Hereditary Neuropathies

Classification Overview

1. Charcot-Marie-Tooth Disease (CMT / HMSN)

CMT Type 1 (Demyelinating, AD)

• Most common subtype: CMT1A — caused by a 1.5-Mb duplication of chromosome 17p11.2-12 containing the PMP22 gene (peripheral myelin protein 22). Point mutations in PMP22 also occur.
• CMT1B: caused by mutations in MPZ (myelin protein zero), the major structural protein of compact myelin.
• CMT1C, 1D, 1E, 1F: caused by mutations in LITAF, EGR2, PMP22 (point mutation), and NEFL.
• NCV: markedly slowed, typically <38 m/sec in median motor nerve (often 15–25 m/sec). Slowing is uniform across the nerve.
• Nerve biopsy: classic onion bulb formations — Schwann cell processes wrapped concentrically around axons due to repeated demyelination and remyelination.
• Clinical features: distal wasting and weakness beginning in the feet/legs (peroneal distribution → "inverted champagne bottle" legs), pes cavus, hammer toes, areflexia, and mild distal sensory loss. Onset in the first or second decade.

CMT Type 2 (Axonal, AD)

• Primary axonal degeneration (not demyelination).
• CMT2A: most common CMT2 subtype; caused by mutations in MFN2 (mitofusin-2), involved in mitochondrial dynamics. Often more severe, with proximal involvement and early upper-limb involvement.
• Other loci include MPZ mutations (CMT2I/J), which can also cause late-onset CMT1 phenotype.
• NCV: normal or mildly reduced (>38 m/sec); CMAP amplitudes are reduced reflecting axonal loss.
• Nerve biopsy: loss of large myelinated axons with clusters of regenerating fibers; no onion bulbs.

X-Linked CMT (CMTX1)

• Caused by mutations in Cx32 (connexin 32), a gap junction protein in noncompact myelin (paranodal loops, Schmidt-Lanterman incisures).
• Over 200 mutations identified. No male-to-male transmission.
• Males are more severely affected (NCVs in intermediate range, 35–45 m/sec); heterozygous females have mild or subclinical disease.
• Some mutations cause CNS involvement: white-matter MRI abnormalities, abnormal brainstem auditory evoked potentials. Patients should be warned about high-altitude travel, which can precipitate transient CNS episodes (ataxia, dysarthria).

CMT Type 4 (AR, Demyelinating)

• Rare AR forms; multiple causative genes (e.g., GDAP1, MTMR2, SH3TC2).
• Typically more severe, earlier onset than AD forms.

Dejerine-Sottas Disease (DSD / CMT3)

• Uncommon hypertrophic neuropathy with onset in childhood; most cases sporadic (de novo dominant mutations in PMP22, MPZ, or EGR2).
• NCV markedly slowed, often <10–15 m/sec. CSF protein elevated.
• Pathology: pronounced onion bulbs, hypomyelination, increased axon-to-fiber diameter ratio.

2. Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

• AD disorder caused by a 1.5-Mb deletion on chromosome 17p11.2-12 (same region as CMT1A duplication — genomic reciprocal).
• Prevalence ~16 per 100,000.
• Recurrent, painless mononeuropathies provoked by minor compression or traction (fibular > ulnar > brachial plexus > radial > median nerves). Most episodes resolve completely within days to weeks.
• About 15% of carriers remain asymptomatic.
• NCV pattern: prolonged distal motor latencies, focal slowing at compression sites, diffuse reduced SNAP amplitudes; sural SNAP absent in >90%.
• Nerve biopsy: tomacula — focal sausage-like thickenings of the myelin sheath — are the pathological hallmark, along with segmental demyelination.

3. Hereditary Sensory and Autonomic Neuropathies (HSAN)

4. Hereditary Neuralgic Amyotrophy (HNA)

• AD disorder linked to the same region as HNPP on chromosome 17q25 (SEPT9 mutations).
• Recurrent episodes of acute severe pain followed by focal weakness and atrophy in the brachial plexus distribution.
• Distinguished from idiopathic neuralgic amyotrophy by earlier onset, greater frequency of attacks, and occasional involvement of cranial nerves or lumbosacral plexus.

Diagnostic Approach

• Slowly progressive distal weakness with few sensory symptoms yet significant sensory deficits on examination
• Skeletal deformities: pes cavus, hammer toes, scoliosis
• Long-standing symptoms since childhood or adolescence
• Family history (though absence does not exclude — ~1/3 arise from de novo mutations)
• Disproportionate symmetry, lack of pain

1. NCV/EMG: critical for distinguishing demyelinating (CMT1) from axonal (CMT2) — key to directing genetic testing. Uniform slowing suggests hereditary; non-uniform/conduction blocks suggest acquired.
2. Genetic testing: next-generation sequencing panels now cover >80 genes. Start with CMT1A PMP22 duplication (most common).
3. Nerve biopsy: reserved for diagnostically challenging cases; shows onion bulbs (CMT1), tomacula (HNPP), or axonal loss.
4. Family screening: EDX of parents/siblings.

Management

• Physiotherapy and orthotics: ankle-foot orthoses (AFOs) for foot drop; orthopaedic correction of pes cavus/hammer toes
• Occupational therapy and ergonomic adaptations
• HNPP: avoid prolonged pressure on nerves; padding of elbows/knees
• HSAN: meticulous foot care to prevent ulcers/osteomyelitis; avoid trauma to insensate extremities
• Pain management: neuropathic pain agents (gabapentin, duloxetine) for HSAN-I lancinating pains
• Experimental / investigational: ascorbic acid (vitamin C) in CMT1A — well tolerated but no benefit shown in RCTs; neurotrophin 3 (NT3) in pilot studies; curcumin for CMT1B MPZ mutants (preclinical); progesterone antagonists (theoretical but side effects limiting); CRISPR-based approaches under investigation for demyelinating forms (PMID 41108054).

• A systematic review on PMP22-related neuropathies (PMID 41300731) consolidates the expanding phenotypic and genotypic spectrum of CMT1A, CMT1E, and HNPP.
• A 2025 systematic review on CRISPR in demyelinating PNS disorders (PMID 41108054) highlights emerging gene-editing strategies.
• A 2025 systematic review confirms that genetic neuromuscular disorders including CMT increase obstetric risk during pregnancy (PMID 39616806).