Neuromuscular Diseases: Hereditary Motor–Sensory Neuropathies (HMSN)
Hereditary Motor–Sensory Neuropathies (HMSN), collectively known as Charcot–Marie–Tooth (CMT) diseases, are a group of inherited peripheral neuropathies characterized by progressive degeneration of motor and sensory nerves. They lead to muscle weakness, atrophy, sensory loss, and foot deformities.
These are among the most common inherited neurological disorders, affecting 1 in 2,500 individuals, with highly variable clinical severity and genetic causes.
Genetic and Molecular Basis
HMSNs are genetically heterogeneous — caused by mutations in genes encoding myelin sheath proteins, axonal transport molecules, or mitochondrial components. The disease mechanism varies depending on whether the myelin (Schwann cell) or the axon is primarily affected.
Main Causative Genes and Proteins
Most common: CMT1A → duplication of PMP22 gene (autosomal dominant).
Pathophysiology
- 1. Mutations in myelin or axonal genes lead to structural and functional impairment of peripheral nerves.
- 2. In demyelinating types (CMT1): defective Schwann cell myelin proteins → segmental demyelination → slower nerve conduction.
- 3. In axonal types (CMT2): disrupted mitochondrial transport → axonal degeneration and loss of distal nerve terminals.
- 4. Chronic denervation of muscles → atrophy, weakness, and deformities.
- 5. Sensory nerve damage causes loss of vibration and proprioception.
- 6. Regenerative cycles → hypertrophic “onion bulb” formation (concentric Schwann cell layers around axons).