Charcot-Marie-Tooth Disease Type X (CMTX)

Charcot-Marie-Tooth disease type X (CMTX) is a subtype of CMT with genetic defects on the X chromosome, which affects the myelin sheath surrounding the nerve fibers of the peripheral nerve cells that connect the brain and spinal cord to muscles and sensory organs.

CMTX is the second most common type of CMT, affecting about 10-16 percent of all cases.


The symptoms of CMTX are similar to those of CMT1 and CMT2 and include muscle weakness and atrophy and decreased sensation (touch, pain, or heat), mostly in the feet, lower legs, hands, and forearms.

Symptoms generally appear in childhood or adolescence and progress slowly. Some patients may experience hearing loss. Due to its X-linked inheritance pattern, CMTX affects males more severely than females.


CMTX is caused by mutations in the GJB1 gene located on the X-chromosome, which encodes for a protein called connexin-32 (also known as gap junction beta 1). This protein forms channels or gap junctions between cells, thereby promoting cell-to-cell communication by allowing the transport of molecules between the cells.

In the nervous system, connexin-32 is located in the membrane of specialized cells called Schwann cells. These cells are found in the peripheral nervous system and are involved in the production and maintenance of the myelin sheath, the protective covering around the nerve cells that aids nerve signal transmission. The connexin-32 protein forms channels through the myelin sheath, allowing efficient transport and communication between the outer myelin layers and the interior of the Schwann cell.

About 300 different mutations in the GJB1 gene have been found to cause CMTX. Most of these mutations result in a change in a single amino acid (building blocks of a protein) in the connexin-32 protein. Some mutations result in the production of a abnormally-sized protein.

It is unclear how the mutations in the GJB1 gene lead to the characteristic symptoms of CMT, such as the loss of myelin and the slowed transmission of nerve impulses. Researchers have suggested that the altered protein may be degraded quickly or trapped inside the cell, preventing it from reaching the cell membrane to form gap junctions.

In some cases, an altered protein reaches the cell membrane but does not form properly functioning gap junctions. The loss of functional gap junctions probably impairs the normal activity of Schwann cells, such as myelin production. Malfunctioning gap junctions could also disrupt the communication between Schwann cells and the underlying nerve cell, disrupting the transmission of nerve impulses.

There have been only a few reports of CMT patients with mutations in the GJB1 gene who experienced loss of myelin in the brain and spinal cord. Brain and spinal cord abnormalities did not generally cause any symptoms but were identified by electrical testing of nerve impulses or imaging studies. Research suggests that the mutated connexin-32 protein is likely compensated in the brain and spinal cord by another connexin protein whose function overlaps with that of connexin-32.


CMTX is inherited in an X-linked manner. Individuals with two X chromosomes are female while individuals with one X and one Y chromosome are male. A female with a defective gene on one of the X chromosomes has a 50 percent chance of passing the disease on 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 which can compensate for the faulty gene, 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 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.


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