Charcot-Marie-Tooth disease

Content of This Page

1- Introduction

2- Causes

3- Symptoms

4- Investigations & Lab Results

5- Complications

6- Treatment

Introduction

Charcot-Marie-Tooth disease is a group of inherited disorders that affect the peripheral nervous system, which includes the nerves outside the brain and spinal cord. It causes progressive weakening and wasting of the muscles, especially in the feet, lower legs, hands, and forearms, along with loss of sensation in these areas.

The disease typically begins in childhood or early adulthood, although onset can vary. It is slowly progressive and results from mutations in genes that affect the structure and function of peripheral nerves. Despite its name, Charcot-Marie-Tooth disease is not related to the teeth.

Although it is a chronic condition, it does not usually affect life expectancy, and many people lead active lives with appropriate management and support.

Causes

1. Genetic Inheritance Patterns

CMT is inherited in several ways:

Autosomal dominant (most common)
Autosomal recessive
X-linked

Each subtype is associated with specific gene mutations and inheritance patterns.

2. Main Types and Associated Genes

CMT Type	Primary Defect	Common Mutated Genes
CMT1	Demyelinating neuropathy	PMP22 (duplication), MPZ, LITAF
CMT2	Axonal neuropathy	MFN2, GARS, GDAP1
CMTX	X-linked (usually in males)	GJB1 (encoding connexin 32)
CMT4	Autosomal recessive	SH3TC2, GDAP1, MTMR2, others

3. Pathophysiology

CMT1: Abnormalities in myelin sheath cause slow nerve conduction
CMT2: Damage to the axon causes reduced nerve signal strength
CMTX: Combination of both axonal and demyelinating features

4. Sporadic Cases

Rare, but some individuals develop CMT without a family history due to de novo mutations

Symptoms

1. Muscle Weakness and Atrophy

Foot and lower leg muscles are most commonly affected
Difficulty lifting the front part of the foot (foot drop)
Frequent tripping, clumsiness, or abnormal walking patterns
Calf muscle wasting, leading to “inverted champagne bottle” appearance
Later involvement of hand and forearm muscles (grip weakness, fine motor difficulties)

2. Sensory Loss

Decreased sensation in the feet, legs, hands, or arms
Numbness, tingling, or burning sensations
Poor proprioception (reduced sense of position and movement)

3. Foot Deformities

High arches (pes cavus)
Hammertoes
Flat feet or other skeletal deformities due to muscle imbalance

4. Gait Abnormalities

Difficulty running or climbing stairs
Steppage gait due to foot drop

5. Reflex Changes

Decreased or absent deep tendon reflexes, especially at the ankles

6. Progression

Slowly progressive
May lead to significant disability over time, though many patients remain ambulatory

Investigations & Lab Results

1. Clinical Evaluation

Family history of neuropathy
Physical exam shows distal muscle weakness, atrophy, foot deformities (e.g., pes cavus), and reduced reflexes

2. Nerve Conduction Studies (NCS) and Electromyography (EMG)

These are essential to confirm peripheral neuropathy and to classify the type:

CMT1 (Demyelinating)
- Markedly slowed nerve conduction velocities (NCVs) (<38 m/s in motor nerves)
- Prolonged distal latencies and conduction blocks
CMT2 (Axonal)
- Normal or mildly reduced NCVs
- Low amplitude responses due to axonal loss
CMTX
- Mixed features, often intermediate conduction velocity

3. Genetic Testing

Confirms the diagnosis and identifies the specific mutation
Often targets common genes first (e.g., PMP22 duplication for CMT1A)
Helpful for family counseling and prenatal diagnosis

4. Laboratory Tests

Usually normal, but used to exclude acquired causes of neuropathy:
- Fasting blood glucose/HbA1c (for diabetic neuropathy)
- Vitamin B12 levels
- Thyroid function tests
- Serum protein electrophoresis (rule out paraproteinemic neuropathy)

5. Nerve Biopsy (rarely needed)

May be used in unclear cases
Shows onion bulb formation in demyelinating types (CMT1) due to repeated demyelination and remyelination

6. Imaging (optional)

MRI of lower legs may show fatty replacement of muscles
Used to assess the extent of muscle atrophy

Complications

1. Mobility Impairment

Progressive muscle weakness, especially in the feet and lower legs, can lead to:
- Difficulty walking
- Frequent tripping or falls
- Need for assistive devices (e.g., braces, walkers, wheelchairs)

2. Foot and Hand Deformities

Common due to muscle imbalance:
- Pes cavus (high-arched feet)
- Hammertoes
- Flat feet
- Claw hand deformity in later stages

3. Loss of Fine Motor Skills

Weakness in the hands can make tasks like writing, buttoning clothes, or using tools difficult

4. Chronic Pain and Cramps

Neuropathic pain due to nerve damage
Muscle cramps and fatigue are common

5. Sensory Impairment

Loss of sensation increases risk of:
- Unnoticed injuries (e.g., burns, cuts)
- Balance issues due to loss of proprioception

6. Psychosocial Effects

Anxiety, depression, and reduced self-esteem due to physical limitations and visible deformities
Social isolation in severe or visibly disabling cases

7. Complications from Surgery or Bracing

Orthopedic surgery (e.g., foot correction) carries risks of infection, delayed healing
Braces may cause skin irritation or pressure sores

Treatment

1. Physical and Occupational Therapy

Physical therapy:
- Strengthening and stretching exercises to maintain muscle tone and flexibility
- Prevent contractures and deformities
- Improve balance and gait
Occupational therapy:
- Helps with fine motor tasks and daily living activities
- Adaptive tools for dressing, writing, eating, etc.

2. Orthopedic Interventions

Braces and orthotics:
- Ankle-foot orthoses (AFOs) to correct foot drop and improve walking stability
- Custom shoes or insoles for foot deformities
Surgical treatment (if needed):
- Correct severe foot deformities (e.g., pes cavus, hammertoes)
- Tendon transfers or osteotomies for better alignment

3. Pain Management

Neuropathic pain medications:
- Gabapentin, pregabalin, amitriptyline, or duloxetine
Over-the-counter analgesics for muscle aches and cramps

4. Genetic Counseling

Recommended for affected individuals and families
Helps understand inheritance patterns and assess risk in offspring

5. Regular Monitoring and Support

Routine follow-up to monitor progression
Psychosocial support for emotional well-being
School and workplace accommodations if needed

6. Experimental and Emerging Therapies

Ongoing research into gene therapy and molecular treatments
Not yet available as standard care