Findings suggest common speech problem ...inherited metabolic disorder

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Another link to a speech impairment and metabolic disorders/nutritional

inverventions

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Researchers Discover First Genes for Stuttering

Findings suggest common speech problem, in some cases, may actually be an

inherited metabolic disorder

EMBARGOED FOR RELEASE

Wednesday, February 10, 2010

5 p.m. EST

Contact:

Wenger

(301) 496-7243

jwenger@...

Stuttering may be the result of a glitch in the day-to-day process by which

cellular components in key regions of the brain are broken down and recycled,

says a study in the Feb. 10 Online First issue of the New England Journal of

Medicine. The study, led by researchers at the National Institute on Deafness

and Other Communication Disorders (NIDCD), part of the National Institutes of

Health, has identified three genes as a source of stuttering in volunteers in

Pakistan, the United States, and England. Mutations in two of the genes have

already been implicated in other rare metabolic disorders also involved in cell

recycling, while mutations in a third, closely related, gene have now been shown

to be associated for the first time with a disorder in humans.

" For hundreds of years, the cause of stuttering has remained a mystery for

researchers and health care professionals alike, not to mention people who

stutter and their families, " said F. Battey, Jr., M.D., Ph.D., director of

the NIDCD. " This is the first study to pinpoint specific gene mutations as the

potential cause of stuttering, a disorder that affects 3 million Americans, and

by doing so, might lead to a dramatic expansion in our options for treatment. "

Stuttering is a speech disorder in which a person repeats or prolongs sounds,

syllables, or words, disrupting the normal flow of speech. It can severely

hinder communication and a person's quality of life. Most children who stutter

will outgrow stuttering, although many do not; roughly 1 percent of adults

stutter worldwide. Current therapies for adults who stutter have focused on

such strategies as reducing anxiety, regulating breathing and rate of speech,

and using electronic devices to help improve fluency.

Stuttering tends to run in families, and researchers have long suspected a

genetic component. Previous studies of stuttering in a group of families from

Pakistan had been done by Dennis Drayna, Ph.D., a geneticist with the NIDCD,

which indicated a place on chromosome 12 that was likely to harbor a gene

variant that caused this disorder.

In the latest research, Dr. Drayna and his team refined the location of this

place on chromosome 12 and focused their efforts on the new site. They sequenced

the genes surrounding a new marker and identified mutations in a gene known as

GNPTAB in the affected family members. The GNPTAB gene is carried by all higher

animals, and helps encode an enzyme that assists in breaking down and recycling

cellular components, a process that takes place inside a cell structure called

the lysosome.

They then analyzed the genes of 123 Pakistani individuals who stutter—46 from

the original families and 77 who are unrelated—as well as 96 unrelated

Pakistanis who don't stutter, and who served as controls. Individuals from the

United States and England also took part in the study, 270 who stutter and 276

who don't. The researchers found some individuals who stutter possessed the same

mutation as that found in the large Pakistani family. They also identified three

other mutations in the GNPTAB gene which showed up in several unrelated

individuals who stutter but not in the controls.

GNPTAB encodes its enzyme with the help of another gene called GNPTG. In

addition, a second enzyme, called NAGPA, acts at the next step in this process.

Together, these enzymes make up the signaling mechanism that cells use to steer

a variety of enzymes to the lysosome to do their work. Because of the close

relationship among the three genes in this process, the GNPTG and NAGPA genes

were the next logical place for the researchers to look for possible mutations

in people who stutter. Indeed, when they examined these two genes, they found

mutations in individuals who stutter, but not in control groups.

The GNPTAB and GNPTG genes have already been tied to two serious metabolic

diseases known as mucolipidosis (ML) II and III. MLII and MLIII are part of a

group of diseases called lysosomal storage disorders because improperly recycled

cell components accumulate in the lysosome. Large deposits of these substances

ultimately cause joint, skeletal system, heart, liver, and other health problems

as well as developmental problems in the brain. They are also known to cause

problems with speech.

" You might ask, why don't people with the stuttering mutations have more serious

complications? Why don't they have an ML disease? " posed Dr. Drayna, senior

author of the paper. " ML disorders are recessive. You need to have two copies of

a defective gene in order to get the disease. Nearly all of the unrelated

individuals in our study who stuttered had only one copy of the mutation. Also,

with stuttering, the protein is still made, but it's not made exactly right.

With ML diseases, the proteins typically aren't made at all. Still, there are a

few complexities remaining to be understood, and we'd like to learn more about

them. "

The findings open new research avenues into possible treatments for stuttering.

For example, current treatment methods for some lysosomal storage disorders

involve injecting manufactured enzyme into a person's bloodstream to replace the

missing enzyme. The researchers wonder if enzyme replacement therapy might be a

possible method for treating some types of stuttering in the future.

The researchers estimate that roughly 9 percent of people who stutter possess

mutations in one of the three genes. Among the next steps, they are conducting a

worldwide epidemiological study to better determine the percentage of people who

carry one or more of these mutations. They are also conducting biochemical

studies to determine specifically how the mutations affect the enzymes. A

long-term goal is to use these findings to determine how this metabolic defect

affects structures within the brain that are essential for fluent speech.

In addition to the NIDCD, researchers at the University of Punjab, Lahore,

Pakistan; the Hollins Communications Research Institute, Roanoke, Va.; the

National Human Genome Research Institute (NHGRI); and the NIH Clinical Center

contributed to this work.

###

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the

Department of Health and Human Services. The NHGRI Division of Intramural

Research develops and implements technology to understand, diagnose and treat

genomic and genetic diseases. Additional information about NHGRI can be found at

its Web site, www.genome.gov.

The NIH Clinical Center (CC) is the clinical research hospital for the National

Institutes of Health. Through clinical research, physician-investigators

translate laboratory discoveries into better treatments, therapies and

interventions to improve the nation's health. For more information, visit

http://clinicalcenter.nih.gov.

NIDCD supports and conducts research and research training on the normal and

disordered processes of hearing, balance, smell, taste, voice, speech and

language and provides health information, based upon scientific discovery, to

the public. For more information about NIDCD programs, see the Web site at

www.nidcd.nih.gov.

The National Institutes of Health—The Nation's Medical Research Agency —

includes 27 institutes and centers and is a component of the U.S. Department of

Health and Human Services. It is the primary federal agency for conducting and

supporting basic, clinical and translational medical research, and it

investigates the causes, treatments and cures for both common and rare diseases.

For more information about NIH and its programs, visit www.nih.gov.

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To learn more about enzyme replacement therapy

http://www.nursingworld.org/MainMenuCategories/ANAMarketplace/ANAPeriodicals/OJI\

N/TableofContents/vol132008/No1Jan08/EnzymeReplacementTherapy.aspx

(Nutriiveda supports the metabolic system, wonder if an answer lies in this

discovery why it's " working " for our children?)

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