CMT2B2 is caused by mutations in the PNKP gene. This gene encodes (provides instructions for producing) polynucleotide kinase 3′-phosphatase, an enzyme involved in DNA repair by processing damaged DNA ends. Mutations in the PNKP gene impair normal DNA repair mechanisms, leading to cellular dysfunction in peripheral nerve cells and impaired nerve signal transmission.
CMT2B2 is autosomal recessive, meaning that both of the gene’s copies must have a CMT-causing mutation to cause this subtype.
Clinical Features
The age of symptom onset in CMT2B2 is variable, but usually by one’s early twenties. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. An earlier onset is not necessarily associated with a more severe disease course over time. Nerve conduction studies usually show normal or only mildly reduced motor conduction velocities, consistent with an axonal form of CMT.
CMT2B2 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
- Dysarthria (some patients)
- Slurred speech (some patients)
- Additional symptoms not listed here
Disease Course
CMT2B2 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.
