Residency · Residency · Medical Genetics Genomics

Hereditary Neuropathies: Charcot-Marie-Tooth Disease Spectrum

Introduction

Charcot-Marie-Tooth disease (CMT) encompasses a genetically heterogeneous group of inherited peripheral neuropathies affecting approximately 1 in 2,500 individuals, making it the most common inherited neuromuscular disorder. CMT is characterized by progressive distal muscle weakness and atrophy, sensory loss, and skeletal deformities. Over 100 causative genes have been identified, with inheritance patterns spanning autosomal dominant, autosomal recessive, and X-linked.

Classification

CMT Type 1 (Demyelinating)

CMT type 1 is defined by nerve conduction velocities below 38 m/s in the upper extremities and shows onion bulb formation on nerve biopsy, reflecting Schwann cell proliferation. CMT1A, caused by PMP22 duplication, accounts for 70% of CMT1 cases and is the most common overall CMT type. CMT1B results from MPZ mutations, CMT1C from LITAF mutations, and CMT1D from EGR2 mutations.

CMT Type 2 (Axonal)

CMT type 2 is characterized by nerve conduction velocities above 38 m/s with reduced amplitudes, reflecting primary axonal degeneration. CMT2A, caused by MFN2 mutations, is the most common axonal form. CMT2E results from NEFL mutations, and multiple rare subtypes (CMT2B through CMT2Z) have been described.

Intermediate CMT

Intermediate CMT features nerve conduction velocities between 25 and 45 m/s with features of both demyelination and axonal loss. CMTX1, caused by GJB1 (connexin 32) mutations, is X-linked and represents the most common CMT subtype after CMT1A. Dominantly inherited intermediate CMT (DI-CMT) subtypes are also recognized.

CMT Type 4 (Autosomal Recessive Demyelinating)

CMT type 4 encompasses severe, early-onset forms that are more prevalent in consanguineous populations. Multiple subtypes exist (CMT4A through CMT4J), with CMT4C caused by SH3TC2 mutations being one of the more common autosomal recessive forms.

Hereditary Motor Neuropathies (dHMN)

The distal hereditary motor neuropathies feature predominantly motor involvement with minimal sensory findings. There is clinical overlap with CMT2 and distal SMA phenotypes.

Hereditary Sensory and Autonomic Neuropathies (HSAN)

HSAN involves predominantly sensory involvement with autonomic dysfunction. HSAN1, caused by SPTLC1 mutations, is a dominantly inherited sensory neuropathy characterized by lancinating pain.

Molecular Pathogenesis

CMT1A -- The PMP22 Duplication Paradigm

CMT1A results from a 1.5 Mb duplication on chromosome 17p11.2 containing the PMP22 gene. Overexpression of PMP22 disrupts myelin assembly and Schwann cell function. The reciprocal deletion of this region causes hereditary neuropathy with liability to pressure palsies (HNPP). This duplication arises by unequal crossing over between flanking repeat sequences known as CMT1A-REPs.

Axonal Transport and Mitochondrial Dynamics

MFN2 (mitofusin 2) is essential for mitochondrial fusion, and mutations impair axonal mitochondrial transport. Axonal forms of CMT often involve genes in cytoskeletal function, RNA processing, or organelle trafficking.

Myelin-Related Genes

MPZ, PMP22, GJB1, and EGR2 encode proteins critical for myelin structure and maintenance. Their disruption leads to demyelination, secondary axonal degeneration, and onion bulb formation.

Clinical Features

Motor Manifestations

The hallmark of CMT is progressive distal lower extremity weakness, manifesting as foot drop and steppage gait. Intrinsic hand muscle wasting develops later in the disease. Pes cavus and hammer toes develop from imbalanced muscle forces acting on the foot architecture. The classic "inverted champagne bottle" leg appearance results from distal atrophy with preserved proximal muscles. Hyporeflexia or areflexia is typical.

Sensory Findings

Distal sensory loss affecting vibration, proprioception, and pain/temperature modalities is present but generally less prominent than motor findings in most CMT types. Neuropathic pain occurs in some subtypes.

Additional Features by Subtype

CMTX1 may show subclinical CNS involvement with white matter changes on MRI and transient stroke-like episodes. CMT2A can include optic atrophy in severe cases. CMT4 subtypes present with early onset, severe disability, scoliosis, and vocal cord paresis (particularly CMT4A).

Diagnostic Approach

Electrophysiology

Nerve conduction studies are the essential first step to classify CMT as demyelinating versus axonal. Uniform slowing characterizes CMT1, in contrast to the patchy demyelination seen in acquired demyelinating neuropathies. The motor NCV in the median nerve below 38 m/s indicates CMT1, while values above 38 m/s indicate CMT2.

Genetic Testing Strategy

The recommended approach begins with testing for PMP22 duplication or deletion using MLPA or array CGH, as this accounts for approximately 50% of all CMT. If negative, GJB1 should be considered, especially if the inheritance pattern suggests X-linkage or NCVs are intermediate. Subsequently, multi-gene CMT panels or whole exome sequencing can be pursued. Despite comprehensive testing, approximately 40% of CMT cases currently lack a molecular diagnosis.

Nerve Biopsy

Nerve biopsy is rarely needed in the era of genetic testing and is reserved for atypical cases or when acquired neuropathy cannot be excluded.

Management

Rehabilitation

Ankle-foot orthoses (AFOs) improve gait stability and reduce falls. Physical therapy focuses on stretching, strengthening, and balance. Occupational therapy optimizes hand function, and assistive devices are introduced as needed.

Surgical Interventions

Orthopedic surgery may be required for severe pes cavus, hammer toes, or hip dysplasia. Tendon transfers can improve foot dorsiflexion.

Avoidance of Neurotoxic Agents

Vincristine is absolutely contraindicated in CMT patients, as it can cause severe, irreversible neuropathy. Caution is also warranted with other potentially neurotoxic drugs including cisplatin, taxanes, nitrofurantoin, and high-dose pyridoxine.

Emerging Therapies

PXT3003 (a combination of baclofen, naltrexone, and sorbitol) is in clinical trials for CMT1A. Antisense oligonucleotides targeting PMP22 overexpression, gene therapy approaches for specific subtypes, and neurotrophin delivery with Schwann cell-targeted therapies are in preclinical development.

Clinical Pearls

PMP22 duplication (CMT1A) accounts for approximately 50% of all CMT and should always be tested first with MLPA or targeted copy number analysis. Vincristine is absolutely contraindicated in CMT patients and can cause fatal neurotoxicity -- this represents a critical pharmacogenomic interaction that must be communicated to all treating physicians. HNPP (hereditary neuropathy with liability to pressure palsies) is caused by the reciprocal deletion of the CMT1A duplication region and presents with recurrent, painless focal neuropathies at compression sites. Despite over 100 known causative genes, approximately 40% of CMT patients remain without a molecular diagnosis, highlighting the ongoing need for gene discovery efforts.

References

1. Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol. 2017;30(5):471-480.
2. Timmerman V, Strickland AV, Zuchner S. Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the Human Genome Project success. Genes. 2014;5(1):13-32.
3. Shy ME, Patzko A. Axonal Charcot-Marie-Tooth disease. Curr Opin Neurol. 2011;24(5):475-483.
4. Pisciotta C, Pareyson D. Gene therapy and other novel treatment approaches for Charcot-Marie-Tooth disease. Neuromuscul Disord. 2023;33(8):627-635.

Read this lecture as Markdown