Charcot-Marie-Tooth disease (CMT) comprises a genetically and clinically heterogeneous group of inherited peripheral neuropathies and remains a major indication for gene-based diagnostic evaluations in neuromuscular practice. Although supportive management has traditionally been applied across most subtypes, there has recently been a notable expansion of disease-modifying approaches due to advances in molecular diagnostics and accumulating preclinical and early clinical evidence. Improved genetic classification, including the recognition of metabolically defined and potentially treatable subtypes, has increased diagnostic precision and the development of subtype-specific therapeutics, with an increasing emphasis on mechanism-based stratification. This review summarizes recent progress in inherited neuropathies from a clinical perspective. We describe ongoing developments in clinical interventions, including combination pharmacotherapy for Charcot-Marie-Tooth disease type 1A (CMT1A), pathway-targeted therapy for CMT associated with sorbitol dehydrogenase deficiency and related metabolic neuropathies, and early biological and gene-based approaches that are being applied in selected subtypes. We also review the evolving preclinical approaches aimed at normalizing the peripheral myelin protein 22 dosage in CMT1A and gene-replacement and other precision therapies for loss-of-function and dominant-negative conditions. Because many subtypes of CMT progress slowly and conventional clinical scales have low sensitivity, we further discuss recent advances in the approaches used in clinical trials, including the refinement of clinical outcome assessments and the identification of candidate biomarkers such as the magnetic resonance imaging-based muscle fat fraction and the circulating level of neurofilament light chain. Collectively these developments are making subtype-specific therapeutic approaches increasingly feasible, although continued progress will depend on aligning disease biology, therapeutic approaches, and outcome measurements.

Axonal Charcot-Marie-Tooth disease (CMT2) has most frequently been associated with mutations in the MFN2 gene. MFN2 encodes mitofusin 2, which is a mitochondrial fusion protein that plays an essential role in mitochondrial function. We report CMT2 in a Korean father and his son that manifested with gait difficulties and progressive atrophy of the lower legs. Molecular analysis revealed a novel heterozygous c.2096T>C (p.Leu699Pro) mutation in the exon 18 of MFN2 in both subjects. We suggest that this novel mutation in MFN2 is probably a pathogenic mutation for CMT2.

Objectives
: Although the diagnosis of hereditary neuropathy with liability to pressure palsies(HNPP) in important for correct prognostic evaluation and genetic counseling, the diagnosis is frequently missed or delayed. Our main aim on undertaking this study was to characterized\ the electrodiagnostic features of HNPP. Material and Methods : Clinical, electrophysiologic and molecular studies were performed on Korean HNPP patients with 17P11.2 deletion. The results of eletrophysologic studies were compared with those of Charcot-Marie-Tooth disease type 1A (CMT1A) patients carrying 17p11.2 duplication. Results : Eight HNPP (50 motor, 39 sensory nerves) and six CMTIA (28 motor, 16 sensory nerves) patients were included. The slowing of sensory conduction in nearly all nerves and the distal accentuation of motor conduction abnormalities are the main features of background polyneuropathy in HNPP. In contrast to CMTIA, where severity of nerve conduction slowing was not different among nerve groups, HNPP sensory nerve conduction was more slowed in the median and ulnar nerves than in the sural nerve (p<0.01), and DML was more prolonged in the median nerve than in the other motor nerves (p<0.01). TLIs were significantly lower in HNPP than in the normal control and CMTIA patients for the median and ulnar nerves (p<0.01), and were also significantly reduced for the peroneal nerve (p<0.05) compared with those of the normal controls. Conclusion : The distribution and severity of the background electrophysiologic abnormalities are closely related to the topography of common entrapment or compression sites, which suggests the possible pathogenetic role of subclinical pressure injury at these sites in the development of the distinct background polyneuropathy in HNPP.

Charcot-Marie-Tooth (CMT) disease was described by Charcot and Marie in France and, independently, by Tooth in England in 1886. CMT is the most common form of inherited motor and sensory neuropathy, and is a genetically heterogeneous disorder of the peripheral nervous system. Therefore, many genes have been identified as CMT-causative genes. Traditionally, subclassification of CMT have been divided into autosomal dominant inherited demyelinating (CMT1) and axonal (CMT2) neuropathies, X-linked neuropathy (CMTX), and autosomal recessive inherited neuropathy (CMT4). Recently, intermediate type (CMT-Int) with NCVs between CMT1 and CMT2 is considered as a CMT type. There are several related peripheral neuropathies, such as D??ine-Sottas neuropathy (DSN), congenital hypomyelination (CH), hereditary neuropathy with liability to pressure palsies (HNPP) and giant axonal neuropathy (GAN). Great advances have been made in understanding the molecular basis of CMT, and 17 distinct genetic causes of CMT have been identified. The number of newly discovered mutations and identified genetic loci is rapidly increasing, and this expanding list has proved challenging for physicians trying to keep up with the field. Identifying the genetic cause of inherited neuropathies is often important to determine at risk family members as well as diagnose the patient. In addition, the encouraging studies have been published on rational potential therapies for the CMT1A. Now, wedevelop a model of how the various genes may interact in the pathogenesis of CMT disorder.