What is Charcot-Marie-Tooth (CMT) disease?

Charcot-Marie-Tooth Disease: A Comprehensive Overview

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy, characterized by progressive motor and sensory impairment affecting both upper and lower limbs, with a global prevalence between 4.7 and 36 per 100,000 people. 1

Clinical Presentation and Pathophysiology

CMT disease presents with a predominantly motor phenotype featuring:

• Symmetrical distal muscle weakness and atrophy
• Foot deformities (foot drop, high arches)
• Sensory deficits in a "glove and stocking" distribution
• Decreased or absent deep tendon reflexes
• Progressive gait difficulties

The disease typically manifests in infancy or early childhood, with patients initially showing clumsiness of gait and foot deformities 2. As the condition progresses, muscle atrophy becomes more prominent, particularly in the distal limbs, creating characteristic "stork legs" or "inverted champagne bottle" appearance of the lower extremities 3.

Classification and Genetics

CMT is genetically heterogeneous with multiple inheritance patterns:

• Autosomal dominant (most common)
• Autosomal recessive
• X-linked

Based on electrophysiological findings, CMT is classified into:

1. Demyelinating forms (CMT1): Reduced nerve conduction velocities due to myelin sheath abnormalities
2. Axonal forms (CMT2): Normal or slightly reduced nerve conduction velocities with decreased compound muscle action potential amplitudes
3. Intermediate forms: Features of both demyelinating and axonal types

More than 30 genes have been identified as causative for different CMT subtypes, with mutations affecting various components of peripheral nerve function 4. Despite advances in genetic testing, molecular diagnosis can only be established in approximately 50-70% of patients, suggesting additional undiscovered genetic causes 4.

Diagnosis

The diagnostic approach to CMT includes:

1. Clinical evaluation: Assessment of motor and sensory deficits, foot deformities, and family history
2. Electrophysiological studies: Nerve conduction studies to determine if the neuropathy is primarily demyelinating or axonal
3. Genetic testing: Molecular analysis to identify specific gene mutations
4. Nerve biopsy: Rarely needed but may show demyelination or axonal degeneration

It's important to note that CMT can be misdiagnosed in certain contexts. For example, in patients with tethered spinal cord syndrome, muscle atrophy with "saber shins" may be misdiagnosed as CMT 3. Similarly, in cases of chemotherapy-induced peripheral neuropathy, severe motor involvement might prompt investigation for predisposing conditions like CMT type 1A 3.

Associated Complications

CMT can affect multiple systems beyond the limbs:

• Respiratory system: Restrictive pulmonary impairment due to phrenic nerve dysfunction, diaphragm weakness, or thoracic cage abnormalities 5
• Sleep disorders: Both central and obstructive sleep apnea, as well as restless legs syndrome 5
• Vocal cord dysfunction: Can mimic asthma and may progress to bilateral involvement with risk of aspiration 5

Treatment Approaches

Currently, there are no approved disease-modifying therapies that can cure CMT, and management focuses on symptom control, rehabilitation, orthotics, and surgery to improve quality of life. 6

Treatment strategies include:

1. Physical therapy: To maintain muscle strength and prevent contractures
2. Orthotic devices: Ankle-foot orthoses to improve gait stability
3. Surgical interventions: For severe foot deformities or other skeletal abnormalities
4. Respiratory support: For patients with diaphragmatic weakness (bi-level positive airway pressure may be more appropriate than CPAP for sleep apnea with restrictive lung disease) 5
5. Pain management: For neuropathic pain

Emerging Therapies

Research into disease-modifying treatments is ongoing, with approaches including:

• Gene silencing
• Gene addition
• Gene editing
• Drug therapies targeting specific pathophysiological mechanisms

Currently, most treatments reaching clinical trials are drug-based, with gene therapies for CMT2S being the only subtype to reach clinical trial stage 6.

Prognosis

CMT is generally slowly progressive, with variable severity even within families carrying the same mutation. While it can cause significant disability, it rarely affects life expectancy. Early diagnosis and appropriate management can help maintain function and quality of life.

Key Considerations for Clinicians

• CMT should be considered in any patient with chronic polyneuropathy without a clear acquired cause 1
• Genetic counseling is essential for affected individuals and their families
• Regular monitoring for complications affecting respiratory function and sleep is important
• Treatment approaches should address both neurological and orthopedic aspects of the disease
• Patients should be referred to multidisciplinary teams with experience in managing hereditary neuropathies