WASHINGTON, D.C.--Scientists have discovered two mutations that may be major contributors to the development of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. The finding, presented here today at the annual meeting of the Society for Neuroscience, could someday lead to a useful diagnostic test and improved treatments.
ALS, which afflicts nearly 30,000 people worldwide, causes a gradual paralysis that usually results in death. Although scientists found a gene that causes an inherited form of the disease in 1993, most cases--more than 90%--are "sporadic," that is, not hereditary, and are due to unknown causes.
Jeffrey Rothstein, a neurologist at Johns Hopkins University, found the mutations in 10 of 20 patients with sporadic ALS. He was following up on earlier observations that many patients have abnormally low levels of EAAT2, a protein that helps deactivate and recycle the neurotransmitter glutamate, in their brains and spinal cords. Because excessive concentrations of glutamate are toxic to neurons, that suggests patients' paralysis might be caused by buildup of the neurotransmitter and the resulting death of neurons that control the muscles.
In the current work, the Hopkins team found a possible explanation for the EAAT2 deficiency in ALS: The mutations they identified are in nucleic acids that translate the genetic code into the protein's structure. He and his colleagues did not find the mutations in healthy subjects or in patients with Alzheimer's disease or Huntington's disease, which are also characterized by neuron death.
The work is preliminary, Rothstein says, and he acknowledges that it leaves many questions unanswered. For instance, the researchers have found the altered proteins only in brain cells that control motor functions; they cannot explain why the mutations are limited to these cells. And many experts are not convinced that faulty glutamate metabolism is the primary culprit in the disease. Rothstein says, however, that the only drug that has shown any promise against ALS is Rilutek, which inhibits glutamate production. Even if the protein mutations do not play a primary role in the disease, he says, they could help neurobiologists track down the actual cause.