What Is CMT4A?
CMT4A is a type of CMT caused by mutations in the GDAP1 gene. This gene provides instructions for producing ganglioside-induced differentiation-associated protein 1, a protein involved in mitochondrial dynamics and cellular stress responses in peripheral nerves. Mutations in the GDAP1 gene disrupt normal mitochondrial function in the peripheral nerves, leading to impaired nerve signal transmission.
CMT4A 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 CMT4A is typically before age 3, beginning in the lower limbs and progressing to the upper body. Progression to severe disability is often rapid. Nerve conduction studies usually show slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT. When a nerve conduction study shows an axonal form of CMT, autosomal recessive CMT2K is the diagnosis.
CMT4A 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
- Kyphoscoliosis (kyphosis + scoliosis)
- Balance difficulties
- Additional symptoms not listed here
Disease Course
CMT4A is typically a severe disease with an early onset, rapidly progressing to significant disability. Life expectancy, however, is not reduced.
