Charcot-Marie-Tooth disease (CMT) is divided into many different types based on how the disease is inherited and the part of the body affected by the disease. While the different subtypes of CMT share similar symptoms and prognoses, understanding the differences between these types is critical for developing and administering treatments.
CMTX is a form of CMT that is principally inherited in an X-linked pattern.
X-linked inheritance occurs when the affected gene is located on the X chromosome, one of our sex-determining chromosomes. Males usually have one X chromosome and one Y chromosome, while females usually have two X chromosomes and no Y chromosomes. Because of this, male children usually receive their only X chromosome from their biological mother, and female children usually receive one X chromosome from their biological mother and one X chromosome from their biological father. Therefore, a man who has the disease-causing gene usually will not pass the gene on to any sons. However, he usually will pass the gene on to all his daughters. In contrast, a woman who has the disease-causing gene has approximately a 50% chance of passing it on to each of her children, regardless of their biological sex. This pattern is called X-linked inheritance.
When the mutation in the affected gene can cause disease, such as in CMTX, the X-linked inheritance pattern also has implications for disease severity. Because females have two X chromosomes, if they have inherited one X chromosome with the affected gene, their other X chromosome typically has a copy of the gene that is not affected by the mutation. In contrast, because males have a single X chromosome, they usually do not have another unaffected copy of the gene. Because of this, males with CMTX tend to have symptoms that are more severe and noticeable at an earlier age, while females tend to have milder symptoms or even no symptoms.
Although CMTX is defined by its inheritance pattern, it is also possible for spontaneous mutations to occur in the X chromosome, meaning that neither parent had the mutation in their X chromosome. In these cases, the spontaneous mutation can still cause disease symptoms, and the affected gene has the potential to be passed on to the affected individual’s children, in an X-linked pattern.
Symptoms of CMTX
Individuals with CMTX have the same classic symptoms found in individuals with CMT1 or CMT2. There is progressive deterioration of the muscles in the feet and hands, typically beginning in early adulthood and worsening over time. Along with weakening of the muscles in the extremities, there is typically also a loss of sensation in the affected areas that may result in numbness. While CMT primarily affects the peripheral nervous system (the body’s nerves), CMTX may also affect the central nervous system (brain and spinal cord). Central nervous system involvement generally comes in two different forms. One form is mild chronic abnormalities, such as difficulty forming clear speech, an imbalanced gait and stiffness. The other form is a stroke-like central nervous system issue that is both sudden and transient. It produces more severe forms of the abnormalities just described in addition to occasional breathing problems and altered consciousness. These sudden symptoms can persist for just a few hours, or up to a few weeks. In some cases, these stroke-like events appear unprovoked, and in others their onset is associated with hyperventilation, exertion, acclimatization after being at a high altitude, fever, head trauma or minor infections.
Causes of CMTX
There are six different genetic subtypes or different genetic causes of CMTX. By far, the most common genetic subtype of CMTX is CMTX1 which accounts for 90% of all CMTX cases and is caused by mutations in the gene GJB1 (which is the more common name for the gene Cx32). For CMTX2 and CMTX3, while the location of the mutation on the X chromosome is known, there is not an identified gene in the affected location (only a small percentage of the DNA code is made up of genes, which code for proteins). CMTX4 is caused by mutations of the AIF gene, also known as the AIFM1 gene. CMTX5 is caused by mutations of the PRPS1 gene, and CMTX6 is caused by mutations of the PDK3 gene.
Treatments for CMTX
While no treatments or cures currently exist for CMT, the science to change that does. The CMT Research Foundation is currently funding cutting-edge research solely focused on drug development.