What Is CMTX3?
CMTX3 is a type of CMT caused by an insertion, a form of chromosome rearrangement in which a segment of genetic material ends up somewhere it does not belong. In CMTX3, a 78 kb segment normally found on chromosome 8 (8q24.3) has been inserted into the X chromosome (at Xq27.1). The material moved in one direction only, with nothing exchanged in return, which is what separates an insertion from a reciprocal translocation.
CMTX3 is X-linked recessive. This means the change responsible sits on the X chromosome, and in people with two X chromosomes (chromosomal females), both copies must carry it to cause CMTX3. For individuals with one X and one Y chromosome (chromosomal males), a single affected copy is sufficient. CMTX3 differs from most X-linked forms of CMT. Its cause is not a mutation inside a gene. The segment from chromosome 8 was inserted into a stretch of the X chromosome that lies between genes.
Reading the Notation
Every other CMT subtype with a known cause is related to a mutation in a single gene. The gene is identified by its HUGO Gene Nomenclature Committee (HGNC) gene symbol. But CMTX3 is the exception. HGNC assigns symbols to genes, not chromosomal rearrangements. So, CMTX3 uses the International System for Human Cytogenomic Nomenclature (ISCN) notation instead. The ISCN standard covers changes at the chromosome level rather than at the gene level.
CMTX3’s notation is:
ins(X;8)(q27.1;q24.3)
Read it left to right. ins gives the type of change, an insertion. (X;8) names the chromosomes involved, the one receiving the material first, and the one donating it second. (q27.1;q24.3) gives the band on each, in that same order. Together, they say that genetic material from band q24.3 of chromosome 8 has been inserted into band q27.1 of the X chromosome.
The notation as published is longer: der(X)dir ins(X;8)(q27.1;q24.3). The der(X) means that the X chromosome is the altered one, and dir means that the inserted segment kept its original orientation rather than being flipped end to end.
Because ISCN names the receiving chromosome first, the notation opens with X while a plain-language description of the same event opens with chromosome 8. Both describe the same insertion.
Clinical Features
CMTX3 symptoms begin by the early teens. They typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show slowed conduction velocities, consistent with a demyelinating form of CMT.
CMTX3 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
- Additional symptoms not listed here
Disease Course
CMTX3 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Onset is by the early teens, but disease progression is generally slow, and life expectancy is not reduced.
