# Hereditary Neuropathies: Charcot-Marie-Tooth Disease

## Introduction

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, affecting approximately 1 in 2,500 individuals. It encompasses a genetically and phenotypically diverse group of disorders unified by progressive length-dependent motor and sensory neuropathy. Over 100 causative genes have been identified, making CMT a model for understanding how genetic advances translate into diagnostic and, increasingly, therapeutic opportunities in neurology.

## Classification

### By Nerve Conduction Studies

| CMT Type | NCV | Pattern | Inheritance | Common Gene |
|---|---|---|---|---|
| CMT1 (demyelinating) | <38 m/s | Uniform slowing | AD | PMP22 duplication (CMT1A, 40–50%) |
| CMT2 (axonal) | >38 m/s | Reduced CMAP amplitudes | AD | MFN2 (CMT2A) |
| CMT intermediate | 25–45 m/s | Mixed features | AD | Various |
| CMT4 | <38 m/s | Demyelinating, severe | AR | Various (consanguineous populations) |
| CMTX | Intermediate | Males more severe | X-linked | GJB1/connexin-32 (10–15% all CMT) |

CMT is classified primarily by nerve conduction study findings. CMT1 (demyelinating) is characterized by motor nerve conduction velocity (NCV) in the upper extremity less than 38 m/s with uniform slowing and autosomal dominant inheritance. CMT2 (axonal) shows motor NCV greater than 38 m/s with reduced compound muscle action potential (CMAP) amplitudes, also with autosomal dominant inheritance. CMT intermediate has motor NCV between 25-45 m/s with features of both demyelinating and axonal injury. CMT4 encompasses autosomal recessive demyelinating forms that are more severe with earlier onset. CMTX is X-linked with intermediate conduction velocities and males being more severely affected.

### Major Genetic Subtypes

CMT1A, caused by PMP22 duplication at 17p11.2, is the most common form overall, accounting for 40-50% of all CMT. It is autosomal dominant and involves duplication of the peripheral myelin protein 22 gene, producing the classic demyelinating phenotype. CMT1B is caused by MPZ (myelin protein zero) mutations and presents with a phenotype ranging from early severe to late-onset mild disease. CMTX1, caused by GJB1/connexin-32 mutations, is the second most common form (10-15%), with males showing moderate-to-severe neuropathy and females being variably affected, often mildly or asymptomatically; NCV may be intermediate. CMT2A, caused by MFN2 (mitofusin 2) mutations, is the most common axonal form and involves disrupted mitochondrial fusion; it can be severe with early onset and may include optic atrophy (CMT2A plus). CMT4 subtypes involve many genes, are autosomal recessive, typically present early with severe disease, and are more common in consanguineous populations.

## Clinical Features

### Motor Symptoms

The hallmark is slowly progressive, symmetric, distal weakness beginning in the feet and legs. Patients experience difficulty walking, frequent tripping, and ankle sprains. Foot deformities develop due to imbalanced muscle weakness, including pes cavus (high arched feet) and hammer toes. Distal leg atrophy produces the characteristic "inverted champagne bottle" or "stork leg" appearance. Hand weakness and atrophy involving the intrinsic hand muscles, thenar, and hypothenar eminences develop later. Scoliosis occurs in some subtypes, especially CMT4.

### Sensory Symptoms

Sensory loss follows a length-dependent pattern, with vibration and proprioception affected more than pain and temperature. Sensory symptoms are often less prominent than motor findings, and patients may be unaware of their sensory loss. Neuropathic pain occurs in some patients but is not a dominant feature in most CMT subtypes.

### Other Features

Depressed or absent ankle reflexes are often the first clinical sign, with reduced knee reflexes in advanced cases. Upper extremity tremor may be present and can be misdiagnosed as essential tremor (Roussy-Levy syndrome). Gait abnormality includes steppage gait due to foot drop, later progressing to a broad-based gait with sensory ataxia. Phrenic nerve involvement and respiratory insufficiency are rare but occur mainly in CMT2C and CMT4 subtypes. Vocal cord paralysis is associated with CMT2C/TRPV4 mutations, and hearing loss occurs in select forms such as CMT1E with PMP22 point mutations.

![Clinical photographs showing pes cavus, hammer toes, and distal leg atrophy in CMT](images/cmt-clinical-features.jpg)

## Diagnosis

### Electrodiagnostic Studies

Nerve conduction studies are the first step in evaluating suspected CMT and distinguish demyelinating from axonal forms. CMT1 shows uniformly slow NCVs in all nerves, unlike acquired demyelinating neuropathies where slowing is non-uniform with conduction block and temporal dispersion. CMT2 demonstrates normal or mildly slow NCVs with reduced CMAP and SNAP amplitudes. The uniform pattern of slowing without conduction block or temporal dispersion is the key feature distinguishing CMT1 from CIDP.

### Genetic Testing Strategy

The recommended approach begins with PMP22 duplication/deletion testing when NCV is less than 38 m/s; this detects CMT1A (duplication) and HNPP (deletion). If PMP22 testing is negative, GJB1 (connexin-32) sequencing follows, especially if the inheritance pattern suggests X-linkage or NCVs are intermediate. If the diagnosis remains elusive, a CMT gene panel or whole exome sequencing is pursued. For axonal CMT, MFN2 sequencing is performed first, followed by a gene panel or WES. A genetic diagnosis is achieved in approximately 60-70% of CMT cases with current testing.

### Distinguishing CMT from Acquired Neuropathies

Uniform slowing across nerves in CMT1 contrasts with non-uniform slowing and conduction block in CIDP. Insidious onset over years differs from the subacute onset over weeks to months seen in CIDP. Family history and skeletal deformities such as pes cavus suggest CMT. Elevated CSF protein can be seen in both conditions. Rarely, patients with CMT may develop superimposed CIDP.

## Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

HNPP is caused by PMP22 deletion, the opposite of the CMT1A duplication. It presents as recurrent, painless, focal demyelinating neuropathies at sites of compression or entrapment, including carpal tunnel syndrome, peroneal nerve palsy, and ulnar neuropathy. Episodes are usually reversible but may leave residual deficits over time. NCS shows multifocal demyelinating features with prolonged distal latencies. Nerve biopsy, which is rarely needed, reveals tomaculous changes (sausage-shaped myelin thickening).

![Nerve conduction study comparison showing uniform slowing in CMT1 versus non-uniform slowing with conduction block in CIDP](images/cmt-ncs-comparison.jpg)

## Management

### Rehabilitation and Supportive Care

Ankle-foot orthoses (AFOs) improve gait stability and prevent falls in patients with foot drop. Physical therapy focuses on stretching exercises, balance training, and low-impact aerobic exercise such as swimming and cycling, while avoiding excessive resistance training. Occupational therapy provides adaptive devices for hand weakness, including button hooks, jar openers, and ergonomic tools. Orthopedic surgery, including tendon transfers, plantar fascia release, and osteotomy, is considered for severe foot deformities when bracing is insufficient. Regular monitoring by a multidisciplinary team involving neurology, physiatry, orthopedics, and genetics is recommended.

### Medications to Avoid

Vincristine is absolutely contraindicated in CMT patients, as it can cause severe, life-threatening worsening of neuropathy. Other potentially neurotoxic medications should be used with caution, including cisplatin, taxanes, nitrofurantoin, prolonged courses of metronidazole, and high-dose pyridoxine. The CMT Foundation maintains an updated list of potentially neurotoxic medications.

### Emerging Therapies

Antisense oligonucleotides and RNA interference targeting PMP22 overexpression are in development for CMT1A. Gene therapy approaches for loss-of-function mutations, such as GJB1 gene replacement for CMTX1, are under investigation. High-dose ascorbic acid did not show benefit in clinical trials for CMT1A. HDAC6 inhibitors and neurotrophin-based strategies are in preclinical development.

![Management algorithm for CMT including rehabilitation, orthotic devices, and surveillance](images/cmt-management.jpg)

## Clinical Pearls

PMP22 duplication testing should be the first genetic test in any patient with a chronic, slowly progressive, symmetric demyelinating neuropathy with pes cavus, as it is the single most common cause of CMT. Uniform slowing of NCVs without conduction block is the electrophysiological hallmark of CMT1 and distinguishes it from CIDP, a distinction with critical treatment implications since CIDP is treated with immunotherapy while CMT is not. HNPP (PMP22 deletion) should be considered in any patient with recurrent, multifocal compressive mononeuropathies, especially with a family history. Vincristine is absolutely contraindicated in CMT patients and can cause devastating, irreversible neuropathy; all CMT patients should carry medical alert information. Genetic testing identifies the cause in approximately 60-70% of CMT cases, and a negative result does not exclude CMT, as many causative genes remain to be discovered.

## References

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