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Genetic testing for Charcot-Marie-Tooth disease

Genetic testing for Charcot-Marie-Tooth disease
Genetic testing for Charcot-Marie-Tooth disease


Duke Health News Duke Health News

DURHAM, N.C. – Duke University Medical Center researchers have identified mutations in a protein they believe is directly related to an inherited form of Charcot-Marie-Tooth (CMT) disease.

The disorder is a peripheral-nerve disease that causes weakness and muscle atrophy in the hands and lower legs, with deformities and some loss of sensation. CMT is the most commonly inherited disorder of the peripheral nervous system, and one of the most common inherited disorders in man. About one in 2,200 to 2,500 people have a form of CMT.

The researchers cautioned that they still do not understand how defects in the mutated gene, called ganglioside-induced differentiation-associated protein-1 (GDAP1), lead to a form of CMT known as CMT type 4A, which is a demyelinating form of the disease destroying the covering around the nerve. They hope that the discoveries will eventually aid in the genetic testing and counseling of potential carriers of the disease.

The researchers studied four Tunisian families with CMT4A and found three different mutations in GDAP1. CMT4A is clinically similar to CMT1, the most common form of CMT known today in the United States, but it is generally more severe and has an earlier average age at onset, said Dr. Jeffery M. Vance, co-director of the Duke Center for Human Genetics and senior author of the article that appears in the Dec. 16 online issue of Nature Genetics. The study was funded by the National Institutes of Health.

"The finding of three different mutations in these four geographically and ethnically close Tunisian families was an unexpected finding. These findings are scientifically important because previously it was thought that these two types of peripheral neuropathies, demyelinating and axonal neuropathies, were distinct diseases," Vance said.

Using an analogy, the peripheral nerve is like an electrical wire, he said. Myelin acts as the outside insulation of the wire or nerve, while the actual metal wire inside is similar to the axon.

Vance's research team had previously localized and narrowed CMT4A to a small region on chromosome 8.

The age at onset for CMT4A is generally 12 months, Vance said. The disease is marked by severe symmetric weakness and atrophy of the foot, followed later by involvement of the distal upper extremities (claw-hands). Some patients become wheelchair-dependent and/or develop spine abnormalities, he said.

CMT differs from muscular dystrophy in that people who have CMT are born with normal muscles. The muscles atrophy because the CMT-impaired nerves that serve them cannot properly send the message from the brain to activate them.

In a second study in the same issue of Nature Genetics, Francesc Palau and colleagues from Laboratori de Genètica i Medicina Molecular Institut de Biomedicina, València, Spain, studied individuals with a loss of axonal nerve fibers in their extremities (an axonal neuropathy). The researchers also found that all of the affected individuals had mutations in the GDAP1 gene.

"These studies demonstrate that the same gene is contributing to the function of both types of cells. Current divisions of diseases of the peripheral nerve are based on the assumption that these two parts of the peripheral nerve are separate functioning entities. Palau and colleagues speculate that the GDAP1 protein might influence the interaction between the nerve cell (axon) and its surrounding insulating sheath (mylein)," Vance said.

For more information about CMT, please visit the Muscular Dystrophy Association's Web site at; or the Web site of the Charcot-Marie-Tooth Association at

The study's co-authors include: Rachel V. Baxter, Kamel Ben Othmane, Julie M. Rochelle, Jason E. Stajich, Christine Hulette, Susan Dew-Knight, Judy E. Stenger, John R. Gilbert and Margaret A. Pericak-Vance, all of the Duke Center for Human Genetics. Other co-authors include: Faycal Hentati, Mongi Ben Hamida and S. Bel of the Institut National de Neurologie in Tunis, Tunisia.

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