VARIATIONS IN 'DETOX' ENZYMES LINKED TO ALS, STRENGTHENING ALS-GULF WAR LINK

TUCSON, Ariz., July 5, 2006 — Genetically determined variations in enzymes required to handle toxins like pesticides, nerve gas and anti-nerve gas medications appear to increase susceptibility to amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), the Muscular Dystrophy Association announced today.

Two sets of findings, published online today in the journal Neurology, point to variations in enzymes known as paraoxonases, or PONs, as ALS risk factors, strengthening a previously proposed link between ALS and service in the Gulf War (1990-1991).

Veterans of that war appear to have about twice the expected risk of developing ALS, and many were exposed to pesticides such as DEET through direct skin applications or the wearing of pesticide-containing collars. Nerve gas exposures occurred among military personnel involved in destroying nerve gas storage areas and involved relatively few people, but many more troops took medication aimed at warding off the effects of an anticipated nerve gas attack.

"Finding that the PON gene and enzyme variations and ALS are correlated provides a missing link between genetic predisposition and environmental toxins," said Sharon Hesterlee, MDA's Research Development Director. "That's been suspected for a long time but never actually substantiated in this disease until now."

One of today's online publications, from the laboratory of neuroscientist Teepu Siddique at Northwestern University in Chicago as well as from Vanderbilt University in Nashville, Tenn., and Duke University in Durham, N.C., is based on a study of 1,891 North Americans with and without ALS.

Mohammad Saeed and colleagues, including neurologist Robert Sufit, who directs the MDA neuromuscular disease clinic at Northwestern, identified a DNA sequence on chromosome 7 that lies between the genes for the enzymes PON2 and PON3 that appears associated with the risk of developing ALS. "The signal is from the intergenic [between genes] region, so the biology has yet to be clarified," Siddique said. He noted that the PON2 enzyme is known to be present in the nervous system.

In 450 of the North American cases, the genes of the ALS-affected person were compared with those of both unaffected parents or one unaffected sibling, to minimize interference from genetic background noise arising from ethnic differences.

In the other study, MDA grantee Denise Figlewicz at the University of Michigan in Ann Arbor along with researchers at Jagiellonian University in Krakow, Poland, identified a specific variant in the PON1 enzyme and another variant in the PON2 enzyme that, when combined, were 3.4 times more prevalent in the ALS patients.

The Polish sample included 185 people with ALS and 437 unaffected participants, all of Eastern European Caucasian origin.

Figlewicz said she "immediately sat up" when she saw the first set of data.

"This was a small sample size from a genetically isolated population, and to get such a statistically significant effect is a sign that you may be looking at something important," she said. "And a gene, or family of genes, already implicated in the Gulf War syndrome is certainly the kind of candidate you pay attention to."

In 1999, epidemiologist Robert Haley and colleagues correlated having the PON1 variant with the development of Gulf War-associated neurologic syndromes (symptoms groups).

ALS begins insidiously, usually in late middle age, with weakness in a leg, arm or the mouth and throat muscles, and progresses rapidly to complete paralysis of the voluntary muscles, including those controlling breathing. Death usually occurs within three to five years.

Ten percent of ALS cases are clearly inherited. For the other 90 percent, the causes remain unknown, although a combination of genetic predisposition and environmental exposures has been proposed.

MDA (www.mda.org) is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services and far-reaching professional and public health education.

It operates 235 neuromuscular disease clinics, of which 37 are ALS-specific research and care centers, throughout the United States.

In 2006, MDA allocated some $7 million to ALS research and another $10 million for ALS health care services. Since its inception, the Association's expenditures for ALS research and services have exceeded $190 million.