CMT2K is 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.
CMT2K can be either autosomal dominant or autosomal recessive, meaning that sometimes it’s just one of the gene’s two copies with a CMT-causing mutation, and sometimes it’s both copies.
Clinical Features
Symptom onset in CMT2K is typically before age 3, beginning in the lower limbs and progressing to the upper body. Patients with autosomal dominant CMT2K (a single, heterozygous pathogenic GDAP1 gene mutation) have a less severe disease course with a later onset. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT. When autosomal recessive CMT2K shows a demyelinating form of CMT on a nerve conduction study, CMT4A is the diagnosis.
CMT2K 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
CMT2K is typically a severe disease with an early onset. However, individuals with autosomal dominant CMT2K are usually less affected and with a later onset than those with autosomal recessive CMT2K. Regardless of age at symptom onset, disease progression is generally slow, and life expectancy is not reduced.
