Charcot-Marie-Tooth Disease Type X (CMTX)

Charcot-Marie-Tooth disease type X (CMTX) is a type of CMT, which comprises a group of inherited disorders of the peripheral nervous system. CMT causes damage to the network of nerves supplying movement and sensation to the arms and legs. People with CMTX carry genetic defects on their X chromosome.


The symptoms of CMTX are similar to those of CMT1 and CMT2. These include muscle weakness and decreased sensation (touch, pain, or heat) mostly in the lower legs, hands, and forearms. Complications typically begin in early adulthood and worsen over time.

Patients often experience foot abnormalities such as pes cavus (high arches), pes planus (flat feet), or curled toes (hammer toes). These symptoms may cause difficulties in walking and increase the risk of ankle damage.

Weakness in the hands may make writing and fastening buttons challenging. Although rare, patients may experience loss of vision or progressive hearing loss.

CMTX may also affect the central nervous system (brain and spinal cord), leading to mild but chronic abnormalities, such as difficulties with clear speech and an imbalanced gait, or a more severe and sudden form associated with breathing problems and altered consciousness. These sudden complications can last weeks and can be associated with fever, head trauma, minor infections, or acclimatization after being at a high altitude.

Causes and subtypes

Six different subtypes of CMTX, each believed associated with a different mutated gene, have been described.

CMTX1 is caused by mutations in the GJB1 gene located on the X chromosome, which codes for a protein called connexin-32 (also known as gap junction beta 1). CMTX1 is the second most common type of CMT, affecting about 10%–16% of all cases.

Connexin-32 forms channels or gap junctions between Schwann cells, thereby promoting cell-to-cell communication. These specialized cells form myelin — a sheath surrounding peripheral nerves, which supply movement and sensation to the arms and legs and enable efficient signal transmission.

More than 400 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.

Although it is unclear how mutations in the GJB1 gene lead to the characteristic symptoms of CMTX1, researchers have suggested that the altered protein may be degraded quickly or trapped inside the cell and therefore can’t reach the cell membrane and form gap junctions. Loss of functional gap junctions impairs the activity of Schwann cells and the production of myelin.

Besides changes in the peripheral nervous system, GJB1 gene mutations have been associated with loss of myelin in the brain and spinal cord.

In CMTX2 and CMTX3, no specific genes have been identified as causing the disease. CMTX4 is caused by mutations in the AIF gene, which codes for a protein found in mitochondria (the cellular structures responsible for producing energy). CMTX5 is caused by mutations in the PRPS1 gene, and CMTX6 results from mutations in the PDK3 gene.


CMTX is inherited in an X-linked manner. Females have two X chromosomes, one inherited from the mother and the other from the father, whereas males have one X chromosome inherited from the mother and one Y chromosome inherited from the father.

A female with a defective gene on one of the X chromosomes has a 50% chance of passing the disease on to her children. A man who has a CMTX-causing gene will not pass on the gene to any sons, but will pass it to all his daughters.

As they have two X chromosomes, females who inherit a faulty gene tend to be affected less severely than males, who do not have another unaffected copy of the gene.

CMTX can also be caused by a spontaneous mutations in the X chromosome, in which case the patient is the first in the family to have the mutation and can pass it down to his or her offspring.


 Last updated: Nov. 22, 2021


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