CMT2DD is caused by mutations in the ATP1A1 gene. This gene provides instructions for producing neurofilament heavy chain, a structural protein that helps maintain the shape, caliber, and stability of peripheral nerve axons. Mutations in the ATP1A1 gene disrupt normal nerve structure, leading to impaired nerve signal transmission.
CMT2DD is autosomal dominant, meaning that just one of the gene’s two copies must have a CMT-causing mutation to cause this subtype.
Clinical Features
The age of symptom onset in CMT2DD is variable, ranging from early childhood to adulthood, but most will have onset by the teens. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. An earlier onset isn’t necessarily associated with a more severe disease course. Nerve conduction studies usually show normal motor conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.
CMT2DD 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
- Balance difficulties
- Additional symptoms not listed here
Disease Course
CMT2DD shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.
