Charcot-Marie-Tooth Disease: Complete Case Discussion & Key Points
Model Case Presentation
Patient Demographics
Name: Master Rohan, Age: 10 years, Gender: Male, Informant: Father (Reliable)
Chief Complaints
- Difficulty walking and frequent falls – 3 years
- Weakness of both legs – 3 years, slowly progressive
- Abnormal foot shape noticed since age 6
History Summary
The child had normal developmental milestones initially but began walking with an unusual gait around age 7. Parents noticed he would frequently trip on uneven ground, had difficulty running, and could not keep up with peers. He has progressive weakness of the feet and lower legs. He walks with a high-stepping gait and has difficulty climbing stairs. There is mild numbness and reduced sensation in both feet. No bladder or bowel involvement. No cranial nerve symptoms. No history of acute deterioration.
Family History (KEY): Father has similar foot deformity and mild gait problems, never formally diagnosed. Maternal side unaffected. Parents are non-consanguineous. No history of prior similar illness in siblings.
Born at term, NVD, uneventful antenatal period. Developmental milestones met on time. Immunizations up to date.
Examination Summary
| Parameter | Finding | Significance |
|---|---|---|
| Vital signs | Normal | — |
| Gait | High-stepping (steppage) gait | Foot drop due to peroneal weakness |
| Foot deformity | Bilateral pes cavus with hammer toes | Intrinsic muscle wasting |
| Muscle bulk | Wasting of peroneal and anterior tibial muscles — "inverted champagne bottle" / "stork legs" | Distal > proximal; chronic denervation |
| Reflexes | Ankle jerks absent bilaterally; knee jerks diminished | Peripheral neuropathy |
| Sensation | Reduced vibration & proprioception distally in both lower limbs | Sensory neuropathy |
| Upper limbs | Mildly reduced grip strength; no wasting yet | Early involvement |
| Cranial nerves | Normal | — |
| Spine | Mild scoliosis | Secondary to muscle weakness |
| Nerves | Thickened, palpable ulnar and peroneal nerves | Hypertrophic neuropathy (onion bulb formation — CMT1) |
Motor system: Weakness grade 4/5 in ankle dorsiflexors and evertors bilaterally. Plantar flexors relatively preserved. No fasciculations. Tone normal.
✅ Complete Diagnosis
Charcot-Marie-Tooth Disease Type 1 (Demyelinating, Autosomal Dominant) — Hereditary Motor and Sensory Neuropathy (HMSN Type I) — with Pes Cavus Deformity, Steppage Gait, and Family History of Similar Illness (Father Affected).
Most likely subtype: CMT1A (PMP22 duplication, chromosome 17p11.2)
📝 History — Exam Q&A
CMT disease (also called Hereditary Motor and Sensory Neuropathy — HMSN) is the most common inherited neuromuscular disorder. It is a group of clinically and genetically heterogeneous peripheral neuropathies characterized by progressive distal muscle weakness, wasting, sensory loss, and foot deformities.
Prevalence: ~1 in 2,500 individuals. More than 80 causative genes have been identified.
- Difficulty walking, frequent falls, tripping on uneven ground
- Progressive weakness of ankles/feet — foot drop
- High-stepping (steppage) gait
- Abnormal foot shape — pes cavus (high arches) with hammer toes
- Reduced sensation in feet (numbness, tingling)
- Difficulty running or keeping up with peers
- Mild hand weakness in later stages (wasting of intrinsic hand muscles)
💡 Key Point
CMT symptoms typically begin in the first or second decade of life. A child presenting with foot deformity + distal weakness + family history of similar problems should raise strong suspicion for CMT.
CMT is a genetic disease, and a positive family history is one of the most important diagnostic clues. Often, other family members (especially a parent) have similar but milder foot deformities that have never been diagnosed. It is important to examine parents!
| Inheritance Pattern | CMT Type | Notes |
|---|---|---|
| Autosomal Dominant (most common) | CMT1, CMT2 | One affected parent; variable expressivity |
| X-linked (CMTX) | CMTX1 | GJB1/Connexin 32 mutation; males more severely affected |
| Autosomal Recessive | CMT4, some CMT2 | Consanguinity a risk factor; earlier onset, more severe |
| De novo mutation | Any | No family history; CMT1A especially |
The classic triad of CMT is:
- Distal muscle weakness and wasting (lower limbs > upper limbs)
- Sensory loss (predominantly proprioception and vibration)
- Foot deformity (pes cavus + hammer toes)
Plus areflexia (absent ankle jerks).
| Type | Pathology | MNCV (median nerve) | Inheritance | Key Gene |
|---|---|---|---|---|
| CMT1 (most common, ~50%) | Demyelinating | < 38 m/s (usually ~20 m/s) | Autosomal Dominant | PMP22 dup (CMT1A) |
| CMT2 (~20%) | Axonal | Normal or > 45 m/s (low amplitude) | Autosomal Dominant | MFN2 (CMT2A) |
| CMT4 | Demyelinating | < 38 m/s (severe) | Autosomal Recessive | Multiple genes |
| CMTX (~10–15%) | Intermediate/Demyelinating | 30–45 m/s (males) | X-linked | GJB1 (Connexin 32) |
| CMT3 (Dejerine-Sottas) | Severe demyelinating | < 10 m/s | AD or AR; de novo | PMP22, MPZ, EGR2 |
| Dominant Intermediate (DI-CMT) | Mixed | 25–45 m/s | Autosomal Dominant | DNM2, YARS, etc. |
💡 Mnemonic
CMT1 = 1 copy too many (PMP22 duplication). HNPP = 1 copy too few (PMP22 deletion).
CMT1A is the most common subtype of CMT, accounting for ~70% of all CMT1 cases and about 40–50% of all CMT.
- Molecular defect: Duplication of a 1.5 Mb region on chromosome 17p11.2 containing the PMP22 gene (Peripheral Myelin Protein 22)
- PMP22 overexpression → abnormal Schwann cell differentiation → demyelination → onion bulb formation
- Inheritance: Autosomal dominant; can also arise as de novo mutation
- NCV: Uniformly and severely slowed (~15–25 m/s); this slowing is stable from early childhood
HNPP is the reciprocal condition to CMT1A. It is caused by a deletion of the 17p11.2 region containing PMP22 (i.e., only one functional copy instead of the normal two).
- Presents with recurrent, episodic focal nerve palsies following minor compression (e.g., crossing legs → peroneal palsy; resting on elbow → ulnar palsy)
- Patients recover spontaneously but may accumulate deficits over time
- NCV shows focal conduction slowing at entrapment sites; generalized mild slowing
- Inheritance: Autosomal dominant
Dejerine-Sottas syndrome (DSS) is a severe infantile-onset hypertrophic demyelinating neuropathy.
- Onset: Infancy — delayed motor milestones (late walking, hypotonia)
- NCV: Severely slowed (<10 m/s)
- CSF: Elevated protein
- Nerve biopsy: Prominent onion bulb formations, hypomyelination
- Palpable hypertrophic nerves
- Genes: De novo or AR mutations in PMP22, MPZ, EGR2, PRX
- Often wheelchair-bound by adolescence
- No acute/subacute onset — Rules out Guillain-Barré Syndrome (GBS)
- No fluctuation or relapsing-remitting course — Rules out CIDP
- No drug exposure (e.g., vincristine, isoniazid) — Rules out toxic neuropathy
- No diabetes, thyroid disease, systemic illness — Rules out metabolic neuropathy
- No CSF pleocytosis history / no autonomic features — Differentiates from other hereditary neuropathies
- Family history — Positive in CMT (often mildly affected parent)
- No proximal weakness / no UMN signs — Distinguishes from spinal muscular atrophy or HSP
🩺 Examination — Exam Q&A
Steppage gait (High-stepping gait): The patient excessively lifts the knee to prevent the foot from dragging on the ground. This occurs due to weakness of the ankle dorsiflexors (tibialis anterior, peroneal muscles), causing foot drop.
When both feet are affected, the gait resembles "walking on stilts" or "marching in place."
Pes cavus (high medial arch) with hammer toes is the classic foot deformity. In severe cases, there is also hindfoot varus — termed cavovarus foot.
Why it occurs: Imbalance between intrinsic and extrinsic foot muscles due to selective denervation. Weakness of the intrinsic foot muscles (lumbricals, interossei) relative to the long toe flexors leads to excessive plantar flexion of the metatarsal heads, raising the arch. Weakness of toe extensors causes hammer toes. This imbalance is progressive and leads to fixed bony deformity over time.
💡 Peekaboo Heel Sign
When the examiner views cavovarus feet from the front, the heels are visible lateral to the forefoot — this is called the "Peekaboo heel sign," indicating hindfoot varus.
Wasting is distal and length-dependent — affecting the distal lower limbs more than the proximal, and lower limbs before upper limbs.
- Peroneal muscles and anterior tibial compartment are affected first → "Inverted champagne bottle" legs or "Stork legs" — thin distal legs with relatively preserved thighs
- Later: Intrinsic hand muscles wasting → "claw hand"
- Proximal muscles are largely spared
Deep tendon reflexes are diminished or absent, especially:
- Ankle jerks — absent early (most sensitive sign)
- Knee jerks — diminished
- Upper limb reflexes may be diminished later
Plantar response is flexor (no UMN involvement). Absence of reflexes with no UMN signs localizes the pathology to lower motor neuron / peripheral nerve.
Sensory loss is distal and symmetric — "stocking-and-glove" distribution.
- Predominantly affected: Vibration sense and proprioception (large fiber/dorsal column sensations) — often presenting as unsteadiness in the dark
- Less affected: Pain and temperature (small fiber)
- Sensory loss is usually mild compared to motor weakness in most CMT types
Note: Patients with CMT often have less functional disability from sensory loss than from motor weakness. Autonomic features are generally absent.
Palpably thickened nerves indicate hypertrophic neuropathy — caused by repeated demyelination and remyelination with concentric Schwann cell proliferation forming onion bulbs.
- Seen in CMT1 (demyelinating types) and CMT3/Dejerine-Sottas — NOT typically in CMT2 (axonal)
- Sites to palpate: Ulnar nerve at elbow, great auricular nerve in the neck, common peroneal nerve at the fibular head
- Also seen in: CIDP, leprosy (with other features)
- Spine: Scoliosis (secondary to weakness)
- Hands: Intrinsic wasting → "claw hand," reduced grip; bilateral in late disease
- Tremor: Postural/action tremor of hands in some subtypes (Roussy-Lévy syndrome = CMT + essential tremor)
- Cranial nerves: Mostly spared; rarely — vocal cord palsy, deafness (specific gene mutations)
- Eyes: Optic atrophy in CMT6 (GDAP1/MFN2 mutations)
- Parents: Always examine parents — mild pes cavus or reduced ankle jerks may confirm AD inheritance
| Feature | CMT1 (Demyelinating) | CMT2 (Axonal) |
|---|---|---|
| Onset | 1st–2nd decade | 2nd decade or later (usually) |
| Severity | Moderate to severe | Milder generally |
| Palpable nerves | Yes (onion bulbs) | No |
| Pes cavus | Common, prominent | Less prominent |
| NCV | <38 m/s (usually ~20 m/s) | Normal or near-normal |
| CMAP amplitude | Reduced | Markedly reduced |
| EMG | Demyelinating pattern | Denervation (fibrillations, neuropathic MUPs) |
| Nerve biopsy | Onion bulb formations | Axonal loss, Wallerian degeneration |
The Coleman block test is an orthopedic test used to assess whether the hindfoot varus deformity in CMT is flexible (correctable) or rigid (fixed).
- A wooden block is placed under the lateral border of the foot, allowing the first ray to drop plantarward
- Flexible deformity: Hindfoot corrects to neutral → can be treated with soft-tissue/tendon procedures
- Rigid deformity: Hindfoot does not correct → requires bony osteotomy
- This guides surgical decision-making for cavovarus foot correction
🔬 Investigations — Exam Q&A
Nerve Conduction Studies (NCS) + Electromyography (EMG) — These are the first and most important investigations.
- They classify the neuropathy as demyelinating vs. axonal, which then guides genetic testing
- NCS is performed on upper limb nerves (median nerve MNCV is the key measure for classification)
- Should be performed in the child AND in available first-degree relatives
| CMT Type | Median Motor NCV | CMAP Amplitude | Pattern |
|---|---|---|---|
| CMT1 (Demyelinating) | < 38 m/s (usually ~15–25 m/s) | Reduced | Uniform slowing (key feature — differentiates from acquired demyelination) |
| CMT2 (Axonal) | Normal or slightly reduced (> 45 m/s) | Markedly reduced | Low amplitude; normal velocity |
| CMTX1 (Males) | Intermediate: 30–45 m/s | Reduced | Not uniformly slow; may have asymmetry |
| CMT3 (DSS) | < 10 m/s | Severely reduced | Extreme slowing |
| DI-CMT | 25–45 m/s (overlapping range) | Reduced | Variable within families |
💡 Uniform vs. Patchy Slowing
In CMT1, conduction slowing is uniform across all nerves and all segments. In acquired demyelinating neuropathies like CIDP, slowing is patchy and multifocal with conduction block. This distinction is diagnostically critical.
Genetic testing is the gold standard for definitive diagnosis and subtype classification.
Step-wise approach:
- Perform NCS → classify as demyelinating (NCV <38) or axonal (NCV >45)
- If demyelinating + AD inheritance → test for PMP22 duplication (CMT1A) first (highest yield, ~40–50% of all CMT)
- If PMP22 negative → test MPZ and GJB1/Connexin 32 (next most common)
- If axonal → test MFN2 first (most common CMT2 gene)
- If all targeted tests negative → Multigene panel / Next-Generation Sequencing (NGS)
Whole-exome sequencing (WES) is increasingly used first-line when the phenotype is atypical or multiple genes are possible.
Nerve biopsy (typically sural nerve) is rarely indicated in the era of genetic testing. It is used only in diagnostic dilemmas.
| CMT Type | Nerve Biopsy Finding |
|---|---|
| CMT1 | Onion bulb formations — concentric layers of Schwann cell cytoplasm around axons, due to repeated de/remyelination. Reduced myelinated fibers. Hypertrophic nerves (macroscopically). |
| CMT2 | Axonal loss with Wallerian degeneration and regenerating clusters. No onion bulbs. Reduced large myelinated fibers. |
| CMT3 (DSS) | Severe onion bulb formation, hypomyelination — very thin or absent myelin sheaths. |
🚨 Important
Absence of inflammatory infiltrate on nerve biopsy is an important negative finding — its presence should prompt consideration of CIDP rather than CMT.
All routine laboratory tests are normal in CMT. This is an important point — CMT is a pure genetic disorder without metabolic derangement.
- CBC, LFT, RFT — Normal
- Blood glucose — Normal (rules out diabetic neuropathy)
- Thyroid function — Normal
- Serum B12 — Normal
- Creatine kinase (CK) — Normal or mildly elevated (can be raised in axonal CMT types)
- CSF: Usually normal; protein may be mildly elevated in CMT1 (not as high as in CIDP or DSS)
High-resolution nerve ultrasound:
- Shows diffuse, uniform enlargement of peripheral nerves in CMT1 (demyelinating types) — corresponding to hypertrophic neuropathy
- Useful adjunct to NCS in differentiating CMT1 from CIDP (CIDP shows multifocal enlargement)
MRI of lower limb muscles:
- Demonstrates selective fatty infiltration and atrophy of affected muscles — can track disease progression
- Useful as a research outcome measure and in monitoring treatment response in clinical trials
The CMT Neuropathy Score (CMTNS / CMTNS-2) is a composite clinical outcome measure assessing:
- Symptoms (sensory, motor)
- Signs (pin sensation, vibration, strength, tendon reflexes)
- NCS parameters (SNAP, CMAP amplitude)
Scores 0–36: Mild (0–10), Moderate (11–20), Severe (>20).
CMT Pediatric Scale (CMTPedS): Validated outcome measure specifically designed for children with CMT — assesses balance, gait, dexterity, and strength relevant to pediatric function.
Neurofilament light chain (NfL): An emerging serum/CSF biomarker of axonal damage — elevated in more severe CMT and being studied as a disease progression biomarker.
💊 Management — Exam Q&A
There is currently no approved disease-modifying treatment or cure for CMT. Management is entirely supportive and symptomatic, centered around:
- Physical and occupational therapy (primary treatment)
- Orthotic devices (AFOs, shoe modifications)
- Orthopedic surgery for foot deformities when indicated
- Pain management
- Drug avoidance (neurotoxic medications)
- Genetic counseling
- Multidisciplinary care (neurology, orthopedics, physiatry, genetics, physiotherapy, OT)
Physiotherapy is the cornerstone of CMT management.
- Stretching exercises: Daily heel-cord (Achilles tendon) stretching to prevent contractures
- Progressive resistance training: The only evidence-based (Grade I recommendation) exercise for CMT — improves strength and function
- Low-impact aerobic exercise: Swimming, cycling — preserve cardiovascular fitness without excessive joint stress
- Balance training: Reduces fall risk
- Gait training
- Occupational therapy: Adaptive devices for hand weakness (jar openers, pencil grips), activities of daily living
💡 Key Point
Obesity should be avoided as it significantly worsens walking ability in CMT. Regular, moderate physical activity is actively encouraged — there is no need for activity restriction.
Orthotic devices are prescribed progressively based on severity:
- Shoe inserts / orthopedic footwear: First-line for mild deformity — redistribute pressure, reduce pain
- Ankle-Foot Orthosis (AFO): Prescribed when foot drop and calf weakness are present. A custom-molded lightweight plastic (or carbon fiber) brace that stabilizes the ankle, corrects foot drop, prevents toe drag, and improves gait. Worn inside normal shoes.
- Wrist splints: For hand weakness to improve function
- Wheelchairs / walking aids: For advanced disease (<5% of CMT patients become wheelchair-dependent)
Surgery is indicated when foot deformity is painful, progressively worsening, or causing falls that cannot be managed with orthotics. Early surgical intervention can minimize progression.
Surgical options (guided by Coleman block test result):
- Flexible deformity: Soft tissue procedures — plantar fascia release, Achilles tendon lengthening, tendon transfers (peroneus longus → peroneus brevis, tibialis posterior transfer)
- Rigid deformity: Bony osteotomies — calcaneal osteotomy (to correct hindfoot varus), metatarsal osteotomies, midfoot osteotomy
- Scoliosis: Spinal fusion if progressive and severe
🚨 Key Point
Surgery does not treat the underlying neuropathy — it only corrects the mechanical deformity. The neuropathy continues to progress, so deformity may recur over time.
Neurotoxic drugs must be avoided as they can cause rapid, severe, and sometimes irreversible worsening of CMT neuropathy.
| Drug | Use / Class | Risk in CMT |
|---|---|---|
| Vincristine | Chemotherapy (vinca alkaloid) | CONTRAINDICATED — even 1–2 doses can cause catastrophic, life-threatening neuropathy in demyelinating CMT. Pfizer specifically contraindicated it in demyelinating CMT forms. |
| Paclitaxel | Chemotherapy (taxane) | Significant risk — can severely worsen neuropathy (especially CMT2A, CMT4F) |
| Isoniazid (high dose) | Anti-TB drug | Peripheral neuropathy risk (mitigated by pyridoxine); use with caution |
| Nitrofurantoin | Antibiotic | Potentially worsens neuropathy; avoid if possible |
| Excessive alcohol | — | Known neurotoxin; should be avoided |
💡 CMTA 2023 Revised List
After rigorous scientific reevaluation in 2022–23, the Charcot-Marie-Tooth Association revised its neurotoxic drug list to retain only Vincristine and Paclitaxel as evidence-backed neurotoxic risks. The original long list of drugs is no longer recommended for blanket avoidance.
Pain in CMT can be musculoskeletal (joint/postural) or neuropathic:
- Musculoskeletal pain: Paracetamol, NSAIDs; correction of foot deformity with orthotics/surgery
- Neuropathic pain: Tricyclic antidepressants (amitriptyline), anticonvulsants (gabapentin, pregabalin, carbamazepine)
- Cramps: Mexiletine (used in some patients); stretching exercises
Genetic counseling is an essential component of CMT management.
| Inheritance | Recurrence Risk (per pregnancy) |
|---|---|
| Autosomal Dominant (CMT1A, CMT2) | 50% for each child |
| Autosomal Recessive (CMT4) | 25% for each child |
| X-linked (CMTX) — carrier mother | 50% of sons affected; 50% of daughters carriers |
| De novo (sporadic) | Low recurrence in parents, but affected child → 50% AD risk for their children |
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) are available options for known mutations.
- CMT is slowly progressive; most patients lead active, independent lives
- Fewer than 5% of CMT1 patients become wheelchair-dependent
- Life expectancy is not shortened in most forms
- CMT2 is generally milder than CMT1 in terms of functional disability
- CMT3 (Dejerine-Sottas) and some AR forms (CMT4) are more severe — earlier wheelchair use
- Variable expressivity means even within families, some are mildly affected while others are more disabled
🔭 Recent Advances — Exam Q&A
Several approaches targeting PMP22 overexpression have been studied:
- Ascorbic acid (Vitamin C): Showed benefit in CMT1A mouse models by reducing PMP22 expression. Phase 2 and 3 clinical trials in humans showed no significant benefit — not recommended.
- PXT3003 (Baclofen + Naltrexone + Sorbitol): Combination drug that downregulates PMP22 mRNA. Phase 2 trial showed safety and tolerability. Phase 3 trial (PLEO-CMT) completed but did not meet primary endpoints. Further development ongoing.
- Progesterone antagonists (Onapristone): Reduce PMP22 expression in animal models; not yet in clinical trials in humans.
Gene-based approaches are the most exciting area of current CMT research.
- Gene silencing (RNAi / ASOs) for CMT1A: Antisense oligonucleotides (ASOs) are synthetic single-stranded nucleic acids that bind PMP22 mRNA → induce its degradation → reduce PMP22 overexpression → improved myelination. Animal studies show normalized motor function and NCV. Human clinical trials are progressing.
- Gene addition for loss-of-function CMT: Delivering a functional copy of mutated genes via AAV (adeno-associated virus) vectors. CMT2S (IGHMBP2 gene) has become the first form of CMT to reach gene therapy human clinical trials.
- Gene editing (CRISPR): Exploratory stage — potential to correct mutations at the DNA level.
With over 80 genes known to cause CMT, NGS-based multigene panel testing has become increasingly important and is now considered first-line in many clinical situations.
- Multigene panels: Can simultaneously screen dozens of CMT-associated genes in a single test — high diagnostic yield, cost-effective
- Whole exome sequencing (WES): Useful when panel testing is negative or phenotype is atypical
- Long-read sequencing: Can detect complex structural rearrangements (e.g., PMP22 duplication) and repeat expansions that short-read sequencing may miss — improving diagnostic rate further
- Clinical acumen remains essential as NGS may yield variants of uncertain significance (VUS)
Neurofilament light chain (NfL) is a structural protein of the neuronal cytoskeleton released into CSF and blood during axonal injury/degeneration.
- Serum NfL is elevated in CMT, correlating with disease severity and axonal loss
- It is the most promising wet biomarker for CMT — can track disease progression and response to therapy in clinical trials
- Limitation: Not specific to CMT; elevated in any axonal damage condition
- Lower limb quantitative muscle MRI (fat fraction) is also being validated as a disease progression outcome measure in clinical trials
The CMT Pediatric Scale (CMTPedS) is a validated outcome measure developed specifically to assess disability in children with CMT.
- Assesses multiple domains: balance (one-leg stand), running (10-metre), long jump, hand grip strength, pegboard dexterity, sensation, and foot dorsiflexion strength
- Validated across multiple international centers
- Used as a primary outcome measure in pediatric CMT clinical trials
- Important because adult CMT scales (CMTNS) may not capture functional limitations relevant to children
⚡ Key Points — Quick Revision
One-Liners for Exam
- Most common inherited neuromuscular disorder: CMT disease (prevalence 1:2,500)
- Also called: Hereditary Motor and Sensory Neuropathy (HMSN) / Peroneal muscular atrophy
- Most common subtype: CMT1A — PMP22 duplication on chromosome 17p11.2
- Classic triad: Distal weakness + sensory loss + pes cavus
- Classic gait: Steppage gait (high-stepping) due to foot drop
- Classic leg appearance: "Inverted champagne bottle" / "Stork legs"
- Foot deformity: Pes cavus + hammer toes (± hindfoot varus = cavovarus)
- Reflexes: Absent ankle jerks (earliest sign)
- CMT1 NCV: <38 m/s; uniformly slowed; ~20 m/s in CMT1A
- CMT2 NCV: Normal; low CMAP amplitude (axonal)
- Palpable thickened nerves: CMT1 (demyelinating) — due to onion bulb formations
- Nerve biopsy CMT1: Onion bulbs (Schwann cell concentric proliferation)
- Nerve biopsy CMT2: Axonal loss + Wallerian degeneration
- Uniform slowing vs. patchy: Uniform = CMT; Patchy with conduction block = CIDP
- HNPP: PMP22 deletion — recurrent pressure palsies
- CMT3 / Dejerine-Sottas: Severe infantile demyelinating; NCV <10 m/s
- CMTX (Connexin 32 / GJB1): X-linked; males more affected; intermediate NCV
- CMT2A: MFN2 gene mutation — most common axonal CMT
- No cure exists — management is supportive
- Primary treatment: Physiotherapy (progressive resistance training — Grade I evidence)
- Orthosis: AFO for foot drop
- Drugs to avoid: Vincristine (CONTRAINDICATED), Paclitaxel
- Surgery indication: Painful or progressive foot deformity not managed by orthotics
- Coleman block test: Distinguishes flexible vs. rigid cavovarus foot
- Peekaboo heel sign: Hindfoot varus visible from front
- Prognosis: Slow progression; <5% wheelchair-dependent; normal lifespan
- Gold standard diagnosis: Genetic testing (NCS guides which gene to test first)
- Emerging therapy: ASO/gene therapy targeting PMP22; NfL as disease biomarker
- Always examine parents: AD inheritance — mild pes cavus in parent may confirm diagnosis
🔑 Differentiating CMT from CIDP — Key Points
- CMT: Insidious, lifelong, slowly progressive; family history present; uniform NCV slowing; no inflammatory infiltrate on biopsy; does NOT respond to steroids/IVIG
- CIDP: Subacute or relapsing-remitting; no family history; patchy NCV slowing with conduction block; responds to steroids/IVIG/PLEX
💡 Examiner Favourites
- Why does CMT present with pes cavus and not pes planus?
- Why is the murmur louder in small VSD? (wrong case, but CMT equivalent: Why does NCV slow uniformly in CMT1 but not in CIDP?)
- What drugs are contraindicated in CMT and why is vincristine especially dangerous?
- How does HNPP differ from CMT1A despite involving the same gene?
- What is the first genetic test to order in a child with demyelinating neuropathy?