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First Gene Mutations Linked to Stuttering

Researchers have pinpointed the first genetic mutations responsible for stuttering. The find links the condition, which afflicts about 5% of children and 1% of adults, to metabolic disorders and could lead to new treatments.

Researchers first uncovered genetic clues to stuttering in 2005. A team led by Dennis Drayna, a molecular geneticist at the National Institute on Deafness and Other Communication Disorders in Bethesda, Maryland, traced the condition to a region of chromosome 12 by comparing the DNA of 46 related Pakistani families with members who stuttered. The pattern of inheritance indicated that a gene somewhere on the chromosome was responsible. "But that's all we knew," Drayna says.

So, in the new study, Drayna and his team focused their search for the gene. They combed through more than 10 million letters of DNA and eventually homed in on a mutation--but it seemed an unlikely suspect. The mutation was in a gene called GNPTAB, which helps tiny structures in the cell known as lysosomes break up nutrients and recycle cellular components. People with lysosomal defects suffer from metabolic disorders, such as Tay-Sachs disease, which wreaks havoc on physical and neurological development and proves fatal within years. "Over the years, many people have suggested many different causes for stuttering," Drayna says. "and inherited metabolic disorder wasn't on anyone's list."

Once the researchers had convinced themselves that GNPTAB really was a prime suspect in stuttering, they began to focus on two other genes, GNPTG and NAGPA, which also play a role in lysosome function. The group then hunted for mutations in these three genes in the 46 affected Pakistani families, plus 77 other Pakistanis who stuttered and 270 unrelated stuttering subjects from the United States and England. They also looked at a large control group of nonstutterers from both Pakistan and North America. The researchers found mutations--four in GNPTAB, three in GNPTG, and three in NAGPA--in 6% of people who stuttered but in less than 0.5% of control subjects, they report today in The New England Journal of Medicine.

Interestingly, mutations in GNPTAB and GNPTG can cause two types of an extremely rare, serious metabolic disease called mucolipidosis. Children with mucolipidosis don't usually live past the age of 10. These children also rarely speak, a behavior thought to be secondary to the disease's devastating primary effects. But Drayna thinks that the failure to speak in these cases might be a direct result of the mangled metabolic cycle. If crucial speech areas of the brain require extremely high-functioning metabolic systems, he speculates, even minor protein mistakes, such as those caused by the genetic mutations in this study, might result in stuttering.

Drayna says he hopes the findings will earn stuttering more respect as a true biological disorder. Experts think it will. "This builds upon the belief that has been growing over the last 10 years that stuttering is not a behavioral disorder, but a genetic disorder with manifestation in the brain," says Gerald Maguire, a psychiatrist and expert in stuttering at the University of California, Irvine. And that could lead to new types of drugs to tackle the condition, says Anne Foundas, a cognitive and behavioral neurologist at Louisiana Statue University School of Medicine in New Orleans. "The implications are great for potential treatment."