Pathogenesis of Charcot-Marie-Tooth Disease
CMT disease results from genetic mutations affecting peripheral nerve structure and function, leading to either myelin sheath abnormalities (demyelinating forms) or direct axonal damage (axonal forms), with the ultimate common pathway being length-dependent axonal degeneration that produces the characteristic distal phenotype. 1
Genetic Mechanisms
The pathogenesis begins at the molecular level with mutations in over 40 different genes, each affecting distinct cellular functions in peripheral nerves 2, 3:
CMT1A (demyelinating form) - The most common subtype (70% of CMT1 cases) results from duplication of the PMP22 gene on chromosome 17p12, causing abnormal myelin formation and maintenance 4, 5
CMT2 (axonal form) - Most frequently caused by MFN2 mutations (33% of CMT2 cases), which disrupt mitochondrial fusion and axonal transport mechanisms 4, 5
CMTX (X-linked form) - Results from Cx32(GJB1) mutations affecting gap junction proteins, accounting for 12% of all CMT cases and producing either demyelinating or axonal patterns 4, 5
Cellular Pathophysiology
The disease mechanisms vary by genetic subtype but converge on common pathways 1:
Demyelinating forms (CMT1) - Mutations in myelin-related genes (PMP22, MPZ, EGR2) cause abnormal myelin development or degeneration, resulting in uniformly slowed nerve conduction velocities 4, 1
Axonal forms (CMT2) - Mutations affect axonal transport, mitochondrial function, or cytoskeletal proteins, leading to primary axonal degeneration with relatively preserved myelin 4, 1
Length-dependent degeneration - Regardless of the primary defect (myelin or axon), the final common pathway involves length-dependent axonal degeneration, explaining why the longest nerves (to distal limbs) are affected first and most severely 1
Progressive Nerve Dysfunction
The pathogenic process unfolds progressively 6, 2:
Mutations cause either abnormal development or degeneration of peripheral nerves starting in infancy in most cases 6, 3
The distal-to-proximal gradient of nerve dysfunction produces the characteristic "stork leg" appearance from peroneal muscle atrophy 5
Secondary skeletal deformities (pes cavovarus) develop from chronic muscle imbalance 5, 6
Pathophysiological Heterogeneity
Important nuances exist across subtypes 1, 7:
CMTX shows asymmetric and nonhomogeneous conduction slowing, unlike the uniform slowing in CMT1A, sometimes mimicking acquired inflammatory neuropathies 1, 7
Some genes produce variable phenotypes - different mutations in the same gene can cause either demyelinating or axonal forms 1
Recessive forms (CMT4) typically have earlier onset and more severe progression than dominant types 1
Some CMT1 cases (especially CMT1B and CMT2A) show inflammatory macrophage infiltration, suggesting secondary inflammatory mechanisms that may respond to immunomodulation 7
Clinical-Pathological Correlation
The pathogenesis directly explains clinical manifestations 5, 6:
Progressive distal muscle weakness and atrophy result from length-dependent axonal loss 5, 1
Sensory deficits in "glove and stocking" distribution reflect the same length-dependent process 5
Areflexia develops from sensory nerve involvement affecting reflex arcs 1
Foot deformities arise from chronic imbalance between intrinsic and extrinsic foot muscles 5, 6