What is the pathology and management of Charcot-Marie-Tooth (CMT) disease?

Pathology and Management of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy characterized by progressive distal muscle weakness, sensory loss, and foot deformities, with genetic testing being the definitive diagnostic approach for accurate classification and management. 1

Pathology

Genetic Basis

• CMT has been linked to 36 loci with mutations identified in 28 different genes 1
• Main genetic subtypes include:
  • CMT1 (demyelinating form): Most prevalent type
    • 70% caused by PMP22 gene duplication (CMT1A) 1
    • 5% caused by MPZ mutations 1
    • 2.5% caused by PMP22 point mutations 1
  • CMT2 (axonal form):
    • 33% caused by MFN2 mutations 1
  • CMTX (X-linked form):
    • 12% caused by Cx32(GJB1) mutations 1
    • Can present with either demyelinating or axonal phenotype

Pathophysiological Mechanisms

• Demyelinating forms (CMT1): Primary defect in Schwann cells leading to demyelination and secondary axonal loss
• Axonal forms (CMT2): Primary axonal degeneration
• Genetic findings indicate pathogenic convergence mainly to the axonal cytoskeleton 2
• Axonal transport defects are a common pathological feature 2

Diagnostic Approach

Clinical Evaluation

• Evaluate for classic signs of peripheral neuropathy:
  • Distal muscle weakness and wasting (typically starting in feet/legs)
  • Sensory loss in "glove and stocking" distribution
  • Foot deformities (pes cavus, hammertoes)
  • Digit contractures 3

Diagnostic Testing

1. Electrodiagnostic Studies (EDX)

   • Essential for distinguishing between demyelinating and axonal types 1
   • Helps guide genetic testing strategy

2. Genetic Testing

   • Provides definitive diagnosis with 100% specificity for established pathogenic mutations 1
   • Testing strategy based on:
     • EDX results (demyelinating vs. axonal)
     • Inheritance pattern (autosomal dominant, recessive, X-linked)
     • Family history

3. Imaging

   • Plain X-rays (standing/weight-bearing when possible) to assess foot deformities 3
   • MRI when X-rays appear normal but clinical suspicion remains high 3

4. Skin Biopsy

   • May be considered to diagnose polyneuropathy, particularly small fiber sensory neuropathy (Level C recommendation) 1
   • Intraepidermal nerve fiber density assessment is useful for identifying distal symmetric polyneuropathy 1

Management

Rehabilitation Approaches

• Exercise Program 3, 4:

  • Strengthening exercises for affected muscle groups
  • Stretching to maintain range of motion
  • Core stability training
  • Balance and resistance training
  • Aerobic exercises to improve general fitness
  • Avoid high-impact activities that increase risk of foot trauma

• Orthotic Devices 3, 4:

  • Mainstay for maintaining mobility and ambulation
  • Footwear/orthoses that accommodate and support foot shape
  • Consider below-knee customized devices for additional protection with deformity or joint instability
  • Extra wide or deep shoes for mild deformities
  • Custom-molded shoes for severe deformities

Surgical Interventions

• Consider surgical intervention when 3:
  • Foot/ankle joint instability is present
  • Deformity with high risk of developing ulcers exists
  • Pain cannot be adequately managed with conservative measures

Preventive Measures

• Regular foot inspection for injuries, especially in areas with sensory loss 3
• Monitor skin temperature and restrict activity during periods of inflammation 3
• Use assistive devices (crutches, walker) to reduce weight-bearing on affected limb when needed 3

Emerging Therapeutic Approaches

• Currently, no FDA-approved drug therapy exists for CMT 5
• Promising experimental treatments under investigation:
  • Histone deacetylase 6 inhibitors (potential therapeutic target for axonal transport defects) 2
  • Progesterone antagonists, neurotrophic factors, ascorbic acid, and curcumin have shown promising results in experimental models 5

Common Pitfalls and Caveats

1. Diagnostic Challenges:

   • CMT can be misdiagnosed as diabetic neuropathy or other acquired neuropathies
   • Important to distinguish CMT (genetic condition) from diabetic Charcot neuropathy (acquired condition) 3
   • 30% of mutations are de novo, so absence of family history does not rule out CMT 1

2. Genetic Testing Efficiency:

   • When testing for CMT1A duplication is restricted to patients with clinically probable CMT1, the yield is 54-80% 1
   • Testing a broader cohort of suspected hereditary neuropathy patients yields only 25-59% positive results 1
   • Novel mutations may require further characterization at specialized centers 1

3. Management Limitations:

   • No curative treatments currently exist
   • Rehabilitation and orthotic devices remain the cornerstone of management 4
   • Surgical outcomes can be problematic, emphasizing the importance of conservative approaches 4

4. Disease Progression:

   • Disease course is variable due to genotypic and phenotypic heterogeneity 5
   • Degradation of clinical phenotype is not linear and progressive 6
   • Long-term monitoring is essential for adjusting management strategies

By understanding the genetic basis and implementing appropriate rehabilitation strategies, patients with CMT can maintain optimal function and quality of life despite this progressive condition.