Charcot-Marie-Tooth (CMT) disease is a group of genetic disorders that cause defects in the myelin sheaths (the insulating material that prevents the loss of electrical signals as they travel along nerve fibers), or the axons themselves (the nerve cell extension), in the peripheral nervous system.
These defects impair the ability of nerve cells to transmit movement impulses to muscles and sensory information to the brain. All types of CMT are inherited from the parents of the affected individual, and can be passed on to their children.
CMT type 1
CMT type 1 is caused by mutations in genes encoding for myelin proteins and is inherited in an autosomal dominant manner, meaning that if one parent is affected and the other is not, then their children have a one-in-two chance of also being affected by CMT type 1.
CMT type 2
CMT type 2 is less common than CMT1 and affects the mitochondria in the axons of the nerve cells, disrupting their function. Mitochondria are the energy factories of the cells. CMT type 2 is inherited in an autosomal dominant pattern as well, but, depending on the mutation, it can also be inherited in an autosomal recessive manner. In such cases, only an individual with two defective copies of the gene will have the disease. So, for a child to inherit an autosomal recessive type of CMT type 2, both parents must either be affected by the disease or be carriers of a single defective copy of the gene.
CMT type 4
CMT type 4 involves many different genes, but its main distinguishing feature is that it is always inherited in an autosomal recessive manner: a single copy of the normally functioning gene can prevent disease symptoms from manifesting. An individual will develop CMT type 4 only if he or she inherits a mutated gene of the same type from both parents.
If they only have a single copy of the mutated gene, they are said to be “carriers” of the disease and can pass it on to their children without being affected themselves.
An affected parent and a carrier parent have a an equal one-in-two chance of either passing the disease onto their children or of having children who are also carriers.
Two carrier parents have an equal one-in-four chance of having a child with the disease or of having a child who is not affected by the disease or who is not a carrier. They have a one-in-two chance of having children who are non-symptomatic carriers.
If one parent does not have or carry the disease, their children will not develop CMT type 4.
CMT type X
CMT type X affects the function of the myelin sheath and is an X-linked condition, meaning that the gene responsible for the disease is situated on the X chromosome. That means the condition affects males and females differently.
CMT type X behaves like a recessive trait in females because they have two X chromosomes. If they only have one copy of the mutated gene, then they may have mild symptoms or none at all.
Because males have only one X chromosome, if they inherit the mutation causing CMT type X, they develop the disease.
Because it is X-linked, CMT type X is inherited in a specific way: a father with the disease cannot have affected sons because he passes his Y chromosome to them. However, he can have daughters who are carriers or affected.
A mother with full symptoms of the disease will have affected sons and carrier daughters, but her daughters will only have the disease if their father also has the disease.
De novo mutations
In some cases of CMT, the mutation is not inherited from the individual’s parents, but originates in their own genes. In these cases, how their CMT will be inherited will not be clear until they have children.
Because the different types of CMT are caused by mutations in different genes, they can occur at the same time in the same person. In some rare cases, this double dose of genetic pathology will lead to higher-severity symptoms. The multiple mutant genes involved will make the odds of that individual’s children inheriting a form of CMT very complicated.
In all cases, genetic testing is recommended to confirm the type of CMT a person has and determine how the disease may be passed onto their children.
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