Faulty Gene That Causes Gehrig’s Disease Is Found

Researchers have identified the faulty gene that causes amyotrophic lateral sclerosis, the severe neuromuscular disorder commonly known as Lou Gehrig’s disease, after the New York Yankees’ durable first baseman who succumbed to the disorder in 1941.

Although details about the genetic defect remain to be learned, scientists say the new finding, reported in today’s issue of the journal Nature, opens the door to prenatal screening and the first effective therapies for the disease.

“This is without question the single greatest discovery in ALS research ever made,” said Donald S. Wood, vice president of the National Multiple Sclerosis Society, which partially funded the research. “Now we can take all those millions of dollars that were focused on finding the gene and direct them toward developing therapies.”

Scientists were greatly surprised by the identity of the gene, which turned out to be a building block for a well-known enzyme associated with the aging process. Impairment of the enzyme, called superoxide dismutase, has previously been linked to the deterioration of bodily functions that accompany aging.

Based on today’s report, scientists are beginning to suspect that the gene may also be involved in other degenerative diseases of aging, such as Huntington’s and Parkinson’s diseases. If so, the finding could also have broad implications far beyond the 30,000 Americans who suffer from ALS.

A key to treating ALS lies in whether its victims produce too much or too little superoxide dismutase, which scavenges oxygen-free radicals in the body before they can react with and destroy crucial tissues. The researchers do not know the answer yet, but they say either scenario offers great promise for intervention.

If the body does not produce enough enzyme, a treatment as simple as administration of antioxidants such as Vitamin C might slow the disorder. If too much is produced, well-known drugs could be used to inhibit the enzyme’s activity.

Either way, the researchers say they expect progress toward a treatment in the near future.

“We hope that this will lead rather quickly to clinical trials,” said geneticist David Patterson of the Eleanor Roosevelt Institute in Denver, one of the key researchers in the collaborative program.

“For the first time, we have the potential for doing something about this (ALS),” Wood said.

And better understanding of how the disorder works could lead to other approaches to therapy as well.

“This obviously is a very important finding, for it establishes the molecular genetic basis of ALS,” said molecular biologist H. Robert Horvitz of the Massachusetts Institute of Technology, co-chairman of the Amyotrophic Lateral Sclerosis Assn.’s Scientific Review Committee.

ALS affects about one in every 100,000 people worldwide, except for certain areas in the Pacific where the incidence is inexplicably much higher. The average age of onset is 56, although it is highly variable. Gehrig was 35 when he contracted it in 1939, and famed British astrophysicist Stephen Hawking was in his early 20s.

The disorder is characterized by the death of nerve cells in the brain and spinal cord that control muscle activity, producing progressive muscle weakness and paralysis. Most ALS victims die within two years after its onset, but some survive much longer. Hawking has had it for three decades.

The disease occurs in two forms--hereditary or familial ALS, in which a defective gene is passed down through a family, and the so-called sporadic form, which arises from random mutations in the gene. Hereditary ALS accounts for about 10% of cases; sporadic ALS accounts for the rest. The two forms are indistinguishable, however, in terms of diagnosis, prognosis and clinical course.

The discovery results from nearly two decades of study on 18 U.S. families with the hereditary form of ALS. The lead researcher was Dr. Robert H. Brown Jr., a neurologist at the Massachusetts General Hospital in Boston, but 32 researchers at 13 institutions participated in the study and were co-authors of the paper.

Two years ago, the team found that the gene that causes the disorder resides on chromosome 21, one of the 23 pairs of chromosomes that contain the complete human genetic blueprint. Focusing on ever-narrower portions of the chromosomes, they ultimately determined that ALS was caused by defects in the gene for superoxide dismutase. They have so far identified 11 defects in 13 families, suggesting that the gene is rather fragile and easily mutated during reproduction.

The team is confident that defects in the same gene will be found in sporadic forms of the disease because the symptoms are identical, but they have not yet checked any such patients for the defects.

The fact that so much is known about superoxide dismutase already will certainly speed the search toward a therapy for ALS. For more than two decades, the enzyme has been known to protect cells from damage because of environmental factors and reactive chemicals that are a natural product of metabolism. Declining levels of superoxide dismutase have been linked to aging and prolonged activity to longevity.

“This link with ALS adds further to the notion that we may be able to slow the rate of normal aging and age-related loss of function by preventing oxidative damage,” said Dr. Gene Cohen, acting director of the National Institute of Aging. “We are very excited by this finding. It has extremely far-reaching implications.”

Brown and others cautioned that the first therapies developed for ALS will most likely slow or halt deterioration of nerve cells rather than reverse it, and therefore will be of most value in individuals newly diagnosed with the disorder rather than those in the last stages.

A Deadly Disease (Southland Edition, A26)

Researchers have discovered the faulty gene--located in an area on chromosome 21 marked below by a dot--that causes Lou Gehrig’s disease, formally called amyotrophic lateral sclerosis or ALS.

What It Does: Causes progressive paralysis by destroying muscle-controlling nerves in the brain and spinal cord.

Affected: An estimated 30,000 Americans.

When It Strikes: Generally begins in middle adulthood. It leads to paralysis of voluntary muscles and death, often within two to five years of its onset.

Key Find: The discovery gives the first insight into the mechanism by which the disorder causes such decay. And it opens the door to the possibility of the first effective therapy.

Sufferers: Include the late U.S. Sen. Jacob Javits, actors David Niven and Dennis Day, Gen. Maxwell Taylor and jazz bassist Charles Mingus. British physicist Stephen Hawking also suffers from the disease.