CMT4E is caused by mutations in the EGR2 gene. This gene plays a key role in regulating the development and maintenance of peripheral nerve myelin. Mutations in the EGR2 gene disrupt normal myelin formation, leading to slowed nerve signal transmission.
CMT4E is autosomal recessive, meaning that both of the gene’s copies must have a CMT-causing mutation to cause this subtype.
Clinical Features
Symptom onset in CMT4E typically occurs in infancy or early childhood. Individuals often experience delayed motor milestones and early weakness. Hypotonia in infancy is common, and respiratory insufficiency can occur. Nerve conduction studies usually show severely slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT.
CMT4E symptoms may include:
- Weakness in the feet and lower legs
- Muscle atrophy
- Foot drop
- A steppage-style walking pattern
- Reduced sensation
- Reduced or absent reflexes
- Foot deformities, including high arches and hammertoes (clawed toes)
- Progressive involvement of the hands and forearms
- Difficulty with fine motor skills and manual dexterity
- Hypotonia
- Respiratory insufficiency (in infancy in some individuals)
- Additional symptoms not listed here
Disease Course
CMT4E shows wide variability in severity and progression. Some individuals remain mildly affected, while others develop more severe weakness and functional impairment. Even within the same family, disease severity and progression can differ substantially. Progression is generally slow. Life expectancy can be affected if respiratory insufficiency is not identified and treated early.
