Charcot-Marie-Tooth disease (CMT) is a general term for hereditary motor and sensory neuropathy (HMSN). It is a group of genetically heterogeneous disorders caused by mutations in genes encoding proteins that maintain the myelin sheath and axons of peripheral nerves.
It is the most common inherited neuromuscular disease, with an estimated prevalence of about 1 in 2,500 4). It affects an estimated 126,000 people in the United States and about 2.6 million people worldwide.
Classification is based on electrophysiological findings and nerve biopsy findings.
Approximately half of CMT cases are CMT1A, caused by PMP22 overexpression due to partial duplication of chromosome 17p11.2.
CMT is basically a hereditary disease and follows autosomal dominant, recessive, or X-linked inheritance patterns. However, sporadic cases due to de novo mutations have been reported in TRPV4, MORC2, CADM3, etc. 1,5,6), and it can develop even without a family history.
CMT progresses slowly and usually begins with symptoms in the feet.
Although CMT is a peripheral nerve disorder, it may be accompanied by ophthalmic findings.
Depending on the genotype, specific systemic findings may be present.
In CMT2A (MFN2 mutation), optic atrophy occurs in 9–20% of patients, causing slowly progressive vision loss and color vision abnormalities 2). Additionally, eye movement disorders, pupillary abnormalities, and retinal changes may occur. CMT2C is also associated with hearing loss (29%) 1). Since ocular symptoms can be the initial manifestation of CMT, caution is necessary.
CMT is caused by mutations in genes that maintain peripheral nerve function, and more than 80 genes are currently implicated. Approximately 90% of individuals confirmed by molecular targeted testing have mutations in PMP22, MPZ, GDAP1, MFN2, or GJB1.
The correspondence between major causative genes and subtypes is shown below.
| Gene | Subtype | Inheritance Pattern |
|---|---|---|
| PMP22 (17p11.2 duplication) | CMT1A (about 50% of all CMT) | Autosomal dominant |
| MFN2 | CMT2A2 (most common among CMT2) | Autosomal dominant |
| GJB1 | CMT1X | X-linked |
| MPZ | CMT1B, CMT2I, CMT2J | Autosomal dominant |
| SORD | CMT2・dHMN | Autosomal recessive |
First, nerve conduction velocity testing is used to distinguish between demyelinating and axonal types, followed by molecular targeted testing (genetic testing). In about 90% of cases, the causative mutation is identified by testing PMP22, MPZ, GDAP1, MFN2, and GJB1. With advances in next-generation sequencing (NGS) and whole-exome sequencing (WES), new causative genes such as SORD, CADM3, and NEFL continue to be discovered4,5,8).
The diagnosis of CMT is made in a stepwise manner.
Currently, there is no disease-modifying drug therapy for CMT. Treatment is mainly symptomatic and supportive, and a multidisciplinary approach is important.
Since best practices have not been established, individualized management according to each patient’s symptoms and disease progression is required.
Currently, there are no disease-modifying drugs, and treatment focuses on symptomatic and supportive care. A multidisciplinary approach combining rehabilitation, orthotic therapy, and surgical correction is standard. Randomized controlled trials of ascorbic acid (vitamin C) showed no significant benefit. Research into potential treatments, such as aldose reductase inhibitors for SOLD mutations, is ongoing; see the section on “Latest Research and Future Prospects”.
The pathophysiological mechanisms of CMT vary greatly depending on the genotype.
Defects in the production and maintenance of peripheral myelin lead to reduced nerve conduction velocity. The basic pathology is abnormal myelin structure due to overexpression of PMP22 (CMT1A) or MPZ mutations (CMT1B).
Mitochondrial dysfunction
MFN2 mutation (CMT2A2): Abnormal mitofusin 2 in the mitochondrial outer membrane impairs mitochondrial fusion.
Autopsy findings: Mitochondria in peripheral nerves and optic nerves show abnormal aggregation and rounding 2).
Systemic degeneration pattern: Longer pathways show more severe degeneration, with a reversal of the “proximal-distal gradient” from the periphery to the proximal region2).
Ion channel abnormalities
TRPV4 mutation (CMT2C): Gain-of-function mutation in a non-selective Ca²⁺-permeable cation channel.
Mechanism: Increased Ca²⁺ channel activity and loss of PI(4,5)P2 binding → Ca²⁺ overload → impaired axonal mitochondrial transport and axonal degeneration1). Neuropathy mutations impair RhoA binding and inhibit neurite outgrowth1).
Axon-glia interaction
CADM3 mutation: Binding of axonal CADM3 to Schwann cell CADM4 mediates major axon-glia adhesion.
Tyr172Cys mutation: Creates a novel disulfide bond and alters protein structure. The mutant protein is retained in the endoplasmic reticulum, reducing cell surface expression5).
Loss of function of sorbitol dehydrogenase leads to sorbitol accumulation. In a diabetic mouse model, sorbitol accumulation in the sciatic nerve induces neuropathy4). In some cases, muscle biopsy reveals desmin-positive inclusions (suggestive of surplus protein myopathy), and the phenotypic spectrum extends to myopathy7).
MORC2 encodes a DNA-dependent ATPase involved in epigenetic silencing, chromatin remodeling, DNA repair, and transcriptional regulation. Some mutations cause Leigh syndrome-like lesions on MRI, but peripheral blood mitochondrial function is normal, indicating a mechanism distinct from mitochondrial disease6).
Neurofilament light chain is essential for axonal structural stability and diameter maintenance. Dominant mutations cause gain-of-function effects that impair neurofilament assembly and intracellular organelle transport, while recessive mutations cause loss-of-function effects that result in the absence of the NF network 8).
Hayashi et al. (2023) reported in autopsies of two cases with the MFN2 p.Arg364Trp mutation marked optic nerve atrophy and loss of myelinated fibers, severe neuronal loss in the lateral geniculate body, and moderate loss of large neurons in layer IV of the primary visual cortex 2). This demonstrated systematic degeneration of the entire visual pathway, not just peripheral nerves.
Rebelo et al. (2021) reported that CADM3 gene mutations cause atypical CMT2 with upper limb predominance 5). They demonstrated a new disease mechanism of impaired axon-glia adhesion through the interaction between axonal CADM3 and Schwann cell CADM4, suggesting that this pathway could serve as a basis for novel therapeutic strategies.
Della Marina et al. (2024) first reported that 15% somatic mosaicism of NEFL mutation causes neuromuscular symptoms 8). The finding that somatic mosaicism can lead to clinical onset provides important implications for evaluating pathological significance in genetic counseling.
Autopsy studies of MFN2-mutated CMT2A2 have revealed multisystem central nervous system degeneration, including the visual pathway and posterior spinal cord, in addition to peripheral nerves 2). This finding prompts reconsideration of CMT as solely a peripheral nerve disease.
Progesterone antagonists, neurotrophic factors, ascorbic acid (vitamin C), and curcumin have been investigated in experimental models, but randomized controlled trials of ascorbic acid have not shown significant efficacy.
Chen H, Sun C, Zheng Y, et al. A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature review. BMC Neurol. 2023;23:250.
Hayashi H, Saito R, Tanaka H, et al. Clinicopathologic features of two unrelated autopsied patients with Charcot-Marie-Tooth disease carrying MFN2 gene mutation. Acta Neuropathol Commun. 2023;11:207.
Gemignani F, Percesepe A, Gualandi F, et al. Charcot-Marie-Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy. Int J Mol Sci. 2024;25:1654.
Yuan RY, Ye ZL, Zhang XR, et al. Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease. Ann Clin Transl Neurol. 2021;8:266-270.
Rebelo AP, Cortese A, Abraham A, et al. A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. Brain. 2021;144:1197-1213.
Yang H, Yang S, Kang Q, et al. MORC2 gene de novo mutation leads to Charcot-Marie-Tooth disease type 2Z: a pediatric case report and literature review. Medicine. 2021;100:e27208.
Massucco S, Gemelli C, Bellone E, et al. Skeletal muscle involvement in biallelic SORD mutations: case report and review of the literature. Acta Myol. 2023;42:113-117.
Della Marina A, Hentschel A, Czech A, et al. Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes. J Neuromuscul Dis. 2024;11:625-645.
