Charcot-Marie-Tooth disease (CMT) is a genetic disease caused by defects (or mutations) in genes that affect the function of the peripheral nerves — the nerves that control movement and sensation in the limbs.
Mutations in these genes degenerate either the nerve fibers (axons) or their surrounding myelin sheath, a thin layer that insulates the nerves fibers. As such, peripheral nerves slowly lose the ability to transmit nerve signals from the brain to the extremities, and vice versa.
Damage to peripheral motor nerves results in symptoms that include muscle wasting and weakness in the arms, legs, hands, or feet. Nerve dysfunction may also result in reduced sensation, such as the ability to feel touch and sense temperature.
More than 40 genes are known to be involved in CMT, with each gene linked to one or more disease subtypes. A single type of CMT can also be caused by mutations in multiple genes. The most common CMT subtype, CMT type 1A, is caused by a duplication of the PMP22 gene.
Mutations causing CMT are inherited either from one or both parents, or they can occur spontaneously during conception, making the child the first in the family to have the disease.
Depending on the disease type, CMT can be inherited in autosomal dominant, autosomal recessive, or X-linked pattern. Autosomal refers to the 22 pairs of chromosomes other than the X and Y sex pair of chromosomes, and autosomal inheritance affects males and females equally.
Autosomal dominant inheritance
In this type of inheritance, the mutation in one of the two copies of a gene is enough for CMT to develop. This means that autosomal dominant CMT develops if an individual inherits the defective gene copy from one parent. Since the defective copy dominates the effect of the normal copy, the parent carrying the faulty gene also has this disorder. In autosomal dominant inheritance, there is a 50% chance of a biological parent passing the faulty gene to a child.
Autosomal recessive inheritance
In this type of inheritance, both copies of the gene must be defective to cause the disease. CMT develops if an individual inherits one defective copy of the gene from each parent. The parents are said to be carriers — the mother and father each carry one mutated copy of the gene — but the mutation’s effect is masked by the other normal copy, so they have no evident CMT symptoms themselves. When both parents are carriers, there is a 25% chance of the child developing CMT.
This form of inheritance is found CMT type 4, a rare form in the U.S.
Some forms of CMT are inherited in an X-linked fashion, which means that the mutated gene is located on the X chromosome.
A woman with a defective gene on one of her two X chromosomes has a 50% chance of passing the disease to her children. If that faulty gene is inherited, daughters usually tend to be affected less severely, because they have another X chromosome (inherited from the father) that can compensate. Sons are more severely affected, because they only have a single X chromosome.
Since males have one X and one Y chromosome, a father cannot pass the defective gene in the X chromosome to a son, but he can to a daughter.
X-linked inheritance is present in CMTX, which account for about 10% to 15% of all CMT cases.
In rare cases, CMT is caused by de novo mutations, or mutations that occur spontaneously. In such instances, neither parent is a carrier of the faulty gene, but the child still develops the disease.
People who have a de novo mutation can pass the disorder to their own children.
Because the different types of CMT are caused by mutations in different genes, mutations affecting more than one gene can occur at the same time in the same person. In these rare cases, this double dose of genetic changes will lead to severe symptoms.
Genetic testing is recommended in all cases to confirm the type of CMT, and for family planning by determining how the disease may be passed to future children.
Last updated: Sept. 30, 2021
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