After seven years of searching, a multinational team of researchers has found the approximate location of the gene that causes one form of the devastating paralytic disorder amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease.
The step, reported in today's New England Journal of Medicine, represents the first major advance in determining the cause of the disease in the 122 years since the disease was identified, according to neurologist Teepu Siddique of the Northwestern University Medical School, leader of the team.
ALS affects an estimated 5,000 Americans each year, about the same number stricken by multiple sclerosis and five times the number afflicted with Huntington's disease. An estimated 300,000 Americans now alive will develop the disorder.
"This finding holds tremendous promise for everyone affected by ALS," said Robert Ross, executive director of the Muscular Dystrophy Assn., which funded the research along with the ALS Association and the National Institutes of Health.
"I think it is a very significant step forward," said USC neurologist W. King Engel. "It narrows the target for the actual gene considerably. The next step will be to get the gene, find the protein that is defective and then find out how that protein defect causes the neural degeneration. But without this narrowing of the target, those other steps could not follow."
Most geneticists declined to predict how long it will take the team to isolate and identify the gene now that they know its approximate site. But for comparison, four years elapsed between the first identification of the site of the cystic fibrosis gene and isolation of the gene, and five years for the Duchenne muscular dystrophy gene. The latter was identified in 1986, and already neurologists are developing experimental treatments based directly on the discovery.
"It's like hearing a cry for help and then having to find out what state, what city, then what neighborhood it is coming from," said Siddique, who did much of the work while at Duke University. "Now we know the neighborhood. Next we have to find the street and the house and then find out what is going on in the house."
ALS gets its common name from New York Yankees first baseman Lou Gehrig--nicknamed the Iron Horse for his durability--who was forced to retire from the game by the disorder in 1939. Gehrig died in 1941.
The disease results in degeneration of the brain and spinal cord cells that control muscle function, which leads to generalized and progressive weakness and wasting of skeletal muscles and paralysis. It does not affect mental functioning. No cure or effective treatment exists.
The symptoms usually become apparent sometime between the ages of 40 and 70, and 90% of patients die within five years after it is diagnosed. Renowned British physicist Stephen Hawking, however, has lived with the disease for 26 years.
Between 5% and 10% of ALS cases are "familial," or inherited from parents. The remainder are believed to arise from mutations that occur during conception or development. Because the symptoms of the two forms are identical, researchers believe the biochemical process that causes them are probably also identical. Identification of a gene that causes the familial form is expected to shed light on the other form as well.
The only observed difference between the two forms is in the sex ratio. The familial form strikes males and females equally; the more common form strikes males twice as often as females.
The team of 34 researchers from the United States, Australia, Belgium and Canada studied members of 23 families with a history of ALS. About 60 of the 510 family members either had the disease or were known to carry the defective gene.
Assembling so many families with a significant number of affected individuals was itself a major achievement, according to molecular geneticist P. Michael Conneally of the Indiana University Medical Center. Because most patients die within five years of diagnosis, he noted, it is extremely difficult to locate families with more than one living member who has the disorder.
Working independently and together, the researchers sifted through 44 of the 46 chromosomes that make up the genetic complement of a human being--it was known that the gene was not on either of the two sex chromosomes. They were looking for known pieces of DNA (deoxyribonucleic acid, the genetic blueprint of life), called markers, that scientists have identified at more or less evenly spaced intervals throughout each chromosome.
They found that four such markers on chromosome 21 were present in more than half of ALS patients, but not in their family members who did not have the disease. That finding indicates that the gene that causes the disorder lies somewhere close to the four markers. The remainder of the ALS patients did not have the four markers and are thought to have a defective gene elsewhere; scientists are searching for that gene.
Lawrence A. Rand, chairman of the ALS Association, said, "For some time we have felt that if a breakthrough were to occur, it would likely come from research to locate and identify the familial ALS gene."
Neurologist Allen D. Roses of the Duke University Medical Center said that this discovery should also provide clues to other degenerative neurological illnesses, such Alzheimer's disease.