CMT4H is caused by mutations in the FGD4 gene. This gene provides instructions for producing frabin, a protein involved in regulating the actin cytoskeleton and maintaining normal Schwann cell structure. Mutations in the FGD4 gene disrupt normal Schwann cell function and impair peripheral nerve myelin formation, leading to slowed nerve signal transmission.
CMT4H 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 CMT4H typically occurs before age 2. Symptoms usually begin in the lower limbs and progress to the upper body. Nerve conduction studies usually show severely slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT.
CMT4H 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
- Additional symptoms not listed here
Disease Course
CMT4H is typically a severe disease. Although severe, progression is generally slow, and life expectancy is not reduced.
