Charcot-Marie-Tooth Disease Clinical Features and Diagnosis

Introduction to Charcot-Marie-Tooth Disease

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

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 4, 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 5
Symptoms typically begin in childhood or adolescence but can present at any age 1, 2

CMT is classified based on electrophysiological findings, including demyelinating forms (CMT1) with slowed nerve conduction velocities 4, 1
Axonal forms (CMT2) have normal or slightly reduced conduction velocities with reduced amplitude 4, 3
Inheritance patterns include autosomal dominant (most common) 4, 3, X-linked (CMTX) 4, 1, and autosomal recessive (less common) 4, 1

CMT1 (demyelinating form) is the most prevalent type 4, 1
CMT1A (PMP22 gene duplication) accounts for approximately 70% of CMT1 cases 4, 1
CMT2 (axonal form) has MFN2 mutations as the most common cause, accounting for approximately 33% of CMT2 cases 4, 1
CMTX (X-linked form) is caused by Cx32(GJB1) mutations and accounts for approximately 12% of all CMT cases 4, 1

Electrodiagnostic studies are essential for classification into demyelinating or axonal subtypes 4, 2
Genetic testing provides definitive diagnosis with 100% specificity for established pathogenic mutations 4, 1
A stepwise approach to genetic testing is recommended based on electrophysiological findings, inheritance pattern, and family history 4, 1, 3
First-tier genetic testing should focus on PMP22 duplication (CMT1A) for demyelinating forms, MFN2 mutations for axonal forms, and Cx32(GJB1) mutations for possible X-linked inheritance 4, 1, 3

Failure to perform electrodiagnostic studies, which are essential for proper classification 4, 3
Overlooking hereditary causes in sporadic cases (30% of mutations are de novo) 4, 3
Incomplete genetic testing (not following the tiered approach) 4, 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

CMT should be differentiated from acquired neuropathies and Charcot arthropathy, which may present with similar symptoms but have different causes and progression patterns, as noted by the European Journal of Nuclear Medicine and Molecular Imaging 6