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Neurology
Genetics
Orthopaedics

Charcot-Marie-Tooth Disease (CMT)

High EvidenceUpdated: 2025-12-24

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Red Flags

  • Rapid progression (exclude CIDP)
  • Asymmetry (CMT is symmetrical)
  • Respiratory involvement (Rare but severe in some types)
  • Foot ulcers (Sensory loss)
Overview

Charcot-Marie-Tooth Disease (CMT)

1. Clinical Overview

Summary

Charcot-Marie-Tooth Disease (CMT) is the most common inherited neurological disorder (1 in 2,500). It is a genetically heterogenous group of neuropathies characterized by progressive distal muscle weakness and atrophy ("Inverted Champagne Bottle" legs), sensory loss, and foot deformities (Pes Cavus). It is classified into Demyelinating (CMT1) and Axonal (CMT2) forms. CMT1A (Duplication of PMP22 on Chr 17) accounts for 50-70% of cases. Diagnosis involves Neurophysiology (Slowing of conduction velocity in CMT1) and Genetic Testing. Management is supportive: Orthotics (AFOs), Physiotherapy, and Orthopaedic Surgery for foot correction. There is no cure, but life expectancy is normal. [1,2]

Key Facts

  • Prevalence: 1 in 2,500.
  • Inheritance: Mostly Autosomal Dominant (AD). X-linked (CMTX) and Recessive (AR) forms exist.
  • The "Champagne Bottle": Wasting of the peroneal and anterior tibial muscles with preservation of thigh muscles creates this classic sign.
  • Pes Cavus: High arches + Hammer toes. Driven by imbalance between weak intrinsics (tibialis anterior/peronei) and strong extrinsic muscles.
  • Tremor: "Roussy-Levy Syndrome" is CMT + Essential Tremor.

Clinical Pearls

"Thickened Nerves": In CMT1 (Demyelinating), the cycle of demyelination and remyelination leads to "Onion Bulb" formation. The Greater Auricular Nerve or Ulnar Nerve may be palpable and thickened.

"Do not label as clumsy": Many children present with "clumsiness" or difficulty running/sports long before a diagnosis is made. Look at the arches!

"CIDP Mimic": CMT1 can look like Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) on NCS. But CMT is uniform/symmetrical, while CIDP is patchy with conduction block.

"Vincristine Warning": If a CMT patient gets cancer, Vincristine (chemo) causes catastrophic, often irreversible neurotoxicity. Avoid it.

2. Epidemiology

Incidence

  • Prevalence: 40 per 100,000.
  • Onset: Usually first or second decade (Childhood/Adolescence).
  • Sex: Equal (except CMTX).
3. Pathophysiology

Classification (The Big Two)

  1. CMT Type 1 (Demyelinating):
    • Defect: Myelin Sheath.
    • NCS: Uniform slowing of conduction velocity (< 38 m/s in upper limbs).
    • Genetics: CMT1A (PMP22 Duplication) is the classic. CMT1B (MPZ mutation).
    • Pathology: Onion Bulb formation (Hypertrophic neuropathy).
  2. CMT Type 2 (Axonal):
    • Defect: Axon (Neuronal).
    • NCS: Normal/Near-normal velocity (> 38 m/s) but Reduced Amplitude (CMAP).
    • Genetics: CMT2A (Mitofusin-2 / MFN2).
  3. Intermediate: Velocities 25-45 m/s. (e.g. CMTX - Connexin 32).

The PMP22 Gene

  • Located on Chromosome 17p11.2.
  • Duplication -> CMT1A. (Too much PMP22 destabilizes myelin).
  • Deletion -> HNPP (Hereditary Neuropathy with Liability to Pressure Palsies).
4. Clinical Presentation

Distal Weakness (Motor)

Sensory Loss

Skeletal Deformities

Reflexes

Lower Limbs
Foot Drop (Steppage gait). Weak dorsiflexion/eversion. Atrophy of calves ("Stork legs" / "Champagne bottle").
Upper Limbs (Later)
Weakness of intrinsic hand muscles. Claw hand deformity. Loss of fine dexterity (buttons/zips).
5. Investigations

Neurophysiology (NCS/EMG)

The Triage Test.

  • It distinguishes Demyelinating (CMT1) from Axonal (CMT2).
  • CMT1:
    • Uniform slowing (allows distinction from acquired demyelination like CIDP/GBS which is patchy).
    • Conduction Block is RARE (if present, think CIDP).

Genetic Testing

  • Panel Testing: Standard care.
  • Protocol:
    • If NCS < 38 m/s -> Test PMP22 Duplication (CMT1A) first.
    • If Negative -> Test GJB1 (Connexin 32).
    • If Negative -> MPZ (CMT1B).
    • If NCS > 38 m/s -> Test MFN2 (CMT2A).

Nerve Biopsy

  • Rarely needed now (Genetics has replaced it).
  • Shows "Onion Bulbs" (Concentric layers of Schwann cell processes).
6. Management

Management Algorithm

        DIAGNOSIS CONFIRMED
                ↓
    ┌───────────┼───────────────┐
  ORTHOTICS    SURGERY       GENETIC
  PHYSIO      (Correction)   COUNSELING
    ↓           ↓               ↓
- AFOs        - Tendon        - Family
- Stretching    Transfer        Screening
              - Fusion        - PGD

1. Conservative

  • Physiotherapy: Maintain range of motion (prevent Tendo-Achilles contracture).
  • Orthotics:
    • AFO (Ankle Foot Orthosis): Plastic splint to correct foot drop.
    • Insoles: For cavus foot support.
    • High-top boots for ankle stability.
  • Exercise: Safe and recommended. Avoid exhaustion.

2. Surgical (Orthopaedic)

  • Soft Tissue: Plantar fascia release, Tendon transfers (e.g. Tibialis Posterior transfer) to correct foot drop.
  • Bone: Osteotomies (calcaneal) or Triple Arthrodesis (fusion) for severe rigid deformity.

3. Drugs to Avoid

  • Vincristine (Chemo): Severe toxicity.
  • Taxanes (Paclitaxel).
  • Nitrofurantoin? (Theoretical risk, usually safe in short courses).
7. Deep Dive: PMP22 Biology

"The Dosage Effect."

  • PMP22 is a transmembrane glycoprotein component of myelin.
  • Goldilocks Principle:
    • Too little (Deletion - HNPP) -> Unstable myelin (focal pressure palsies).
    • Too much (Duplication - CMT1A) -> Toxic aggregate formation in the Schwann cell -> Demyelination.
    • Just right (2 copies) -> Stable myelin.
  • Therapeutic Implication: Can we silence the extra copy? Antisense Oligonucleotides (ASOs) and Progesterone antagonists (PMP22 is upregulated by progesterone) are in trials.
8. Surgical Atlas: The Cavus Foot Correction (Detailed)

"Flattening the Arch." The specific muscular imbalance in CMT drives the deformity:

  • Weak: Tibialis Anterior (Dorsiflexor) & Peroneus Brevis (Evertor).
  • Strong: Peroneus Longus (Plantarflexor of 1st Ray) & Tibialis Posterior (Invertor).
  • Result: The strong Peroneus Longus pulls the 1st metatarsal down (plantarflexed 1st ray), creating a "tripod" effect where the heel varus compensates.
  • The Procedure (Steindler Release + Osteotomies):
    1. Plantar Fascia Release: Cut the tight band.
    2. Jones Procedure: Transfer EHL tendon to neck of 1st metatarsal (lift the dropped head).
    3. Dorsiflexion Osteotomy: Break the 1st metatarsal and re-align it up.
    4. Calcaneal Osteotomy: Correct the heel varus (Lateralising slide).
9. Deep Dive: CMT Type 1A (The Classic)

"The Duplication."

  • Genetics: Trisomy of PMP22.
  • Onset: First decade.
  • Course: Very slow progression. Most patients remain ambulant throughout life (though may need sticks/AFOs). Life expectancy is NORMAL.
  • Phenotype: Classic Hypertrophic Demyelinating Neuropathy.
  • Hearing Loss: Can occur (5%).
8. Deep Dive: CMT Type 2A (The Axonal)

"The Mitochondrial One."

  • Genetics: Mutation in Mitofusin 2 (MFN2). This protein regulates mitochondrial fusion.
  • Mechanism: Axonal transport failure due to mitochondrial dysfunction.
  • Phenotype:
    • More severe than CMT1A.
    • Earlier onset (sometimes under 10y).
    • Optic Atrophy: Can co-exist (HMSN VI).
    • Often non-ambulant by 20s.
9. Surgical Atlas: The Cavus Foot Correction

"Flattening the Arch." The specific muscular imbalance in CMT drives the deformity:

  • Weak: Tibialis Anterior (Dorsiflexor) & Peroneus Brevis (Evertor).
  • Strong: Peroneus Longus (Plantarflexor of 1st Ray) & Tibialis Posterior (Invertor).
  • Result: The strong Peroneus Longus pulls the 1st metatarsal down (plantarflexed 1st ray), creating a "tripod" effect where the heel varus compensates.
  • The Fix:
    1. Plantar Fascia Release: Cut the tight band.
    2. Jones Procedure: Transfer EHL tendon to neck of 1st metatarsal (lift the dropped head).
    3. Dorsiflexion Osteotomy: Break the 1st metatarsal and re-align it up.
    4. Calcaneal Osteotomy: Correct the heel varus.
10. Technical Appendix: HNPP

Hereditary Neuropathy with Liability to Pressure Palsies.

  • Genetics: DELETION of PMP22 (The opposite of CMT1A).
  • Presentation: Recurrent, painless mononeuropathies triggered by minor compression.
    • e.g. "Saturday Night Palsy" (Radial nerve) after sleeping on arm.
    • "Peroneal Palsy" after crossing legs.
  • NCS: Show background demyelination + focal conduction blocks at compression sites.
  • Prognosis: Good. Most palsies recover.
11. Complications
  • Falls: Foot drop.
  • Ulcers: Sensory loss + deformity (pressure points).
  • Hip Dysplasia: Linked to CMT.
  • Sleep Apnoea: Diaphragmatic weakness (rare but serious).
12. Prognosis & Outcomes
  • Life Expectancy: Generally Normal.
  • Ambulation:
    • CMT1A: >90% retain walking ability.
    • CMT2A: Higher risk of wheelchair.
  • Quality of Life: Chronic pain and fatigue are major issues.
13. Evidence and Guidelines
  • CMT International Consortium Guidelines.
14. Patient Explanation

What is CMT?

It is a condition where the nerves in your legs and arms don't work fully. It is genetic (passed down). It makes the muscles weak and can change the shape of your feet.

Will I end up in a wheelchair?

Most likely not. While walking can become difficult (you might trip), the vast majority of people with the common type (CMT1A) keep walking their whole lives.

Can I pass it on?

Yes. It is usually a 50/50 chance for each child. We can offer genetic counselling to discuss this.

15. References
  1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8:654-67.
  2. Rossor AM, et al. Charcot-Marie-Tooth disease. Pract Neurol. 2013.
16. Examination Focus

Common Exam Questions

1. Genetics:

  • Q: What is the genetic abnormality in CMT1A?
  • A: Duplication of the PMP22 gene on Chromosome 17.

2. Signs:

  • Q: What is "Inverted Champagne Bottle" appearance?
  • A: Severe wasting of the distal lower limb (calves) with preservation of the thigh bulk.

3. Physiology:

  • Q: How do you differentiate CMT1 from CMT2 on NCS?
  • A: CMT1 slows conduction velocity (under 38m/s). CMT2 reduces amplitude (Axonal loss).

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.

Last updated: 2025-12-24

At a Glance

EvidenceHigh
Last Updated2025-12-24

Red Flags

  • Rapid progression (exclude CIDP)
  • Asymmetry (CMT is symmetrical)
  • Respiratory involvement (Rare but severe in some types)
  • Foot ulcers (Sensory loss)

Clinical Pearls

  • **"Do not label as clumsy"**: Many children present with "clumsiness" or difficulty running/sports long before a diagnosis is made. Look at the arches!
  • **"CIDP Mimic"**: CMT1 can look like Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) on NCS. But CMT is uniform/symmetrical, while CIDP is patchy with conduction block.
  • **"Vincristine Warning"**: If a CMT patient gets cancer, Vincristine (chemo) causes catastrophic, often irreversible neurotoxicity. Avoid it.
  • 38 m/s) but **Reduced Amplitude** (CMAP).
  • **CMT1A**. (Too much PMP22 destabilizes myelin).

Guidelines

  • NICE Guidelines
  • BTS Guidelines
  • RCUK Guidelines