What is the diagnostic approach to Charcot-Marie-Tooth (CMT) disease?

Diagnostic Approach to Charcot-Marie-Tooth Disease

The diagnostic approach to Charcot-Marie-Tooth (CMT) disease requires electrodiagnostic studies to classify the neuropathy as demyelinating or axonal, followed by targeted genetic testing based on the electrophysiological findings and inheritance pattern. 1

Clinical Evaluation

• Look for characteristic distal muscle weakness and atrophy, particularly in lower limbs creating a "stork leg" appearance due to peroneal muscle atrophy 1
• Assess for sensory deficits in a "glove and stocking" distribution 1
• Evaluate for bilateral pes cavovarus (high arch with inverted heel), which is the most common foot deformity 1
• Check for progressive gait abnormalities with foot drop and steppage gait 1
• Note decreased or absent deep tendon reflexes 1
• Document age of symptom onset (typically childhood or adolescence but can present at any age) 1
• Determine inheritance pattern through detailed family history (autosomal dominant most common, followed by X-linked and autosomal recessive) 1, 2

Electrodiagnostic Studies

• Perform nerve conduction studies (NCS) to classify the neuropathy as: 3, 1

  • Demyelinating (CMT1): Markedly slowed nerve conduction velocities
  • Axonal (CMT2): Normal or slightly reduced conduction velocities with reduced amplitude
  • Intermediate: Conduction velocities between demyelinating and axonal ranges

• Note that electrodiagnostic findings guide subsequent genetic testing and are essential for proper classification 1, 2

• Be aware that conduction slowing can be asymmetric and nonhomogeneous in X-linked CMT (CMTX), sometimes mimicking acquired inflammatory neuropathies 4

Genetic Testing Algorithm

• Follow a tiered approach to genetic testing based on electrophysiological findings and inheritance pattern: 3, 1

First-tier genetic testing:

• For demyelinating forms (CMT1): Test for PMP22 duplication (accounts for 70% of CMT1 cases) 3, 1
• For axonal forms (CMT2): Test for MFN2 mutations (accounts for 33% of CMT2 cases) 3, 1
• For possible X-linked inheritance: Test for GJB1 (Cx32) mutations (accounts for 12% of all CMT cases) 3, 1

Second-tier genetic testing:

• For demyelinating or axonal forms: Test for MPZ mutations (accounts for 5% of cases) 3
• For demyelinating forms: Test for PMP22 point mutations (accounts for 2.5% of cases) 3

Third-tier genetic testing:

• For demyelinating forms: Test for EGR2, LITAF, GDAP1 mutations 3
• For axonal forms: Test for RAB7, PRX, NEFL, HSPB1 mutations 3
• For X-linked forms: Test for additional rare mutations based on clinical presentation 3

Imaging Studies

• Consider MRI in cases where diagnosis remains unclear after electrodiagnostic studies and initial genetic testing 3
• If MRI is unavailable or contraindicated, consider nuclear imaging scan (scintigraphy), CT scan, or SPECT-CT 3

Common Diagnostic Pitfalls to Avoid

• Failure to perform electrodiagnostic studies, which are essential for proper classification 1, 2
• Overlooking hereditary causes in sporadic cases (30% of mutations are de novo) 1, 2
• Incomplete genetic testing (not following the tiered approach) 1, 2
• Misdiagnosis as acquired neuropathies (diabetic, toxic, or inflammatory) 1, 4
• Failure to recognize asymmetric and nonhomogeneous conduction slowing in CMTX, which can mimic acquired inflammatory neuropathies 4

Special Considerations

• In children, electrodiagnostic studies may be problematic; consider proceeding directly to genetic testing in symptomatic children with strong clinical suspicion 3
• For patients with cryptogenic polyneuropathy and classical hereditary neuropathy phenotype, genetic testing may be considered (Level C recommendation) 3
• There is insufficient evidence to support routine genetic testing in cryptogenic polyneuropathy patients without a classical hereditary phenotype (Level U recommendation) 3