What Is CMTX1?
CMTX1 is a type of CMT caused by mutations in the GJB1 gene. This gene provides instructions for producing connexin 32, a protein that forms gap junction channels in Schwann cells and plays a critical role in intercellular communication within the myelin sheath. Mutations in the GJB1 gene disrupt normal Schwann cell function and impair myelin maintenance, leading to impaired nerve signal transmission.
CMTX1 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 CMTX1, each of her children has a 50% chance of inheriting her CMT. In contrast, a chromosomal male with CMTX1 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 CMTX1 is variable, ranging from infancy to early adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Earlier onset is not necessarily associated with a more severe disease course. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an intermediate form of CMT. Motor development delay and cognitive impairment have been reported in some.
CMTX1 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
- Cognitive impairment (some patients)
- Additional symptoms not listed here
Disease Course
CMTX1 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 CMTX1 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 GJB1 gene on their other X chromosome, which males do not have.
Historic CMTX1 Names
CMTX1 was originally called “CMT1X” or simply “CMTX” when scientists first published its discovery in 1993. This subtype was classified as CMT1 because the responsible mutation is within a gene that is implicated in peripheral myelin. This made sense. “CMTX” made sense, too, because this was the only X-linked subtype at the time. However, additional genomic discoveries made this naming convention difficult to maintain and scale.
Published literature does not provide a specific date, but around 2008, the designation “CMTX1” began to appear more consistently in the literature as additional X-linked subtypes were identified. This was driven by the additional X-linked CMT discoveries: CMTX2, CMTX3, CMTX4, CMTX5, and CMTX6. And with this emergence, the “CMTX” classification for these six CMT subtypes.
Today, “CMT1X,” “CMTX,” and “CMTX1” each refer to CMT caused by a dominant mutation in the GJB1 gene. Scientists and researchers tend to favor “CMT1X” or “CMTX.” Later generation physicians and clinicians tend to favor “CMTX1.” Patients favor whichever name their physician used when making the diagnosis.
Experts in CMT (EIC) does not try to adjudicate the naming divergence for this CMT subtype. But for consistency, “CMTX1” is used throughout the EIC platform. Whichever you choose, these refer to the same CMT subtype caused by dominant mutations in the GJB1 gene.
