What is Charcot-Marie-Tooth disease?

Charcot-Marie-Tooth Disease: Definition and Overview

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of inherited peripheral neuropathies—not to be confused with Charcot neuro-osteoarthropathy (Charcot foot), which is an entirely different condition affecting diabetic patients with neuropathy. 1

Core Disease Characteristics

CMT represents the most common inherited neuromuscular disorder, affecting approximately 1 in 2,500 people worldwide. 1, 2 The disease is characterized by:

• Progressive distal muscle weakness and atrophy, creating the characteristic "stork leg" appearance from peroneal muscle wasting 1, 3
• Sensory deficits in a "glove and stocking" distribution 1, 3
• Bilateral pes cavovarus (high arch with inverted heel) as the most common foot deformity 1
• Progressive gait abnormalities with foot drop and steppage gait 1
• Decreased or absent deep tendon reflexes 1
• Preserved cognitive function and normal development 1

Age of Onset and Progression

Symptoms typically begin in childhood or adolescence, though presentation can occur at any age. 1 The disease follows a slowly progressive course with variable severity depending on the specific genetic subtype. 2

Genetic Classification System

CMT is classified using three complementary approaches:

By Electrophysiological Pattern:

• CMT1 (demyelinating form): Slowed nerve conduction velocities, representing the most prevalent type 1
• CMT2 (axonal form): Normal or slightly reduced conduction velocities with reduced amplitude 1

By Inheritance Pattern:

• Autosomal dominant (most common) 1
• X-linked (CMTX) 1
• Autosomal recessive (less common) 1

By Specific Genetic Mutation:

• CMT1A (PMP22 gene duplication): Accounts for approximately 70% of CMT1 cases 1
• CMT2 with MFN2 mutations: Accounts for approximately 33% of CMT2 cases 1
• CMTX with Cx32(GJB1) mutations: Accounts for approximately 12% of all CMT cases 1

Diagnostic Algorithm

Electrodiagnostic studies are mandatory for proper classification into demyelinating versus axonal subtypes and must be performed before genetic testing. 1, 3

Step 1: Electrodiagnostic Testing

Nerve conduction studies distinguish demyelinating from axonal forms, which directly guides subsequent genetic testing strategy. 1, 3

Step 2: First-Tier Genetic Testing

• For demyelinating forms: Test for PMP22 duplication (CMT1A) first 1
• For axonal forms: Test for MFN2 mutations first 1
• For possible X-linked inheritance: Test for Cx32(GJB1) mutations first 1
• Genetic testing provides 100% specificity for established pathogenic mutations 1, 3

Step 3: Expanded Genetic Panel

If first-tier testing is negative, proceed with broader genetic panels based on clinical phenotype and family history. 1

Critical Differential Diagnosis

CMT must be differentiated from acquired neuropathies (diabetic, toxic, inflammatory) and from Charcot neuro-osteoarthropathy (Charcot foot), which is a completely separate condition affecting diabetic patients. 1, 4, 3

Key distinguishing features:

• CMT shows uniform or homogeneous conduction slowing on nerve studies, whereas acquired inflammatory neuropathies show asymmetric patterns 5
• Exception: CMTX can mimic acquired inflammatory neuropathies with asymmetric and nonhomogeneous conduction slowing 1
• Family history is often present, though 30% of mutations are de novo 1
• CMT1 shows diffuse nerve enlargement on ultrasound, while CIDP shows asymmetrical or focal enlargement 5

Common Diagnostic Pitfalls to Avoid

• Failing to perform electrodiagnostic studies before attempting genetic diagnosis—this is essential for proper classification 1, 3
• Dismissing hereditary causes in sporadic cases—remember that 30% of mutations are de novo 1
• Incomplete genetic testing by not following the tiered approach based on electrophysiology 1
• Misdiagnosing as acquired neuropathies (diabetic, toxic, or inflammatory) without considering hereditary causes 1, 3
• Confusing CMT with Charcot foot (Charcot neuro-osteoarthropathy)—these are entirely different conditions with different pathophysiology, populations, and management 1, 4

Management Principles

Currently, no drug therapy exists for CMT. 2 Management focuses on:

• Rehabilitation therapy for functional optimization 2
• Surgical correction of skeletal deformities when indicated 2
• Individualized treatment plans based on specific clinical presentation and patient goals 6