CMT2HH is caused by mutations in the JAG1 gene. This gene provides instructions for producing Jagged-1, a protein involved in Notch signaling, which plays an important role in cell communication and development, including in the nervous system. Mutations in the JAG1 gene disrupt normal signaling pathways in peripheral nerve cells, leading to impaired axonal function and nerve signal transmission.
CMT2HH 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
Symptom onset in CMT2HH is typically before age 3 and affects the lower limbs more than the upper limbs. Vocal cord paresis may impact breathing, necessitating mechanical ventilation. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.
CMT2HH 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
- Vocal cord paresis (some may require tracheostomy)
- Stridor
- 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
CMT2HH shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow. Life expectancy may be reduced if vocal cord paresis/breathing is not appropriately monitored and treated.
