Hereditary Neuropathies (CMT)

Hereditary neuropathies are a genetically and phenotypically heterogeneous group of peripheral nerve disorders, of which Charcot-Marie-Tooth disease (CMT) is the most common. With a global prevalence of 10–30 per 100,000, CMT is the most common inherited neuromuscular condition, presenting with chronic, slowly progressive, length-dependent sensorimotor polyneuropathy. Advances in clinical genetic testing have broadened the recognized spectrum, identified new subtypes such as SORD-related neuropathy and CANVAS, and opened the door to gene-targeted therapeutic approaches.

Classification of Hereditary Neuropathies

Hereditary neuropathy phenotypes are defined by the degree of motor versus sensory involvement and further subclassified by electrophysiology and inheritance pattern. CMT affects both sensory and motor modalities and is the most common phenotype.

Core Clinical Features of CMT

CMT is a chronic, slowly progressive, symmetric, length-dependent polyneuropathy with predominantly distal motor weakness and atrophy greater than sensory loss. Clinicians should suspect hereditary neuropathy in patients with chronic distal-predominant motor or sensory deficits, diminished reflexes, and foot deformity — particularly when there is a family history.

Age of Onset Patterns

• Autosomal recessive CMT: Manifests early, from birth through childhood
• CMT1 (demyelinating): Typically childhood through early adulthood
• CMT2 (axonal): May present later, from early to late adulthood
• Pediatric presentation: One-third of CMT patients present in infancy or childhood; early signs include toe walking, delayed motor milestones (with normal cognition/language), clumsiness, and frequent falls

CMT1: Demyelinating Forms

CMT1A — PMP22 Duplication (Most Common CMT)

CMT1A accounts for 37% of all CMT and 55% of genetically confirmed cases. It is caused by a 1.5-Mb duplication on chromosome 17p11.2 leading to three copies of the PMP22 gene, which encodes peripheral myelin protein 22 — a structural protein in the myelin sheath.

• Onset: First two decades of life; early symptoms include falling, tripping, and footdrop
• Foot morphology: Pes cavus and hammer toes in up to 90%; often precedes clinically apparent weakness and is first evaluated by orthopedists
• Progression: Distal lower extremity weakness → intrinsic hand weakness and atrophy over time
• Electrodiagnosis: Uniform motor conduction slowing with velocities around 20 m/s (median motor NCV ~17–20 m/s); conduction block and temporal dispersion are absent
• Additional features: Sensorineural hearing loss and vestibular impairment (particularly relevant in children for speech development); phrenic nerve involvement causing hypoventilation (uncommon); increased prevalence of obstructive sleep apnea (~37%)

CMT1B — MPZ Mutations

CMT1B is caused by heterozygous variations in MPZ, encoding myelin protein zero, a transmembrane protein involved in myelin layer adhesion. Clinically and electrophysiologically similar to CMT1A, but MPZ variants can also produce an intermediate electrophysiologic phenotype or a later-onset axonal form (CMT2J).

Other CMT1 Subtypes

CMT2: Axonal Forms

Axonal CMT accounts for approximately 30% of genetically confirmed cases. Clinically similar to demyelinating CMT but often with later onset. Nerve conduction studies demonstrate low-amplitude motor and sensory responses with relatively preserved conduction velocities. More than 30 genes are known to cause CMT2, and the genetic yield for axonal neuropathy is around 20%.

CMT2A — MFN2 Mutations (Most Common Axonal CMT)

MFN2-related CMT (CMT2A) is the most common autosomal dominant axonal subtype, accounting for 3–4% of all CMT and 7–12% of genetically confirmed cases. Mitofusin 2 plays a role in mitochondrial fusion, fission, and axonal transport.

• Clinical features: Earlier symptom onset correlates with more severe progression and higher likelihood of wheelchair dependence
• Progression: May appear more rapid than other CMT subtypes in some patients
• Associated features: Optic atrophy, hearing loss, vocal cord paralysis, diaphragmatic weakness with hypoventilation, upper motor neuron signs, and cognitive impairment in certain MFN2 variants

CMTX: X-Linked Forms

X-linked CMT accounts for 10–15% of CMT. CMTX1 is the second most common CMT overall (after CMT1A), caused by variants in GJB1, encoding connexin 32 — a gap junction protein highly expressed in Schwann cells and oligodendrocytes.

Autosomal Recessive CMT (CMT4)

Autosomal recessive inheritance accounts for <10% of CMT. CMT4 is generally demyelinating with 11 gene subtypes (CMT4A–4J). These forms usually have earlier onset (infancy/childhood), a more progressive course, and both distal and proximal weakness, which may lead to loss of ambulation.

Notable AR Subtypes

• CMT4A (GDAP1): Presents in early childhood with rapidly progressive distal weakness; predominantly demyelinating but may have mixed features
• SORD-related neuropathy: A recently discovered, potentially treatable AR CMT caused by biallelic SORD variants; likely one of the most common AR forms based on allele frequency; motor-predominant axonal neuropathy with a distinctive pattern of plantar flexion weakness greater than dorsiflexion; onset in adolescence/early adulthood; pathomechanism involves toxic sorbitol accumulation
• PCK2-related CMT: A newly reported demyelinating AR form with some features mimicking acquired demyelination (temporal dispersion, conduction block)

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

HNPP results from a dominantly inherited deletion or sequence variant of PMP22 at chromosome 17p11.2 — the reciprocal of the CMT1A duplication. Prevalence is estimated at 7.3–15 per 100,000, making it one of the more common hereditary neuropathies.

Hereditary Sensory and Autonomic Neuropathies (HSAN)

HSAN is characterized predominantly by degeneration of sensory and autonomic fibers, with variable motor involvement. Patients develop distal sensory loss, skin ulcerations (sometimes requiring acral amputation), autonomic dysfunction, and in some subtypes, severe pain.

Distal Hereditary Motor Neuropathies (dHMN)

Distal hereditary motor neuropathies present with progressive distal weakness and atrophy without prominent sensory deficits. They are distinguished from motor neuron diseases (ALS, SMA) by symmetric distal-predominant weakness and less prominent upper motor neuron involvement.

• Electrodiagnosis: Low-amplitude CMAPs with preserved sensory responses; chronic neurogenic changes primarily in distal muscles on EMG
• Onset: Typically within the first two decades of life
• Notable subtypes: SMA with respiratory distress type 1 (IGHMBP2) presents with diaphragmatic paralysis in the first year; dHMN type VII has vocal cord paralysis with hand weakness; TRPV4-related neuropathy presents with scapuloperoneal weakness
• Overlap: Some genes (e.g., SORD, TRPV4, GARS1, HSPB1, HSPB8) cause both dHMN and CMT2 phenotypes

Diagnostic Approach

Electrodiagnostic Evaluation

Electrophysiology is typically the first step in diagnostic classification, confirming the presence of neuropathy and determining whether it is primarily demyelinating or axonal.

Nerve Ultrasonography

Nerve cross-sectional areas are often enlarged at proximal and distal sites in hereditary demyelinating neuropathies. Ultrasonography is a useful adjunct, especially in the pediatric population where electrodiagnostic testing may not be feasible. In HNPP, enlargement is characteristically seen at common entrapment sites.

Genetic Testing Strategy

CMT Mimicking CIDP

CIDP is frequently on the differential diagnosis for demyelinating CMT. A retrospective study found that 3.2% of CIDP diagnoses were instead genetically confirmed CMT. Red flags for misdiagnosis include younger age of onset, prominent distal atrophy at presentation, and lack of response to immunotherapy. Some CMT subtypes (GJB1, FIG4, PCK2) may exhibit acquired demyelination features including conduction block and temporal dispersion, further complicating the distinction. In the pediatric population, severe autosomal recessive forms with rapid progression can closely mimic CIDP.

Other Genetic Disorders with Associated Neuropathy

Peripheral neuropathy is a component of many complex genetic syndromes with central nervous system involvement and systemic manifestations.

Management

Supportive Care

The mainstay of treatment for CMT and other hereditary neuropathies remains symptomatic management, with emphasis on optimizing gait, function, and preventing complications.

• Physical therapy: Maintain strength in affected muscles, optimize core strength, gait and balance training, stretching to prevent joint contractures; water-based therapies are optimal for neuromuscular patients
• Orthotics: Ground reaction ankle-foot orthoses (AFOs) are used by most people with CMT to support distal weakness and provide proprioceptive input; nighttime bracing may help prevent contractures
• Assistive devices: Shoe inserts, ankle braces, canes, walkers, and wheelchairs as needed
• Pain management: Address neuropathic pain and fatigue, which are common and impact quality of life
• Hearing evaluation: Particularly important in pediatric patients given the impact on speech and language development
• Respiratory monitoring: Screen for phrenic nerve involvement and obstructive sleep apnea in CMT1

Surgical Considerations

• Goal: Stabilize the foot, improve function, and reduce pain when bracing and therapy are insufficient
• Approaches: Range from soft tissue release and tendon transfer to osteotomy and full reconstruction
• Arthrodesis: Joint fixation is generally a last resort; triple arthrodesis is not recommended in children
• Progressive disease: Risk of recurrence despite surgery — timing and approach require thorough discussion with the patient and family

Pediatric Management

• Age-appropriate activities (outdoor play, swimming, dance) may be more feasible than structured therapy in young children
• Early intervention programs and focused functional occupational/physical therapy help build compensatory habits
• Ground reaction AFOs improve gait efficiency and reduce fall risk
• Orthopedic care should be part of a multidisciplinary approach

Emerging Therapeutics

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