Charcot-Marie-Tooth disease (CMT)

Charcot-Marie-Tooth (CMT) disease is a group of progressive disorders that affect the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Symptoms of Charcot-Marie-Tooth disease usually begin in adolescence or early adulthood, but onset may occur anytime from early childhood to late-adulthood. Typically, the earliest symptoms involve muscle weakness in the feet, which can cause foot abnormalities such as high arches (pes cavus) or curled toes (hammer toes). It may become difficult to hold up the foot or to walk on the heel of the foot. These difficulties may cause a higher than normal step (or gait) and can increase the chance of ankle injuries and tripping.

As the disease progresses, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair. Affected individuals may also develop muscle weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. Because signals to sensory cells can be disrupted in Charcot-Marie-Tooth disease, people with this disorder may feel aching or burning sensations in the feet and lower legs, or experience a decreased sensitivity to touch, heat, and cold. In rare cases, sensory loss can include gradual hearing impairment, deafness, and even loss of vision.

Charcot-Marie-Tooth disease is mainly divided in CMT type 1 characterized by abnormalities in myelin, the protective substance that covers nerve cells, and CMT type 2 which shows abnormalities in the fiber, or axon, that extends from a nerve cell and transmits nerve impulses. Type 4 Charcot-Marie-Tooth disease affects either the axon or myelin. In intermediate forms of Charcot-Marie-Tooth disease, abnormalities can occur in both axons and myelin. Type X Charcot-Marie-Tooth disease is caused by mutations in a gene on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as 1A, 2A, 4A, and X1) are distinguished by the specific gene that is altered. Charcot-Marie-Tooth disease is the most common inherited disorder in Neurology, affecting an estimated 150,000 people in the United States. It occurs in all races and ethnic groups. Worldwide, this disorder affects about 1 in 2,500 individuals.

Faculties at the Hussman Institute for Human Genomics (HIHG) have made significant discoveries in CMT, beginning with the identification of chromosomal locations that harbor CMT genes by Dr. Vance in the1990ies to the identification of a number of underlying genes by Drs. Vance and Zuchner. The discovery of the GDAP1 gene provided the most common recessive CMT gene. In 2004, Drs. Vance and Zuchner published the identification of the mitofusin 2 gene, which causes up to 30% CMT type 2. Finally, the dynamin 2 gene was the first CMT gene identified for the so-called intermediate CMT forms.

Currently, Dr. S. Zuchner directs several projects that develop cell culture models for axonal CMT and a mouse model for mitofusin 2. These projects aim at a deeper understanding of the pathology in CMT and hopefully open opportunities for future treatment options. We also continue to include patients into our studies and we use the latest genomic technology available to identify the remaining CMT genes. This research is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the Charcot-Marie-Tooth Association of North America (CMTA).

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