, muscle weakness, and atrophy in distal limbs and by distal sensory impairment and hyporeflexia. Similarly to the other CMT1 subtypes, the motor NCV is also reduced in CMT1C and hypertrophic nerve changes are found. Finally, onion bulb formation and segmental demyelination/remyelination are observed through nerve biopsy.

CMT1D
This form of CMT1 is caused by a mutation in the EGR2 gene [16][17][18]. The inheritance is autosomal dominant. Symptoms are present from an early age, specifically between the first and second decade of life, and usually begin in patients' feet and legs, while upper extremities may be affected at later stages. CMT1D is also both clinically and genetically heterogeneous, and its phenotype overlaps, in part, with both congenital hypomyelinating neuropathy (CHN) and discrete subaortic stenosis. Distal limb muscle weakness, muscle atrophy, steppage gait, and foot drop are the main symptoms.
The motor NCV is reduced.

CMT1E
Similarly to CMT1A, CMT1E is, at least in some instances, caused by a mutation in the PMP22 gene [19]. The inheritance is au-

CMT2D
This form of CMT2 is caused by a mutation in the glycyl-tRNA synthetase (GARS) gene [33], which encodes an enzyme that is responsible for charging tRNA molecules with glycine via an aminoacylation reaction. The inheritance is autosomal

CMT2N
This form of axonal CMT disease type 2 is caused by a heterozygous mutation in the alanyl-tRNA synthetase (AARS) gene on chromosome 16q21 [47], which encodes the amino acid synthetases, responsible for the initiation of the attachment of their respective amino acids to the corresponding tRNA.
The inheritance is autosomal dominant. CMT2N onset varies between the age of 6 to 54 years, with fluctuating severities.
The most frequent presenting symptoms are muscle weakness and atrophy in the distal limbs, which affects the lower limbs the most. Additional symptoms include walking difficulties, foot drop, hypo-or areflexia, distal sensory impairment, foot deformities, pes cavus, hammertoes, and ankle sprains. Finally, sensorineural deafness was also reported in one household.

CMT2O
CMT2O is caused by a heterozygous mutation in the dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) gene on chromosome 14q32 [48]. The inheritance is autosomal dominant.

CMT2W
This type of CMT disease is caused by a heterozygous mutation in the histidyl-tRNA synthetase (HARS) gene on chromosome 5q31 [56]. The inheritance is autosomal dominant.
HARS catalyzes the covalent ligation of histidine to its cognate tRNA, representing an early step of protein biosynthesis.
Its age of onset greatly varies, ranging from childhood to late adulthood; similarly, its severity also highly fluctuates.      Charcot-Marie-Tooth disease type 5 (CMT5, HMSN5) CMT5, also referred to as HMSN5 is sometimes defined as peroneal muscular atrophy with pyramidal features. CMT5 was originally described in patients with peroneal muscular atrophy and hereditary spastic paraparesis [88]. However, this type is pathologically heterogeneous and is not limited to one definite genetic cause. It was suggested a mutation Charcot-Marie-Tooth disease type 6 (CMT6, HMSN6) CMT6, also known as HMSN6, is caused by a heterozygous mutation in the MFN2 gene on chromosome 1p36 (  [95,96].

Other CMT-related neuropathies
Both HNPP and giant axonal neuropathy (GAN) are the most common disorders associated with genetic neuropathy ( Table 3). Specifically, when the chromosomal 17p11.2-p12 region is deleted, HNPP, an asymmetric demyelinating neuropathy characterized by temporary weakness and loss of sensation, is induced [112,113]. In fact, HNPP is known to occur due to decreased mRNA expression resulting from the deletion of the PMP22 gene and it is rarely caused by a frame shift mutation of the PMP22 gene. Pathological findings in HNPP patients suggest the presence of the tomacula (i.e., an inexperienced herbaceous area) and a decreased structural integrity of the herpes simplex, which result in a structure which can be easily damaged by physical traumas.
caused by a mutation of the gigaxonin, a new cytoskeletal protein expressed in neurons [114]. The formation of nerve microfibrillation around the Ranvier nodule is mainly a result of the swelling of the axon, which causes in turn a remarkable increase in its diameter and an abnormal shape. Interestingly, neurofibrillary tangles are also found in the brain of such patients, suggesting a correlation with the mental retardation reported in this disease.

CONCLUSION
In the present review article, an accurate description of the latest clinical and genetic features related to CMT disease was attempted, aiming at improved diagnoses. In fact, given that CMT is a rare disease with different phenotypes depending on their causative mutations, understanding the genetic mutations behind CMT and their etiology is essential for both an appropriate diagnosis and future therapeutic approaches.
Furthermore, as the approach to treatment becomes possible, the diagnosis of the causative genes assumes a crucial role and the recognition of the genotype-phenotype correlation is required. Finally, this review article summarizes the necessary items needed for the patient-specific diagnosis of the CMT subtypes, which will be helpful to clinicians and CMT researchers.

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.