Charcot-Marie-Tooth disease (CMT) is a genetic disease caused by defects (or mutations) in genes that affect the function of peripheral nerves — the nerves that control motor (movement) and sensory (taste, smell, or touch) functions.
The defective genes may cause degeneration of either the nerve fibers (axons) or the surrounding myelin sheath, a thin layer that insulates the nerves fibers. Thus, peripheral nerves slowly lose the ability to transmit nerve signals from the brain to the extremities, and vice versa.
The degeneration of peripheral motor nerves results in muscle atrophy and weakness in the extremities, including arms, legs, hands, or feet. In some cases, peripheral sensory nerves are affected resulting in reduced sensation, such as the ability to feel heat, cold, or pain.
CMT disease is genetic
An individual’s DNA contains coding sequences called genes, which provide the information necessary to make proteins in different parts of the body, including the nerve cells. Each gene exists as a pair, with one copy inherited from each parent.
CMT develops due to the presence of a defective, or mutated, gene that is either inherited from one or both parents or occurs as a spontaneous mutation, making the child the first in the family to have the disease.
How CMT is inherited
The faulty genes causing CMT can be inherited in three ways: autosomal recessive inheritance, autosomal dominant inheritance, and X-linked inheritance. Autosomal refers to chromosomes other than the X and Y sex chromosomes.
Autosomal dominant inheritance
Most common types of CMT are inherited in an autosomal dominant manner. In this case, a defect (mutation) in one of the two copies of a gene is enough for CMT to develop. Thus, autosomal dominant CMT develops if an individual inherits the defective gene from just one parent. Since the defective copy of the gene dominates the effect of the normal copy, the parent carrying the faulty gene also has the condition. In autosomal dominant inheritance, there is a 50% chance that an affected person will pass the faulty gene onto his or her children.
CMT type 1, the most common type of CMT that causes the breakdown of the myelin sheath, is inherited in an autosomal dominant manner.
Autosomal recessive inheritance
The less common types of CMT are inherited in an autosomal recessive manner.
In this case, both copies of the gene must be defective to cause the disease. Therefore, autosomal recessive CMT develops if an individual inherits one defective copy of the gene from each parent. The parents are said to be carriers — each carries one defective copy of the gene, but its effect is compensated or masked by the other normal copy, so they do not exhibit CMT symptoms themselves. When both parents are carriers, there is a 25% chance of the child developing the condition.
CMT type 4, a rare and severe type of CMT that affects the myelin sheath, is inherited in an autosomal recessive manner.
Some forms of CMT are inherited in an X-linked fashion, which means that the abnormal gene is located on the X chromosome that determines the sex of an individual.
Individuals with two X chromosomes are females while individuals with one X and one Y chromosome are males. A female with a defective gene on one of the X chromosomes has a 50% chance of passing on 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, while sons are more severely affected because they only have a single X chromosome.
Since males have one X and one Y chromosome, the defective gene carried on the X chromosome is inherited by all of the daughters of an affected man, while none of his sons inherit the X chromosome with the defective gene. So, the disease cannot be passed from father to son.
CMT type X, which affects the nerve axons, is inherited in an X-linked manner.
In rare cases, CMT is caused by gene mutations that occur spontaneously in an individual’s own DNA. In such a case, neither parent is a carrier of the faulty gene, but the child still develops the disease.
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