Give me high yield points for Professor Neurology on topic CMT
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"Charcot-Marie-Tooth" disease genetics treatment
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I now have comprehensive data from Bradley's Neurology, Goldman-Cecil, and Campbell's Orthopaedics. Let me compile the high-yield neurology summary.
🧠CMT (Charcot-Marie-Tooth Disease) - High Yield for Neurology Professor
1. DEFINITION & OVERVIEW
- Most common hereditary peripheral neuropathy (prevalence ~1:2500)
- Also called Hereditary Motor and Sensory Neuropathy (HMSN) or Peroneal Muscular Atrophy
- Genetically and phenotypically heterogeneous; mutations in 100+ genes identified
- Caused by mutations affecting peripheral myelin sheath (CMT1) or axonal structure (CMT2)
2. GENETICS & CLASSIFICATION
CMT1 - Demyelinating (AD)
| Subtype | Chromosome | Gene | Mechanism | Notes |
|---|---|---|---|---|
| CMT1A | 17p11.2 | PMP22 | Duplication | Most common - ~50% of ALL CMT cases |
| CMT1B | 1q22-23 | MPZ (myelin protein zero) | Point mutation | 4-5% of CMT1; clinically like CMT1A |
| CMT1C | 16p13.1 | LITAF/SIMPLE | Point mutation | Rare |
| CMT1D | 10q21 | EGR2 | Point mutation | Rare |
| CMT1E | 17p11.2 | PMP22 | Point mutation (not duplication) | - |
CMT2 - Axonal (AD)
| Subtype | Gene | Notes |
|---|---|---|
| CMT2A | MFN2 (Mitofusin-2) | Most common CMT2; severe phenotype - many wheelchair-bound |
| CMT2B | RAB7 | Late onset |
| CMT2I/J | MPZ | Late onset, marked sensory loss, deafness, pupillary changes |
Key mnemonic: CMT1A = PMP22 Duplication on chr 17 (the "classic"); CMT2A = MFN2 mutation
CMTX - X-linked
- GJB1 gene (Connexin-32, Cx32) - gap junction protein in Schwann cells
- XL-CMT - accounts for 10-20% of all CMT
- Males more severely affected; females often asymptomatic or mildly affected
- Intermediate NCV (35-45 m/sec) - does NOT fit neatly into CMT1 or CMT2 categories
CMT4 - Autosomal Recessive (AR)
- <10% of all CMT
- Childhood onset, more rapidly progressive, often wheelchair-bound by adolescence
- CMT4A: GDAP1 gene (chr 8q13) - most common AR form (25-30% of AR cases)
- CMT4B: MTMR2 mutations - pathognomonic finding = redundant loops / focally folded myelin on biopsy
- CMT4C: SH3TC2 gene - associated with severe scoliosis
- CMT4D: associated with dysmorphic features + hearing loss
Related Disorder - HNPP
- Hereditary Neuropathy with Liability to Pressure Palsies
- Caused by PMP22 deletion (reciprocal of CMT1A duplication) on chr 17
- Recurrent focal pressure neuropathies (peroneal, ulnar, radial)
3. ELECTROPHYSIOLOGY - CRITICAL HIGH YIELD
| Type | NCV (Motor - Forearm) | Amplitude | Key Finding |
|---|---|---|---|
| CMT1 | 15-35 m/sec (slowed, uniform) | Normal/reduced | Uniform slowing (unlike CIDP which is non-uniform) |
| CMT2 | >45 m/sec (near-normal) | Reduced | Axonal - low amplitude, normal velocity |
| CMTX | 35-45 m/sec (intermediate) | Variable | Intermediate velocity |
| CMT4 | 20-30 m/sec | Reduced | Severely slowed |
| DSD | <15 m/sec (extremely slow) | - | Presents in early childhood |
Exam trap: CMT1 shows uniform, diffuse slowing - differentiates it from CIDP (segmental, non-uniform slowing with conduction block). CMT2 can have normal velocity - do NOT miss it by NCV alone.
4. CLINICAL FEATURES
Classic Presentation
- Onset: first or second decade (but can present in adults)
- Slowly progressive distal weakness and wasting
- Begins in the feet and legs, then hands later
Cardinal Signs (memorize all)
- Pes cavus (high-arched feet)
- Hammer toes
- Distal leg muscle wasting - classic "inverted champagne bottle" / "stork legs"
- Distal sensory loss (vibration and position first)
- Absent or reduced ankle jerks (areflexia)
- Steppage gait (foot drop)
- Palpably thickened nerves (in demyelinating forms)
Helpful Discriminators from Idiopathic Pes Cavus
- Positive family history
- Weakness + sensory deficits
- Distal atrophy
- Absent ankle jerks
- Gait abnormalities
Fine Motor Involvement
- Difficulty with buttons, zippers, keys, jewelry (late finding)
- Handwriting difficulties
Typical Functional Milestones
- Children: slow runners, impaired balance (skating, walking on logs)
- By 3rd decade: often require ankle-foot orthoses (AFOs)
- CMT1A: majority remain ambulatory (rarely need wheelchair)
- CMT2A (MFN2): many become wheelchair-dependent
5. PATHOLOGY - NERVE BIOPSY
| Finding | Type |
|---|---|
| Onion bulb formation (Schwann cell processes wrapping repeatedly around axon) | CMT1 (demyelinating) |
| Axonal loss, reduced myelinated fiber density | CMT2 (axonal) |
| Redundant loops / focally folded myelin | CMT4B (MTMR2 mutations) |
| Loss of myelinated fibers, hypomyelination | CMT4 generally |
Onion bulbs = hallmark of repeated demyelination/remyelination = CMT1 on biopsy
6. DIAGNOSIS APPROACH
- Clinical + Family History (AD pattern, positive family history in ~90%)
- NCV/EMG - classify demyelinating vs. axonal; uniform vs. non-uniform
- Genetic testing - sequence PMP22 duplication first (FISH or pulse-field electrophoresis), then gene panel
- Nerve biopsy - rarely needed; reserved for atypical cases; shows onion bulbs in CMT1
- CSF protein - may be mildly elevated in CMT1 (normal in CMT2 and CMT4)
Diagnostic Algorithm for Suspected CMT
- Start with PMP22 duplication testing (covers ~50% of cases)
- If negative → test GJB1 (Cx32) for CMTX, MPZ for CMT1B
- If still negative → multigene panel (MFN2 for CMT2A, etc.)
- ~10-20% remain genetically uncharacterized
7. IMPORTANT ASSOCIATIONS & COMPLICATIONS
- Scoliosis: reported in 10-26% of CMT patients; progression common (33% of those with scoliosis)
- Hip dysplasia: occasionally associated
- Respiratory involvement: rare, mostly in severe forms
- Deafness/hearing loss: CMT2I (MPZ mutations), CMT4D
- Pupillary abnormalities: CMT2I (MPZ Thr124Met mutation)
- Glaucoma: CMT4B2 (SBF2 mutations)
- Pregnancy: can transiently worsen symptoms
8. TREATMENT (No Disease-Modifying Therapy Currently)
| Category | Intervention |
|---|---|
| Orthoses | Ankle-foot orthoses (AFOs) - mainstay |
| Physiotherapy | Strength, balance, stretching |
| Occupational therapy | Fine motor aids |
| Orthopaedic surgery | Pes cavus correction (plantar fascia release, tendon transfers, osteotomies), triple arthrodesis for severe cases, scoliosis surgery |
| Avoid | Neurotoxic drugs (vincristine, taxanes, amiodarone - can precipitate or worsen neuropathy) |
| Emerging | Gene therapy, PMP22 antisense oligonucleotides (for CMT1A), progesterone receptor antagonists (reduce PMP22 expression) |
Exam favorite: Vincristine is absolutely contraindicated in CMT - can cause fatal neuropathy.
9. KEY DIFFERENTIALS
| Condition | Key Distinguishing Features |
|---|---|
| CIDP | Acquired, non-uniform NCV slowing, conduction blocks, responds to immunotherapy |
| Friedreich's ataxia | Spinocerebellar + spinal cord involvement, cardiomyopathy, diabetes |
| Hereditary spastic paraplegia | Upper motor neuron signs dominate |
| Distal SMA | Pure motor, no sensory loss |
| HNPP | Episodic pressure palsies, PMP22 deletion (vs. duplication in CMT1A) |
10. QUICK RECALL TABLE
| Feature | Value |
|---|---|
| Prevalence | 1 in 2500 |
| Most common subtype | CMT1A (50% of all CMT) |
| CMT1A gene/mechanism | PMP22 duplication, chr 17p11.2 |
| 2nd most common | CMTX (GJB1/Cx32, 10-20%) |
| CMT2 most common | CMT2A (MFN2 gene) |
| CMT1 NCV | 15-35 m/sec (demyelinating) |
| CMT2 NCV | >45 m/sec, low amplitude (axonal) |
| Classic triad | Pes cavus + hammer toes + inverted champagne bottle legs |
| Nerve biopsy (CMT1) | Onion bulbs |
| HNPP | PMP22 deletion (reciprocal of CMT1A) |
| Contraindicated drug | Vincristine |
Sources: Bradley and Daroff's Neurology in Clinical Practice; Goldman-Cecil Medicine International Edition; Campbell's Operative Orthopaedics 15th Ed 2026Recent guideline: Clinical practice guidelines for CMT diagnosis and management - Neurologia 2025 [PMID: 38431252] | CMT and related neuropathies - Nature Reviews Disease Primers 2026 [PMID: 41571707]
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