Senataxin Gene Linked to Juvenile-Onset ALS

For release: Wednesday, June 23, 2004

Researchers funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) have identified the gene that causes a rare juvenile-onset form of amyotrophic lateral sclerosis (ALS). The discovery of the Senataxin gene, on chromosome 9q34, may provide clues to the mechanisms of related brain disorders. The study appears in the June 2004 issue of the American Journal of Human Genetics. ¹

ALS is a progressive disorder that destroys motor neurons, the cells that control voluntary muscle activity such as speaking, walking, and writing. Affected muscles gradually weaken and waste away, and patients eventually are unable to move voluntarily. About 10% of all cases of ALS are inherited.

Mutations in the Senataxin gene cause ALS4, a juvenile-onset form that usually begins before age 25. These mutations likely lead to a protein that has harmful cellular effects. Unlike classical ALS, which is a fatal disease, ALS4 causes weakness that is slowly progressive, and affected individuals typically have a normal life span. Sensation in ALS4 is not altered.

A team of researchers led by Phillip F. Chance, M.D, a professor of pediatrics and neurology at the University of Washington, Seattle, studied four unrelated families (from the US, Belgium, Austria, and England), each of whom had multiple family members affected by a childhood- or adolescent-onset, slowly progressive motor neuron disorder with minimal or no sensory nerve impairment. Electrophysiological studies and autopsies confirmed the diagnosis of a chronic motor nerve disorder that initially affected distal muscles (those farthest away from the center of the body). Further analysis revealed an alteration in the DNA sequence of the Senataxin gene on chromosome 9 in the US family. The scientists then studied DNA samples from the other three families, and similar mutations were found in two additional families.

Although the exact function of the Senataxin gene is unknown, scientists believe that the mutated protein may disrupt normal mechanisms through which cells rid themselves of defective RNA transcripts.

"The abnormal Senataxin protein in ALS4 may impair the capacity of neurons to produce error-free mature messenger RNA, leading to neuronal degeneration," said Dr. Chance. "Given the precedence for RNA processing defects in other forms of motor neuron disease, it is hoped this discovery will bring additional insight into motor neuron degeneration."

"We are excited to find the cause of ALS4," said Kenneth H. Fischbeck, M.D., scientific team member and chief of the NINDS Neurogenetics Branch. "Each discovery of a gene responsible for motor neuron disease brings us closer to new therapies and hopefully ways to prevent the onset and progression of ALS."

The findings may provide insight into the mechanisms of other forms of ALS and motor neuron diseases in general, since many of these disorders have overlapping features. The same gene is mutated in a rare form of ataxia, a disorder that is unrelated to motor neuron disease.

Classical ALS (also known as Lou Gehrig's disease) typically strikes people between 40 and 60 years of age, and most patients die within 3-5 years of symptom onset. Intellect, memory, and personality are not affected in most cases.

The NINDS, a component of the National Institutes of Health within the U.S. Department of Health and Human Services, is the nation's primary supporter of biomedical research on the brain and nervous system.

Reference:

¹ Chen Y, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. "DNA/RNA helicase gene mutations in a form of juvenile Amyotrophic Lateral Sclerosis (ALS4)." American Journal of Human Genetics, Vol. 74, No. 6, pp. 1128-1135.

- By Paul Girolami

Date Last Modified: Tuesday, September 09, 2008

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