Published online 10 February 2010 | Nature | doi:10.1038/news.2010.61

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Mutations found in genes responsible for directing enzymes to their cellular destination.

Stuttering may be caused by mutations that affect speech neurons. Sebastian Kaulitzki/iStockphoto

Often dismissed as a psychological problem, stuttering may be the result of genetic mutations implicated in daily metabolic processes, a new study shows.

Stuttering — a common speech disorder characterized by repetition, prolongation of sounds, and interruptions in the flow of speech — affects about 60 million people worldwide. Studies on twins and adopted individuals show that it is highly heritable, and the new work suggests that 10 different mutations on three genes coding for enzymes could be to blame.

"As a disorder it gets no respect," says senior investigator Dennis Drayna, a geneticist at the National Institute on Deafness and Other Communication Disorders in Bethesda, Maryland. "I think our results go a long way towards convincing sceptics that stuttering is indeed a biological problem."

The study, published today in The New England Journal of Medicine1, builds on work from 20052 in which Drayna identified chromosome 12 as a region of interest. In the new study, which looked at around 400 stutterers, he and his colleagues identified specific mutations on the long arm of chromosome 12 that occurred in stutterers — but almost never in non-stuttering control patients.

Not everyone who stutters, the team says, can trace the disorder back to the three genes; it would involve only an estimated 9%. "Our mutations account for, optimistically, only a modest fraction," says Drayna, "but that's still a lot of people."

Many experts agree that the work is an important step towards understanding the genetic contribution in a little-understood disorder. "The closer we come to identifying specific gene sequences, and what they code for, the better we understand why stuttering has been a mystery for so long," says Nan Ratner, a speech expert at the University of Maryland in College Park.

Recycling problems

The three genes identified with stuttering — known as GNPTAB, GNPTG and NAGPA — share a common role in the body: the enzymes they encode help to direct other enzymes that act in cellular organelles called lysosomes, which continuously break down and recycle cell parts and send them off to be reused. Any of the 10 mutations identified by Drayna's team can interfere with this process, sending the targeted enzymes to a different location and causing the lysosome to accumulate cell parts that aren't degraded properly.

Researchers don't understand why these particular mutations in lysosomal processes would lead to stuttering, but Drayna suspects that there are specific neurons for speech in the brain that are uniquely susceptible to this abnormality. "Who'd have ever thought that we'd be doing the enzymology of speech?" he asks.

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He and his colleagues next plan to use mice as a model for the human communication disorder, by mutating the genes in question. But first they will have to figure out how disruptions to mouse songs, distress calls and courtship and aggression vocalizations sound. "We have no idea what stuttering in mice sounds like," Drayna says. "But the fact that you can do biochemistry on speech is quite a surprise."

The work suggests that enzyme replacement therapy might even one day be used to treat stuttering. Manufactured enzymes could be injected into the person's bloodstream, from which cells could take them up and replace the faulty enzymes.

Drayna says he hopes his work will not only "medicalize" stuttering — bringing it into clinical biomedicine — but legitimize it as well. "Many people with this disorder say it has ruined their lives," he says. Although most young children who stutter lose the speech impediment as they get older, for others the disorder continues into adulthood.