What Is CMT2A?
CMT2A is a type of CMT caused by autosomal dominant mutations in the MFN2 gene. This gene provides instructions for producing mitofusin-2, a protein crucial for the normal fusion and transport of mitochondria within nerve cells. Mutations in the MFN2 gene disrupt mitochondrial function in peripheral nerves.
The original cause for CMT2A was believed to be associated with the KIF1B gene (published in 1998). However, in 2004, the actual cause, a mutation in the MFN2 gene, was verified. Since then, this subtype has been known by various names, including CMT2A1, CMT2A2, and CMT2A2A. Regardless of which name, they are all CMT2A. ClinGen fully retracted KIF1B’s connection to CMT in 2020. However, some genetic testing companies still include KIF1B on their gene panels. Read the history here.
CMT2A is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.
Clinical Features
The age of symptom onset in CMT2A is variable, ranging from early childhood to adulthood. Symptoms typically begin in the lower extremities and progress to involve the upper limbs. An earlier onset is often associated with a more severe disease. Nerve conduction studies usually show normal or only mildly reduced motor conduction velocities, consistent with an axonal form of CMT.
CMT2A symptoms may include:
- First symptoms typically appear in the lower extremities
- Variable age of onset, from childhood through adulthood
- Weakness in the feet and lower legs
- Muscle atrophy
- Foot drop
- A steppage-style walking pattern
- Reduced sensation, with pain and temperature sensation often more affected than vibration or position sense
- Reduced or absent reflexes
- Foot deformities, including high arches and hammertoes (clawed toes)
- Contractures or scoliosis, particularly in individuals with early-onset disease
- Rare features such as optic atrophy, hearing loss, tremor, pyramidal signs, or spasticity
- Approximately 25% may beonly mildly affected, suggesting incomplete/low penetrance
- Additional symptoms not listed here
Disease Course
CMT2A shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease, particularly when symptoms begin early in life. Disease progression is generally slow, and life expectancy is not reduced.
