March 1, 2010

First Genes Tied to Stuttering

Photo of a young man talking

Researchers have identified 3 genes as a source of stuttering. The speech disorder can stem from a glitch in cell metabolism, the results suggest, which may point to new approaches for treatment.

People who stutter repeat or prolong sounds, syllables or words, disrupting the normal flow of speech. Stuttering can severely hinder communication and a person’s quality of life. Most children who stutter later outgrow it, but many don’t. About 1% of adults stutter worldwide. Although there’s currently no cure, a variety of treatments are available.

Because stuttering tends to run in families, researchers have long suspected a genetic component. In previous work involving families from Pakistan, a team led by Dr. Dennis Drayna of NIH's National Institute on Deafness and Other Communication Disorders (NIDCD) found a region on chromosome 12 that seemed to be involved.

In the new study, Drayna and his colleagues analyzed the region more closely in volunteers from Pakistan, the United States and England. The team included scientists at the University of Punjab in Pakistan, the Hollins Communications Research Institute in Virginia, NIH’s National Human Genome Research Institute (NHGRI) and the NIH Clinical Center.

As reported in the February 25, 2010, edition of the New England Journal of Medicine, the researchers identified mutations in a gene known as GNPTAB in the affected family members. GNPTAB encodes a protein involved in breaking down and recycling cellular components inside a cell structure called the lysosome. GNPTAB and 2 other proteins called GNPTG and NAGPA make up a signaling mechanism that steers enzymes to the lysosome to do their work.

Because of the close relationship among these 3 genes, the researchers next turned their attention to GNPTG and NAGPA. They found mutations in both genes in people who stutter. The scientists estimate that roughly 9% of people who stutter have mutations in 1 of the 3 genes.

GNPTAB and GNPTG have previously been tied to metabolic diseases known as mucolipidosis, in which improperly recycled cell components accumulate in the lysosome. Mucolipidosis ultimately leads to joint, skeletal, heart, liver and other health problems as well as developmental abnormalities in the brain.

"You might ask, why don't people with the stuttering mutations have more serious complications?" Drayna asks. "Nearly all of the unrelated individuals in our study who stuttered had only one copy of the mutation," he explains. Mucolipidosis is recessive, meaning you must have 2 copies of a defective gene to get the disease. And unlike mucolipidosis, he points out, "with stuttering the protein is still made, but it's not made exactly right."

This is the first study to pinpoint specific gene mutations as the potential cause of stuttering. Current treatments for some lysosome storage disorders involve injecting manufactured enzyme into a person's bloodstream to replace the missing enzyme. A similar approach might prove effective in treating some types of stuttering in the future.

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