CMTX5 is caused by mutations in the PRPS1 gene. This gene provides instructions for producing phosphoribosyl pyrophosphate synthetase 1, an enzyme involved in nucleotide synthesis that is essential for normal cellular function. Mutations in the PRPS1 gene impair nucleotide production and disrupt normal metabolic processes in peripheral nerve cells, leading to axonal dysfunction and impaired nerve signal transmission.
CMTX5 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 CMTX5-causing mutation in their single copy of the PRPS1 gene will have CMTX5. Individuals with two X chromosomes (chromosomal females) who have just one mutated copy will not have CMTX5.
Clinical Features
CMTX5 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 and reduced amplitudes, consistent with an intermediate form of CMT.
CMTX5 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, often in early childhood, prelingual
- Vision disturbances (some patients)
- Additional symptoms not listed here
Disease Course
CMTX5 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. Sensorineural hearing loss often begins prelingual. Some patients experience complete deafness by early adulthood.
