Charcot-Marie-Tooth Disease

Demyelinating CMT (CMT1)

• PMP22 gene mutations (chromosome 17p11.2) account for ~80% of CMT1 cases; encodes peripheral myelin protein 22, critical for myelin formation and stability
• Alterations in protein folding, trafficking, or incorporation into myelin lead to Schwann cell dysfunction and myelin decompaction
• Segmental demyelination with onion-bulb formations (concentric layers of Schwann cell processes around axons) characterize pathology
• Progressive loss of large myelinated fibers with relative sparing of unmyelinated fibers
• Nerve conduction velocity characteristically slowed (<38 m/sec) due to impaired saltatory conduction

Axonal CMT (CMT2)

• Mutations in genes encoding axonal cytoskeletal proteins, mitochondrial function, or motor/sensory neuron proteins (e.g., MFN2, KIF5A, NEFL)
• Mechanisms include impaired axonal transport, mitochondrial dysfunction, proteasomal degradation dysfunction, and compromised cytoskeletal architecture
• Primary axonal degeneration with secondary myelin changes (contrasting CMT1's primary demyelination)
• Selective loss of large-diameter motor and sensory axons with relatively preserved nerve conduction velocities (>38 m/sec)
• Age-related accumulation of axonal degeneration with progressive functional decline

X-linked CMT (CMTX)

• GJB1 gene mutations encoding connexin 32, a gap junction protein essential for internodal myelin integrity and Schwann cell-axon communication
• Hemizygous males show demyelinating features; heterozygous females demonstrate variable manifestations due to random X-inactivation
• Disrupted cell-to-cell communication in peripheral myelin

Autosomal Dominant CMT (60% of cases)

• CMT1A: PMP22 duplication/mutation (most common form; ~17p11.2 duplication in 70% of CMT1 cases)
• CMT1B: MPZ gene mutations (myelin P0 protein)
• CMT1C: LITAF gene mutations
• CMT1D: EGR2 gene mutations (early growth response 2)
• CMT2 subtypes: MFN2 (mitochondrial fusion protein; most common axonal form), KIF5A (kinesin family motor protein), NEFL (neurofilament light chain), HSPB1 (heat shock protein)

Autosomal Recessive CMT

• CMT4A-J: Various genes including GDAPl1, SH3TC2, FDG4, FIG4, SURF1, TFG, COX6A1
• Typically more severe phenotype with earlier age of onset
• Often demyelinating pattern despite autosomal recessive inheritance

X-linked CMT

• CMTX1: GJB1 mutations (80% of X-linked cases; males severely affected; females variably affected)
• CMTX2-6: Rare forms with mutations in other genes

Risk Factors (Non-genetic)

• Family history (highly penetrant; however, incomplete penetrance and variable expressivity occur)
• Consanguinity in autosomal recessive forms
• Advanced paternal age (de novo mutations)

Cardinal Features

• Distal lower extremity weakness and atrophy: Begins insidiously in the intrinsic foot muscles, progressing proximally; peroneal muscle atrophy creates characteristic "inverted bottle legs" or "stork legs" appearance
• Distal sensory loss: Stocking-glove distribution affecting vibration and proprioception preferentially; pain and temperature sensation relatively spared
• Foot deformities: High arches (pes cavus), hammer toes, inversion deformities develop secondary to differential denervation of foot muscles
• Gait abnormality: Steppage gait compensating for foot drop; patients lift knees excessively to clear toes from ground

Physical Examination Findings

• Diminished or absent deep tendon reflexes: Achilles reflex lost early and disproportionately; ankle jerk absence is a cardinal sign
• Palpably thickened peripheral nerves: Particularly sural and ulnar nerves; may be grossly enlarged in demyelinating types
• Muscle atrophy patterns: Bilateral symmetric distal > proximal distribution; intrinsic hand muscle involvement occurs later
• Sensory examination abnormalities: Decreased vibration sense (most sensitive), proprioception loss; variable light touch and pain sensation depending on severity
• Upper extremity involvement: Typically manifests 10+ years after lower extremity symptoms; distal hand weakness and atrophy; may be minimal in some patients

Uncommon Manifestations

• Tremor: Low-frequency postural tremor ("pseudo-myotonic tremor") may occur, particularly in CMT1
• Vocal cord paresis: Reported in some CMTX1 and rare CMT1 cases
• Scoliosis: Develops in 5-10% of patients, more common in early-onset disease
• Nystagmus: Occasional finding in some CMT subtypes

Age-Related Presentation

• Infantile-onset (CMT4 variants): Can present as early as infancy with severe weakness, developmental delays
• Childhood-onset (typical): Ages 5-25 years; most common presentation; often detected when child noted to be clumsy, falls frequently, or ankle weakness apparent
• Adult-onset: Rarer; can occur with late-manifestation mutations or high genetic anticipation

Clinical Assessment

• Detailed family history with pedigree construction; assess for affected parents, siblings, grandparents
• Age of symptom onset; rate of progression; current functional status
• Characterize distribution: distal > proximal; lower > upper extremities (typical pattern)
• Assess footwear wear patterns (lateral toes worn more due to inversion)
• Quantify disability using Charcot-Marie-Tooth Neuropathy Score (CMTNS) for standardization and prognostication

Electrodiagnostic Studies (Essential for Classification)

• Nerve Conduction Studies (NCS):
• Demyelinating pattern (CMT1): Median motor nerve conduction velocity <38 m/sec; prolonged distal latencies (>4.5 msec median); conduction blocks or temporal dispersion
• Axonal pattern (CMT2): Motor nerve conduction velocity ≥38 m/sec with reduced amplitudes; relatively preserved conduction velocities
• Early prolonged latencies and slowing may be sole abnormality in early/mild disease
• Sural sensory nerve response typically reduced or absent

• Electromyography (EMG):
• Chronic denervation pattern: reduced recruitment of motor units with high-amplitude, long-duration polyphasic action potentials
• Fibrillation potentials and positive sharp waves in severely denervated muscles
• Differentiates myopathic (polyphasic, short duration) from neuropathic patterns

Laboratory Studies

• Serum creatine kinase (CK): Normal or mildly elevated (<2-3× upper limit of normal)
• Vitamin B12, folate, thyroid function: Rule out acquired causes of neuropathy
• Glucose tolerance testing or HbA1c: Exclude diabetic neuropathy in similar phenotype
• Genetic testing:
• Single-gene testing: If specific clinical/family history suggests particular subtype (e.g., PMP22 duplication in CMT1A)
• Multigene panel: Comprehensive testing covering CMT genes; increasingly first-line approach
• Whole exome or whole genome sequencing: For atypical presentations or negative panel results
• Duplication/deletion analysis: Particularly for 17p11.2 region (PMP22) given high frequency in CMT1

Imaging Studies

• Nerve ultrasound (emerging modality): Demonstrates nerve enlargement and echogenicity changes; may help differentiate CMT subtypes
• MRI brain/spine: Generally normal in uncomplicated CMT; useful if atypical features (e.g., central nervous system involvement, myelopathy)
• Foot X-rays: Document pes cavus, hammer toes, other structural changes

Diagnostic Criteria (Clinical Diagnosis)

• Progressive distal weakness and atrophy (lower > upper extremities)
• Distal sensory loss
• Diminished or absent reflexes (especially Achilles)
• Family history consistent with Mendelian inheritance (or proven pathogenic genetic variant)
• Electrodiagnostic confirmation (demyelinating vs. axonal pattern)
• Normal or mildly elevated CK
• Exclusion of other inherited or acquired neuropathies

Diagnostic Challenges

• de novo mutations: Absence of family history may delay diagnosis; occurs in ~10% of CMT cases
• Phenotypic overlap: CMT2 may mimic hereditary sensory and autonomic neuropathy (HSAN) or distal hereditary motor neuritis (dHMN); genetic testing clarifies
• Subclinical manifestations in carriers: Heterozygous females in CMTX1 may show minimal symptoms or absent reflexes alone

Genetic Counseling & Patient Education (Foundation)

• Autosomal dominant inheritance: 50% risk to each offspring regardless of gender
• X-linked (CMTX1): Hemizygous males severely affected; heterozygous females variably affected; affected males pass trait to all daughters (carrier) and sons unaffected
• Autosomal recessive: 25% risk to offspring if both parents carriers; consanguinity assessment critical
• Encourage genetic testing of asymptomatic family members to enable early intervention and lifestyle modification
• Educate regarding disease trajectory, realistic expectations, and psychosocial support resources

Pharmacological Management

• No disease-modifying therapy currently approved for most CMT types; treatment is symptomatic and supportive
• Baclofen (5-20 mg TID): Addresses spasticity if present (rare in uncomplicated CMT); mechanism—GABA-B agonist reducing excitatory neurotransmission
• Lamotrigine (investigational for CMT1X): Preliminary evidence in small studies; may stabilize nerve conduction in CMTX1; dosing 25-100 mg BID
• Ascorbic acid (Vitamin C): High-dose supplementation (1500 mg daily) explored in PMP22 duplication-related CMT1A; mixed evidence; mechanism—may reduce myelin instability
• NSAIDs (Ibuprofen): For musculoskeletal pain or cramping; topical agents for localized discomfort
• Tricyclic antidepressants (Amitriptyline 10-75 mg nightly): Address neuropathic pain if present
• Pregabalin or Gabapentin: Reserved for neuropathic pain complications

Physical Medicine & Rehabilitation (Cornerstone of Management)

• Tailored physical therapy: Strengthening exercises targeting proximal lower and upper extremity muscles to preserve function and prevent contractures; low-impact aerobic conditioning
• Stretching programs: Prevent muscle contractures, particularly in Achilles tendon and hip flexors
• Occupational therapy: Assess activities of daily living; adaptive equipment (button hooks, dressing aids); workplace ergonomics
• Gait training: Strategies to reduce fall risk; energy-efficient walking patterns
• Cardiopulmonary fitness: Regular exercise improves motor performance and prevents secondary deconditioning; avoidance of prolonged immobilization

Orthotic & Surgical Interventions

• Ankle-foot orthoses (AFO): Primary intervention for foot drop and ankle instability; improves gait, reduces falls; polypropylene or carbon-fiber designs; custom-molded preferred
• Foot orthoses/inserts: Address pes cavus, improve weight distribution, reduce plantar pressure
• Knee-ankle-foot orthoses (KAFO): Considered if knee weakness becomes limiting
• Surgical correction: Reserved for severe, progressive foot deformities limiting mobility
• Triple arthrodesis: Fuses hindfoot joints to correct pes cavus
• Tendon transfers: For severe toe deformity or ankle weakness
• Achilles tendon lengthening: If contracture limits dorsiflexion
• Consider only after growth plate closure and careful patient selection

Monitoring & Disease Surveillance

• Baseline and serial electrodiagnostic studies: Useful for research; clinical utility for routine follow-up limited but may guide prognosis
• Annual clinical examination: Assess strength (manual muscle testing or quantitative), sensory status, functional mobility, new symptoms
• Pulmonary function testing: If respiratory symptoms develop or bulbar involvement suspected (rare)
• Cardiac assessment: CMT2 with MFN2 mutations occasionally associated with cardiac involvement; baseline ECG reasonable
• Psychosocial screening: Depression and anxiety common; refer for counseling/psychiatry as needed

Lifestyle Modifications

• Appropriate footwear: Supportive, protective shoes; avoid high heels; custom insoles for cavus feet
• Fall prevention: Home safety assessment; removal of tripping hazards; adequate lighting; grab bars; consideration of assistive devices (cane, walker)
• Activity modification: Avoid prolonged standing; frequent rest breaks; high-impact activities may accelerate disability
• Smoking cessation: General health benefit; may mitigate ischemic complications in inherited neuropathies

Musculoskeletal Complications

• Contractures: Achilles tendon shortening with equinus deformity; hip/knee flexor contractures; progressive if untreated; managed with aggressive stretching, night splinting, surgical release
• Severe foot deformities: Pes cavus with metatarsophalgia; claw toes; ankle inversion; compromise gait and footwear fitting
• Scoliosis: Develops in 5-10% of patients; more common in childhood-onset disease; progressive in 50% of affected individuals; rarely requires surgical fusion unless severe/symptomatic

Integumentary Complications

• Plantar ulceration: Results from combined sensory loss (delayed pressure/trauma detection) and biomechanical foot changes (pes cavus increases plantar pressure); risk of secondary infection and osteomyelitis
• Management: Protective footwear, pressure-relieving orthoses, meticulous foot hygiene, education on daily foot inspection, possible surgical weight redistribution
• Calluses and corns: Develop over pressure areas; require regular podiatric care

Pain Syndromes

• Neuropathic pain: Dysesthesias, paresthesias in feet (minority of patients); managed with tricyclic antidepressants, pregabalin, or topical agents
• Musculoskeletal pain: From contractures, abnormal gait biomechanics, overuse of upper extremities as compensation; address with physical therapy, NSAIDs, stretching

Functional Impairment

• Progressive mobility limitation: Advancing weakness necessitates graduated use of assistive devices (canes, walkers, wheelchairs); impacts quality of life, independence, employment
• Wheelchair dependence: Variable onset; typically later in disease course in CMT1; earlier in severe CMT4 variants; social and psychological impact substantial

Rare/Severe Complications

• Respiratory involvement: Extremely rare; reported in early-onset severe forms (CMT4) with possible involvement of phrenic nerve; can necessitate assisted ventilation
• Bulbar dysfunction: Extremely uncommon; reported in isolated cases; may compromise swallowing
• Autonomic dysfunction: Occasional mild

Buzzwords that give away the diagnosis

• **"Inverted champagne bottle" / stork legs plus pes cavus and hammer toes**: distal wasting that stops mid-calf, with steppage gait and absent ankle jerks, in a teenager or young adult with an affected parent — think CMT before acquired neuropathy.
• Onion-bulb formation on nerve biopsy and palpably thickened nerves: the histologic signature of repeated demyelination–remyelination in CMT1. Biopsy is essentially never needed clinically, but stems still use it as the giveaway.

The single association examiners love

• PMP22 dosage at 17p11.2: duplication causes CMT1A; the reciprocal deletion causes hereditary neuropathy with liability to pressure palsies (HNPP), which presents with recurrent painless focal palsies after trivial compression. Same gene, opposite copy number, opposite phenotype.
• CMTX1 (GJB1/connexin 32): suspect when affected males are more severe than their mildly affected mothers/daughters and there is no male-to-male transmission.

Best next step

• Nerve conduction studies before genetics: NCS separate demyelinating (uniformly slowed velocities) from axonal (low amplitudes, near-normal velocities), which determines which gene or panel to order. Targeted PMP22 duplication testing is the highest-yield first genetic test in a demyelinating phenotype, consistent with ACMG guidance on stepwise molecular testing.

Distractors to avoid

• CMT is not CIDP: CMT shows uniform, symmetric slowing without conduction block, a decades-long indolent course, and foot deformity. CIDP shows non-uniform slowing with conduction block, elevated CSF protein, and responds to IVIG/steroids per AAN guidance. Do not give immunotherapy for CMT — there is no disease-modifying drug.
• Do not credit vitamin C, steroids, or IVIG as treatment; ankle-foot orthoses and rehabilitation remain the cornerstone.
• Neurotoxic drug exposure is the testable safety point: vincristine can precipitate rapid, sometimes irreversible deterioration in CMT1A and should be avoided; other agents (e.g., taxanes, platinums, amiodarone, nitrofurantoin) warrant caution.
• Sensation is not spared: large-fiber modalities (vibration, proprioception) go first, unlike pure distal hereditary motor neuropathy.