CMT4B1 is caused by mutations in the MTMR2 gene. This gene provides instructions for producing myotubularin-related protein 2, an enzyme involved in phosphoinositide metabolism that plays an important role in maintaining normal myelin structure in peripheral nerves. Mutations in the MTMR2 gene disrupt Schwann cell function and impair peripheral nerve myelin maintenance, leading to slowed nerve signal transmission.
CMT4B1 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 CMT4B1 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 show slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT. CMT4B1 often includes facial muscle weakness and delayed motor milestones.
CMT4B1 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
- Facial muscle weakness
- Delayed motor development
- Breathing muscle weakness
- Kyphoscoliosis (kyphosis + scoliosis)
- Balance difficulties
- Additional symptoms not listed here
Disease Course
CMT4B1 is typically a severe disease with an early onset, rapidly progressing to significant disability. Life expectancy may be reduced due to untreated breathing muscle weakness (severe kyphoscoliosis may complicate this).
