CMTX6 is caused by mutations in the PDK3 gene. This gene provides instructions for producing pyruvate dehydrogenase kinase 3, an enzyme that regulates energy production by controlling the activity of the pyruvate dehydrogenase complex within mitochondria. Mutations in the PDK3 gene disrupt normal energy metabolism in peripheral nerve cells, leading to axonal dysfunction and impaired nerve signal transmission.
CMTX6 is X-linked dominant. This means the gene lives on the X chromosome, and in people with two X chromosomes (chromosomal females), a mutation in one copy of the gene causes CMT. For individuals with one X and one Y chromosome (chromosomal males), a mutation in their single copy of the gene is sufficient to cause CMT.
When a female has CMTX6, each of her children has a 50% chance of inheriting her CMT. In contrast, a chromosomal male with CMTX6 will pass it to all his daughters but none of his sons because males pass their X chromosome only to their daughters.
Clinical Features
The age of symptom onset in CMTX6 is in the first decade. 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.
CMTX6 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
- Sensorineural hearing loss (some patients)
- Additional symptoms not listed here
Disease Course
CMTX6 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. Females who have CMTX6 can have a much less severe disease than males with this subtype. Experts believe this is due to females having a second, unaffected copy of the PDK3 gene on their other X chromosome, which males do not have.
