What is Charcot-Marie-Tooth (CMT) disease and its clinical features?

Charcot-Marie-Tooth Disease and Its Clinical Features

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, sensory loss, and foot deformities, with a prevalence of approximately 1:2,500 people. 1, 2

Clinical Presentation

• Distal muscle weakness and atrophy, particularly in the lower limbs, creating a characteristic "stork leg" appearance due to peroneal muscle atrophy 2
• Sensory deficits in a "glove and stocking" distribution 2, 3
• Bilateral pes cavovarus (high arch with inverted heel) is the most common foot deformity 1
• Progressive gait abnormalities with foot drop and steppage gait 1, 3
• Decreased or absent deep tendon reflexes 1
• Relatively normal cognitive function and development 1
• Symptoms typically begin in childhood or adolescence but can present at any age 1, 2

Genetic Classification

CMT is classified based on:

• Electrophysiological findings (essential for proper classification):

  • Demyelinating forms (CMT1): Slowed nerve conduction velocities 1
  • Axonal forms (CMT2): Normal or slightly reduced conduction velocities with reduced amplitude 1, 3
  • Intermediate forms: Conduction velocities between demyelinating and axonal ranges 1

• Inheritance patterns:

  • Autosomal dominant (most common) 1, 3
  • X-linked (CMTX) 1
  • Autosomal recessive (less common) 1

Genetic Subtypes and Prevalence

• CMT1 (demyelinating form) is the most prevalent type 1

  • CMT1A (PMP22 gene duplication) accounts for approximately 70% of CMT1 cases 1
  • CMT1A is also the most common form of sporadic CMT1, accounting for 76-90% of cases 1

• CMT2 (axonal form)

  • MFN2 mutations are the most common cause, accounting for approximately 33% of CMT2 cases 1

• CMTX (X-linked form)

  • Caused by Cx32(GJB1) mutations 1
  • Accounts for approximately 12% of all CMT cases 1
  • Can present with either predominantly demyelinating or axonal features 1

• Less common genetic causes:

  • PMP22 point mutations (approximately 2.5% of CMT cases) 1
  • MPZ mutations (approximately 5% of CMT cases) 1

Diagnostic Approach

• Electrodiagnostic studies are essential for classification into demyelinating or axonal subtypes 1, 2

• Genetic testing provides definitive diagnosis with 100% specificity for established pathogenic mutations 1

• A stepwise approach to genetic testing is recommended based on:

  • Electrophysiological findings (demyelinating vs. axonal) 1
  • Inheritance pattern (autosomal dominant, X-linked, autosomal recessive) 1, 3
  • Family history (positive or negative) 1

• First-tier genetic testing should focus on:

  • For demyelinating forms: PMP22 duplication (CMT1A) 1
  • For axonal forms: MFN2 mutations 1
  • For either type with possible X-linked inheritance: Cx32(GJB1) mutations 1, 3

Common Pitfalls in Diagnosis

• Failure to perform electrodiagnostic studies, which are essential for proper classification 1, 3
• Overlooking hereditary causes in sporadic cases (30% of mutations are de novo) 1, 3
• Incomplete genetic testing (not following the tiered approach) 1, 3
• Misdiagnosis as acquired neuropathies (diabetic, toxic, or inflammatory) 2
• Failure to recognize asymmetric and nonhomogeneous conduction slowing in CMTX, which can mimic acquired inflammatory neuropathies 1

Management

• Currently, no approved disease-modifying treatments exist 4
• Management focuses on symptomatic interventions 4
• Orthopedic interventions may be needed for foot deformities:
  • Early soft tissue release and tendon transfers for flexible deformities 5
  • Osteotomies or arthrodesis for rigid deformities 5
• Gene therapy approaches are under investigation as potential future treatments 4, 6