A long-assumed hereditary link to stuttering is coming into focus with the discovery of genetic mutations that crop up in some people with the speech problem but rarely in others. After testing hundreds of people who stutter, researchers have nailed down defects in three genes that may account for a fraction of cases, researchers report online February 10 in the New England Journal of Medicine.
The World Health Organization defines stuttering, or stammering, as a disorder of speech rhythm in which a person knows what he or she wants to say but involuntary repeats, prolongs or stops saying words. Scientists don’t fully understand why most children who stutter overcome it, why stuttering persists into adulthood in others and, above all, what causes the condition.
Earlier genetic work with an extended Pakistani family that included many stutterers led researchers to suspect that mutations occurred on chromosome 12. In the new study, scientists examined genes on a specific strand of that chromosome using DNA obtained from 123 stutterers in Pakistan and 270 in United States and Britain.
The researchers also tested the genes of 96 people in Pakistan and 276 in the United States and Britain who didn’t stutter as a control group. The study participants did not include anyone under 8 years old.
In 21 of the stutterers, the researchers found that one of three genes on chromosome 12 was mutated, a rate of about 5 percent. One of these mutations also showed up in one of the Pakistani nonstuttering controls. None occurred in any of the Western controls.
The three genes carrying the mutations are called GNPTAB, GNPTG and NAGPA. All encode enzymes that play a role in the proper function of lysosomes, compartments in cells that serve as recycling centers for materials a cell has cleaned up from adjacent areas. These extraneous materials are pulled into lysosomes, where they are chopped up and digested.
If the recycling process in lysosomes goes awry on a large scale, the result can be a fatal cascade of cell death, tissue damage and organ failure, says study coauthor Dennis Drayna, a geneticist at the National Institute on Deafness and other Communication Disorders in Rockville, Md.
But people who stutter typically have no such dire disease, as was the case in these study participants who stuttered and tested positive for one of the three mutations.
What’s more, most of the 21 people with a mutation carried the defect in only one copy of an affected gene, meaning they got the mutation from only one parent.
The mutations cause alterations in the enzymes ultimately encoded by these three genes, but beyond that, the biological implications are murky. “It’s not clear what happens to the cells,” Drayna says. “There could be a group of neurons in the brain that are exquisitely sensitive to this problem.”
“A remarkable feature of this study is the nature of the implicated biologic pathway — an unlikely culprit to explain stuttering,” says neuroscientist Simon Fisher of the Wellcome Trust Centre for Human Genetics at the University of Oxford in England, writing in the same issue of the New England Journal of Medicine. These mutations may only partially reduce the activity of the enzymes, he surmises. Further tests of these defective enzymes may clarify the picture and ultimately explain why the mutations seem to “affect only neural circuits affecting speech fluency,” he says.
Syuichi Ooki, a physician at Ishikawa Prefectural Nursing University in Kahoku, Japan, wasn’t surprised that these mutations appeared in genes involved in a rudimentary area of cell metabolism. Mutated genes can induce biological changes downstream and have a “cascade” effect, Ooki says. “Therefore, mutation of genes involved in a basic metabolic process can unexpectedly affect human behavior.”
Up to 3 million people in the United States stutter. Drayna estimates these mutations could account for about 140,000 of those individuals.
Identifying specific genes implicated in stuttering might allow scientists to better understand the origins of the condition, described since biblical times, Drayna says. “We may be able to trace, down to individual cells, the connections in the brain that are affected.”