Gehrig's Disease Gene Found

Mutation May Be Responsible for Some Types of ALS Cases

A group of Medical School researchers has found an altered gene that may be responsible for Lou Gehrig's disease, suggesting that doctors should start looking for ways to attack dangerous free elements left to roam in the central nervous systems of patients with the fatal disorder.

An international team of more than 30 scientists, led by Associate Professor of Neurology Robert H. Brown Jr, reports today the discovery of an altered gene likely responsible for 40-60 percent of familial, or hereditary, cases of amyotrophic lateral sclerosis (ALS). The disease's familiar name refers to the New York Yankees star who died of the disorder in 1941.

ALS is a progressive and fatal degenerative disease of the central nervous system. Patients are usually stricken between the ages of 40 and 70. Their motor neurons begin to die and they lose control over their muscles. Life expectancy once symptoms are observed is usually between just two and five years.

Only five to 10 percent of ALS cases are thought to be hereditary, a condition known as familial ALS, but today's finding proposes a model of damage for all cases of the disease. There is no clinical difference between familial ALS patients and the other 90 percent of ALS patients, whose condition is known as sporadic ALS.

The Medical School researchers, working at the Massachusetts General Hospital, report in today's issue of Nature that they have found a gene encoding an altered form of an enzyme, called SOD, common to 13 of 18 families with histories of ALS.


"I'm very hopeful that this will help us to find new ways to treat these patients," Brown said in a telephone interview yesterday.

Lynn M. Klein, vice president of the ALS Association, said in a phone interview yesterday that the discovery could lead to more accurate genetic counseling and testing.

"It's a very exciting time," Klein said. "This is the most significant research finding in the history of ALS research since it was first identified in 1869."

SOD is responsible for mopping up dangerous free radicals, in this case negatively charged oxygen molecules called "superoxides," which if left unchecked may lead to cell death. A similar mechanism, involving a different set of free radicals, has been implicated in Parkinson's disease.

It is estimated that about 30,000 Americans are affected by ALS at any given time, with 5,000 new cases diagnosed every year. According to the ALS Association, some 300,000 Americans alive today will eventually die of ALS.

The new finding suggests that if patients' supplies of SOD can be replenished by treatment with either SOD itself or a similar protein, there may be hope for a cure.

"There are some fascinating questions to be asked, and this is going to open the whole field," said Professor of Genetics Louis M. Kunkel. "One may be able to use compounds which scavenge radicals [to treat ALS patients]. It's more promising than many other genetic diseases."

Kunkel said several such compounds are already known to exist which act similarly, including some vitamins. Research into the applicability to ALS of such substances and their delivery still needs to be done, he said.

Klein cautioned that a large amount of research still lies ahead. SOD is just one player, albert "a bigger piece than we've ever had before," she said, but scientists are still searching for other altered genes responsible for cases of familial ALS not present in the current sample.

Brown said the research team will next look at three areas: analyzing SOD activity levels in affected patients, testing for free radical damage in patients and searching for drugs to eliminate free radicals.

In a phone interview yesterday, Irwin Fridovich, a professor of bio chemistry at Duke University Medical Center, proposed several possible explanations for the increased susceptibility of neurons to decreased SOD levels in ALS patients.

Fridovich said neurons may produce more free radicals than other cells, or may have less ability to repair damage, or may simply be more sensitive to superoxide levels.

Kunkel suggested that the extreme sensitivity and fragility of neurons to their environments could also cause increased susceptibility to low levels of SOD.

Free radical levels in neurons may be especially high because the cells do not divide. Brown said, allowing for buildup of reaction products.

Fridovich said he anticipates that further experiments with the altered SOD will find the protein less active, and that accumulation of damage to cells caused by superoxides not eliminated by SOD could eventually cause the death of many cells.

SOD recently made headlines when studies linked it to aging. Scientists were able to prolong the lives of fruit flies and nematodes by increasing levels of the enzyme in experimental subjects of both species