What is CMT Type X?

CMTX, or what is X-Linked CMT, is a group of CMT subtypes that are caused by a mutation in a gene that is found on the X-chromosome. When there was only one known X-Linked subtype, it was classified as CMT1 and was named CMT1X. This had to do with the gene mutation that causes this subtype causing a problem with peripheral nerve myelin. At the time, it made sense that this subtype would be a CMT1 subtype since CMT1 collectively was and still is demyelinating CMT. However, as more X-Linked CMT causes were discovered, the CMTX classification emerged, and there are now six subtypes that make up the CMTX classification: X1, X2, X3, X4, X5, and X6. Today, CMT1X and CMTX1 refer to the same subtype, they are synonymous with one another.

X-Linked Inheritance

CMTX is its own classification because each of the subtypes are inherited in a way that the other subtypes are not. How each of the other CMT subtypes are inherited applies equally to chromosomal females (XY) as it does to chromosomal males (XX). X-Linked inheritance is a little different and this is because the number of X-chromosomes is different between chromosomal females and chromosomal males.

Chromosomal females have two X-chromosomes, inheriting one from each parent. Chromosomal males have one X-chromosome, only inherited from their mom, and one Y-chromosome, only inherited from their dad. When a chromosomal female has X-Linked CMT, each of her children, regardless of their gender, have an equal chance of inheriting her X-Linked CMT-causing gene mutation. When a chromosomal male has X-Linked CMT, however, none of his chromosomal male children will inherit his X-Linked CMT-causing gene mutation, but each of his chromosomal female children will.

This X-Linked CMT inheritance uniqueness occurs because chromosomal males have only one X-chromosome, and they pass this only X-chromosome, and all the gene mutations of this X-chromosome, onto their chromosomal female children. To their chromosomal male children, they pass on their Y-chromosome and never their X-chromosome. For these reasons, the CMTX subtypes are the only ones in which chromosomal gender is a factor with inheritance.

What causes CMTX

  • CMT1X/X1 is caused by mutations in the GJB1 gene. GJB1 is the abbreviation for the GAP JUNCTION PROTEIN BETA 1 gene. This gene is formerly known as CX32, which is short for the CONNEXIN32 gene. CMT1X/X1 is the second most common CMT subtype, accounting for approximately 17% of all CMT cases, second only to CMT1A, which accounts for approximately 60% of all CMT cases.
  • The exact gene mutation responsible for CMTX2 is not yet known, but the area of the X-chromosome expected to have the responsible mutation has been narrowed down to (mapped) Xp22.2.
  • CMTX3 is caused by genomic rearrangement between Xq27.1 and 8q24.3. This means that the genes normally found at the X-chromosome segment “q27.1” and the genes normally found at the chromosome 8 segment “q24.3” have been swapped.
  • CMTX4 is caused by mutations in the AIFM1 gene.
  • CMTX5 is caused by mutations in the PRPS1 gene.
  • CMTX6 is caused by mutations in the PDK3 gene.

What are the symptoms of CMT Type X?

The symptoms of CMTX can be wide-ranging, the progression can be variable, and the overall severity can vary as well. Chromosomal males who have CMTX tend to have a more severe disease than chromosomal females, regardless of which CMTX subtype. This is believed to occur because chromosomal females have a second X-chromosome that chromosomal males do not have. This second X-chromosome is thought to work as a buffer of sorts that can lessen the overall disease severity. Chromosomal females can still have an overall severe disease though.

CMTX symptoms are much like the symptoms of other CMT subtypes, and can include, but are not limited to:

  • Progressive muscle weakness and atrophy (especially in the feet, lower legs, and hands)
  • Loss of sensation and numbness in affected areas
  • Structural foot deformities (high arches, hammer toes, etc.)
  • Drop foot (also called foot drop)
  • Achilles tendon contractures (shortening/tightening of the tendon)
  • Gait disturbances (due to foot deformities, ankle instability, foot drop, etc.)
  • Muscle cramping
  • Toe-walking
  • Respiratory Impairment

Symptoms of a more severe disease might include but are not limited to:

  • Central Nervous System Involvement (varying degrees of cognitive impairment, optic neuropathy)
  • Speech impairments (difficulty forming words)
  • Deafness

Although these symptoms can be present, there is no way to predict if they will, the degree to which they will, nor the progression of any symptom.

When do the symptoms of CMTX start?

Like the other CMT subtypes, CMTX symptom onset is quite wide-ranging from early childhood to one’s fifties or sixties. For some chromosomal females who have CMTX, their symptoms might be so dismissively mild that they go unnoticed until late in life. Most who have CMTX, however, will start to show symptoms by the time they are in their twenties.