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Ancient Mutation to Blame for Stuttering  

WASHINGTON, D.C.—The long list of hypotheses generated to explain why people stutter includes some whoppers. In the 1600s, for example, scientist and philosopher Francis Bacon proposed that stutterers have tongues that are too stiff and prescribed warm wine to make them more pliable.

“Even if it wasn’t effective, it’s a treatment I wouldn’t mind trying once in awhile,” joked Luc De Nil, a  psychologist at the University of Toronto in Canada who studies speech disorders. De Nil spoke here yesterday at a session on stuttering at the annual meeting of the American Association for the Advancement of Science (which publishes ScienceNOW).

Scientists now know that genetics play a role in stuttering. The speech disorder tends to run in families, and twin studies indicate that it is about 50% to 70% heritable. Dennis Drayna, a geneticist at the National Institute on Deafness and Other Communication Disorders in Rockville, Maryland, who participated in the session, described how he and his colleagues used 44 Pakistani families to pinpoint a handful of mutations responsible for the disease. Together, these mutations likely account for perhaps 5% to 10% of all stuttering cases worldwide, Drayna estimates.

“In Pakistan, 70% of all marriages are between either first or second cousins,” Drayna says. That makes for some complex relationships. In one of the families Drayna studied, two brothers and a sister married two sisters and a brother that are the offspring of their first cousin. All this intermarrying “results in a population structure with a greatly increased incidence of genetic disorders,” he says. This enabled the researchers to detect mutations in three genes—GNPTAB, GNPTG, and NAGPA—involved in the function of lysosomes, the cellular sacs where debris gets recycled. Together, the three genes help the lysosomes do their job. Drayna and his colleagues speculate that the brain contains a group of neurons that are unique to speech production and also “uniquely sensitive to this metabolic deficit.” 

Mutations can either arise independently or they can be passed on from an ancestor. To figure out what happened with one mutation found in the Pakistani families, Drayna and his colleagues analyzed one of the mutations in the GNPTAB gene in eight unrelated Pakistani people who carry it. Their analysis, published in January in the Journal of Human Genetics, suggests that the mutation was passed on from a common ancestor who lived about 14,000 years ago

The genes that Drayna and his colleagues fingered have already been well studied. Mutations in two of them cause a rare genetic disease called mucolipidosis. The most severe form of the disease is fatal, and even the milder form can cause mild retardation and skeletal problems.

Patients who have lysosome diseases like mucolipidosis can be treated with enzyme replacement therapy. But Drayna points out that enzymes wouldn’t work for stuttering. Stuttering problems are neurological, and enzymes are too large to cross the tightly woven blood-brain barrier. Still, researchers are now developing medications that can correct the misfolding of the mutant proteins that cause these diseases. These drugs are small molecules that can cross the blood-brain barrier. Although stutterers that carry these mutations show no signs of mucolipidosis or other lysosome diseases, Drayna speculates that those drugs could be a useful therapy. He and his colleagues have unpublished data that show that stutterers who carry the mutation do have abnormal proteins.

The researchers are recruiting more families in Pakistan to search for even more mutations, and Drayna says they are “hot on the trail” of a mutation on chromosome three. He and his colleagues are also attempting to make an animal model of stuttering by inserting the human mutation into mice. “Mouse vocalization is extremely rich and complex, but it’s poorly understood partly because most of it is too high—it’s ultrasonic,” says Drayna. So a mouse stutter might be difficult to detect. But the payoff could be enormous. “You can manipulate mice and their brains at great detail,” Drayna says. “We’re actually putting all of our human mutations into mice as we speak, and with any luck they will teach us more about the underlying neuropathology.” 

Jennifer McGuire, an art therapist who has struggled with stuttering since childhood, would welcome any new treatments. “Stuttering has colored my whole life,” she told journalists at a press briefing on Saturday. As a child, McGuire would sometimes order entrees that were easy to say even if they weren’t what she wanted. “It was exhausting,” she said. McGuire, who is pregnant, hopes that if she has a child who stutters, the work of Drayna and others will mean that he or she will have access to effective therapies.

Margaret Rogers, scientific director at the American Speech-Language-Hearing Association in Rockville, Maryland, says Drayna’s work is “very promising.” The research, says Rogers, may lead to blood tests that would allow therapists to identify which kids are likely to continue stuttering even after childhood. “Right now, there are really no good predictors to say, ‘Is my child going to continue to stutter or not?’ ” she says. Identifying mutations associated with persistent stuttering “may help us to more efficiently allocate therapeutic resources towards those kids.”

Follow our full coverage of AAAS 2011.