CMT2P is caused by mutations in the LRSAM1 gene. This gene provides instructions for producing leucine-rich repeat and sterile alpha motif–containing protein 1, an E3 ubiquitin ligase involved in protein regulation and intracellular trafficking, including endosomal pathways in nerve cells. Mutations in the LRSAM1 gene disrupt normal cellular maintenance in peripheral nerve cells, leading to impaired axonal function and nerve signal transmission.
CMT2P 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
CMT2P symptom onset is variable, ranging from early childhood to late adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.
CMT2P 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
CMT2P 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.
