MEDICINE CHARCOT-MARIE-TOOTH DISEASE : Genetic Defect Identified as Cause of Nerve Ailment

Texas and Belgian researchers have identified a novel genetic defect as the cause of a little-known, inherited disease of the peripheral nerves.

Based on their discovery, the scientists have devised a simple blood test that for the first time makes possible a simple, painless diagnosis of the disorder, called Charcot-Marie-Tooth disease, or CMT. Named for the 19th-Century British and French scientists who discovered it, CMT affects at least 125,000 Americans, who suffer foot and hand deformities and loss of sensation resulting from the wasting of muscles.

This is the first time that such a defect has been linked to a relatively common inherited disorder, and the defect itself may have implications for other neuromuscular diseases as well. “This is another step toward discovery of the causes of all these disorders, which will open the doors to treatments and cures,” said Robert Ross, executive director of the Muscular Dystrophy Assn., which has been sponsoring the research.

James R. Lupski of the Baylor College of Medicine in Houston and his colleagues report today in the journal Cell that the newly discovered genetic defect is a duplication of a small segment of chromosome 17, one of the 23 pairs of chromosomes that contain the blueprint for making a human being. A second team headed by molecular biologist Christine Van Broeckhoven of the University of Antwerp has identified the same genetic defect. Their results will be published next month in the journal Neuromuscular Disorders.

“It’s a real breakthrough for us as well as for others with genetic diseases,” added Linda Crabtree, executive director of CMT International in St. Catharines, Canada. Even though no therapy is now available for the disorder, she added, early detection will allow victims to redirect their lives toward occupations that do not require a lot of manual dexterity.

Some experts believe the incidence of CMT is underreported because many physicians are unfamiliar with it. The wasting of muscles in the arms and legs--which typically begins around age 12--can lead to crippling deformities, although these can sometimes be corrected by surgery or the wearing of braces. The disease also exhausts its victims, making it difficult to carry out everyday activities.

The disease, which is not life-threatening, exists in at least three distinct genetic forms, although the form studied by Lupski accounts for the overwhelming majority of cases, he said. CMT is currently diagnosed either by a surgical biopsy of nerve tissues or by a technique in which an electrical voltage is applied to the nerves and the speed of transmission is measured. That transmission is slower in CMT victims.

Either diagnostic technique can be “quite uncomfortable,” according to Lupski. He should know because he developed CMT as a child and had to undergo 11 operations as a teen-ager to retain his mobility. Ironically, he is one of the small minority of CMT victims who do not have the genetic defect he discovered.

The researchers do not yet know the precise biological cause of CMT but suspect that the duplication of the chromosome segment produces either too much or too little of a certain protein or somehow renders the protein defective.

Meanwhile, Lupski said, researchers should look for such duplications in other genetic diseases. In particular, because of the arcane techniques used to link genetic defects to specific chromosomes, the presence of the duplicated segment can make it appear to researchers that the defective gene is on a different chromosome than where it is actually located.

“That may be happening with other diseases where they can’t find the gene,” he said. That may be one reason why researchers have had a particularly difficult time identifying genes associated with such neurological disorders as schizophrenia and Alzheimer’s disease.