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Gene Variant Linked to Lou Gehrig's Disease

Discovery might lead to promising treatments, experts say

WEDNESDAY, Aug. 1, 2007 (HealthDay News) -- Researchers have uncovered a gene variant that raises the risk of developing amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease.

The findings could one day open the door to eradicating this terrible disease.

"The holy grail for this disease is to be able to identify who's at risk before they get ALS and implement a series of actionable events so that they don't get the disease, but that is in the 10-year time frame," said study senior author Dietrich A. Stephan, director of discovery research at Translational Genomics Research Institute, a nonprofit organization in Phoenix. "This lays the groundwork for building a genetic risk-assessment tool as well as developing therapeutics to the new biology we've uncovered, but it's a long-term goal."

Others concurred.

"It's a very exciting paper, but it needs to be followed up by other studies," said Nathalie Kayadjanian, associate director of biomedical research at the ALS Association. "This opens an avenue but needs to be confirmed to be sure we're on the right track and we're going to move forward."

ALS is a rare but fatal neurodegenerative disease that involves a progressive loss of motor neurons from the spinal cord, brain stem and cerebral cortex, eventually resulting in paralysis and death within two to five years of diagnosis, without intensive intervention.

"ALS is a horrific disease for which there are no effective therapies," Stephan emphasized.

About 10 percent of people with ALS have the familial version, resulting from known gene mutations.

"We know a fair amount about the genetic underpinning of familial ALS," Stephan said.

The remaining 90 percent have what's known as the sporadic form of the disease, which is believed to be caused by the interaction of different environmental factors and, as yet, mostly unidentified genes.

"We have zero understanding up until today of what genetics lead to that disease," Stephan said. "This study is really a major inroad into getting biological insights into the genetic underpinnings."

For this study, published in the Aug. 2 issue of the New England Journal of Medicine, Stephan and his colleagues performed a genome-wide association analysis of 386 white patients with sporadic ALS and 542 normal control participants.

In the end, the researchers identified several gene sites that were associated with sporadic ALS. The most significant association was for a SNP (single nucleotide polymorphism) near the FLJ10986 gene. The FLJ10986 protein was found to be produced in spinal cord and cerebrospinal fluid of both ALS and control patients.

A SNP is a unit of DNA whose sequence can vary from person to person and can influence susceptibility to disease.

"The genes seem to be involved with what's called the cytoskeleton of motor neurons," Stephan explained. "Motor neurons connect the brain to the muscles, and the cytoskeleton is sort of a scaffold within the neuron itself that allows the neuron to hold its shape and also push back and forth the things that motor neurons need. Motor neurons can be up to a meter long, so that trafficking system and skeleton within it is very critical. It appears that several of these genes lead to instability of the skeleton, which probably leads to disconnection of motor neurons from muscles."

According to Stephan, the research team identified about 10 candidate genes that seem to be consistently associated with sporadic ALS. These deserve further study, he said.

The findings also suggest that there is no single gene underlying ALS. Instead, the disease appears to sit at the confluence of several genes, not to mention environmental factors.

The new study was funded, in part, with a grant from the Muscular Dystrophy Association.

More information

To learn more, visit the ALS Association.

SOURCES: Dietrich Stephan, Ph.D., director of discovery research, Translational Genomics Research Institute, Phoenix; Nathalie Kayadjanian, Ph.D., associate director of biomedical research, the ALS Association, Calabasas Hills, Calif.; Aug. 2, 2007, New England Journal of Medicine
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