Hereditary Motor and Sensory Neuropathy (HMSN): Types and Characteristics
Overview and Classification
HMSN, also known as Charcot-Marie-Tooth (CMT) disease, is a genetically heterogeneous group of inherited peripheral neuropathies classified by inheritance pattern, electrophysiological findings (demyelinating versus axonal), and causative gene mutations. 1, 2, 3
The classification system divides HMSN into major subtypes based on:
- Inheritance pattern: Autosomal dominant, autosomal recessive, or X-linked 2, 3
- Electrophysiological characteristics: Demyelinating (slow nerve conduction velocity) versus axonal (near-normal nerve conduction velocity) 1, 2
- Genetic mutations: At least 28 different genes identified across 36 loci 1
Major HMSN Types
HMSN Type I (CMT1) - Demyelinating Form
HMSN Type I is the most common variant, characterized by autosomal dominant inheritance, markedly slow motor nerve conduction velocity (<38 m/s), and nerve hypertrophy with onion bulb formation. 2, 4
Clinical Features:
- Onset in infancy or early childhood with distal muscle weakness and atrophy 2, 3
- Pes cavus (high-arched feet), foot drop, and clumsiness of gait 3, 5
- Depressed or absent tendon reflexes 2
- Distal sensory loss in stocking-glove distribution 2
- Progressive course with eventual involvement of upper extremities 2
Genetic Subtypes:
- CMT1A (HMSN Ia): Most common form (54-80% of CMT1 cases), caused by PMP22 gene duplication on chromosome 17p11.2 1, 4
- CMT1B (HMSN Ib): Caused by MPZ (myelin protein zero) mutations on chromosome 1, accounting for approximately 5% of cases 1
- CMT1 with other genes: Including PMP22 point mutations (2.5%), EGR2, LITAF, and other rare variants 1
Electrophysiological Findings:
- Motor nerve conduction velocity typically <38 m/s (often 15-30 m/s) 1, 2
- Prolonged distal motor latencies and absent or prolonged F-waves 1
- Uniform slowing across multiple nerves (distinguishing it from focal demyelinating processes) 1
HMSN Type II (CMT2) - Axonal Form
HMSN Type II presents with autosomal dominant inheritance and near-normal or mildly reduced motor nerve conduction velocity (>38 m/s), reflecting primary axonal degeneration rather than demyelination. 2, 5
Clinical Features:
- Similar clinical presentation to HMSN Type I but often with later onset 2
- Distal muscle weakness and atrophy, particularly peroneal muscles 5
- Sensory abnormalities less prominent than motor findings 5
- Absent or severely reduced compound muscle action potentials 5
Genetic Characteristics:
- MFN2 mutations account for approximately 33% of CMT2 cases 1
- Other genes include GARS, NEFL, HSPB1, and RAB7 1
- No MFN2 mutations found in demyelinating (CMT1) phenotypes 1
Electrophysiological Findings:
- Motor nerve conduction velocity >38 m/s (mean 36.5 ± 7.4 m/s in some series) 5
- Reduced or absent sensory nerve action potentials (75% of affected individuals) 5
- Evidence of axonal loss with regenerative sprouting on nerve biopsy 5
HMSN Type III (Déjérine-Sottas Disease)
HMSN Type III is a severe, early-onset autosomal recessive demyelinating neuropathy presenting in infancy with marked motor and sensory deficits. 2, 4
Clinical Features:
- Onset in infancy with severe motor delays 2, 4
- Profound weakness, hypotonia, and areflexia 4
- Severe sensory loss affecting all modalities 4
- Palpably enlarged peripheral nerves 4
- Very slow nerve conduction velocities (<10 m/s in many cases) 4
Pathological Features:
- Marked hypomyelination or amyelination of peripheral nerves 4
- Prominent onion bulb formation 4
- Severe loss of myelinated fibers 4
X-Linked HMSN (CMTX)
X-linked HMSN, caused by GJB1 (connexin 32) mutations, accounts for approximately 12% of all CMT cases and presents with intermediate nerve conduction velocities. 1, 5
Clinical Features:
- Males severely affected; females mildly affected or subclinical 5
- No male-to-male transmission (all daughters of affected fathers are affected) 5
- Onset in early childhood with pes cavus and distal weakness 5
- Can present with either demyelinating or axonal electrophysiological pattern 1
Electrophysiological Findings:
- Intermediate nerve conduction velocities (25-45 m/s) 1
- Absent or severely reduced compound muscle action potentials in 42% of cases 5
- Absent or severely reduced sural sensory nerve action potentials in 75% of cases 5
Genetic Considerations:
- Testing for GJB1 mutations indicated when pedigree lacks male-to-male transmission 1
- Should be considered in both demyelinating and axonal phenotypes 1
Autosomal Recessive HMSN Variants
Autosomal recessive demyelinating HMSN shows a broad spectrum of pathological features and can be subdivided into four morphological subtypes. 4
Subtypes Include:
- AR HMSN Type I with basal lamina onion bulbs: Clinically similar to AD HMSN Type I 4
- AR HMSN Type I with focally folded myelin: Electrophysiologically comparable to AD HMSN Type I 4
- AR HMSN Type III with amyelination: More severe clinical and electrophysiological involvement 4
- AR HMSN Type III with hypomyelination: Severe phenotype with early onset 4
Rare HMSN Variants and Special Forms
Familial Amyloid Polyneuropathy (FAP)
FAP represents a distinct form of hereditary neuropathy with specific amino acid substitutions in transthyretin, presenting with progressive sensorimotor and autonomic neuropathy. 2
Refsum's Disease
Autosomal recessive disorder caused by defective phytanic acid metabolism, presenting with peripheral neuropathy, retinitis pigmentosa, and cerebellar ataxia. 2
HMSN with Proximal Dominance (HMSN-P)
Novel variant with proximal-dominant weakness linked to chromosome 3 centromere region, initially reported in Japanese populations but now recognized worldwide. 6
Clinical Features:
- Proximal muscle weakness predominates over distal involvement 6
- May include urinary disturbance and paroxysmal dry cough in some families 6
- Can be misdiagnosed as familial ALS 6
Diagnostic Approach
Clinical Evaluation
The diagnosis begins with identifying the classic phenotype: distal muscle weakness and atrophy, depressed tendon reflexes, sensory loss in stocking-glove distribution, and family history. 1, 2, 3
Electrodiagnostic Studies
Nerve conduction studies are essential to classify HMSN as demyelinating (motor NCV <38 m/s) versus axonal (motor NCV >38 m/s), which guides genetic testing strategy. 1
Genetic Testing Algorithm
For patients with demyelinating phenotype (CMT1), test first for CMT1A duplication (yield 54-80%), then consider MPZ mutations, GJB1 if X-linked pattern possible, and other genes based on specific features. 1
For patients with axonal phenotype (CMT2), test for MFN2 mutations first (33% yield), then consider other CMT2-associated genes. 1
Genetic testing provides 100% specificity (no false positives) and high sensitivity for established pathogenic mutations. 1
Common Pitfalls
- Do not assume sporadic cases are non-genetic: CMT1A accounts for 76-90% of sporadic CMT1 cases 1
- Consider X-linked inheritance when pedigree lacks male-to-male transmission 1
- Normal or exaggerated reflexes can occur in pure motor AMAN variants, particularly in atypical presentations 1
- Small fiber involvement may show normal conventional nerve conduction studies, requiring skin biopsy for diagnosis 7
Clinical Spectrum and Phenotypic Variability
HMSN demonstrates wide phenotypic variability even within the same family, ranging from distal-dominant to proximal-dominant patterns, and from pure motor-sensory to autonomic involvement. 6
The clinical concept of HMSN extends beyond the classic distal-dominant motor-sensory neuropathy to include: