CMTX4 is caused by mutations in the AIFM1 gene. This gene provides instructions for producing apoptosis-inducing factor, mitochondria-associated 1, a protein involved in mitochondrial energy production and regulation of programmed cell death. Mutations in the AIFM1 gene disrupt normal mitochondrial function in peripheral nerve cells, leading to impaired axonal integrity and nerve signal transmission.
CMTX4 is X-linked recessive. This means the gene lives on the X chromosome. Individuals with one X and one Y chromosome (chromosomal males) who inherit a CMTX4-causing mutation in their single copy of the AIFM1 gene will have CMTX4. Individuals with two X chromosomes (chromosomal females) who have just one mutated copy will not have CMTX4.
CMTX4 is also called Cowchock Syndrome, named after F. Susan Cowchock, MD. Although different names, they refer to the same symptoms and AIFM1 gene mutations. Providers favor CMTX4 over Cowchock Syndrome because CMT is very non-syndromic. Some literature uses Cowchock Syndrome, and some uses CMTX4, but this does not mean you have both, as they refer to the same thing. For consistency across the Experts in CMT platform, CMTX4 is used.
Clinical Features
CMTX4 symptoms onset in infancy to early adulthood. They typically begin in the lower extremities and, over time, progress to involve the upper limbs. Severe sensorineural hearing loss from an early age is common. Some may have poor vision. Nerve conduction studies usually show somewhat slowed conduction velocities, consistent with an axonal form of CMT.
CMTX4 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
- Poor vision (some patients)
- Cognitive impairment (some patients)
- Additional symptoms not listed here
Disease Course
CMTX4 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Onset varies from infancy through early adulthood, but disease progression is generally slow, and life expectancy is not reduced.
