2 Genes Play Role in Narcolepsy, Studies Suggest
Two related genes known to affect hunger are also the long-sought cause of the excessive sleepiness of narcolepsy, according to Stanford and Texas researchers.
The genes’ effects were studied in dogs and mice, but the genes also have been found in humans. Researchers say the discovery may bring a narcolepsy cure within reach.
Two reports on the subject are appearing in the journal Cell. The dog study is in today’s issue and the mouse study is scheduled for publication Aug. 20.
Narcoleptics suffer from sudden and uncontrollable sleep attacks when they would rather be awake: in classes, during conversations, on the job, even while driving. Unlike the condition of the average sleep-deprived American, this occurs no matter how much sleep the narcoleptic gets.
Narcoleptics live in a nightmarish haze, said Sue Carella of Narcolepsy Network, a patient organization.
In one of the two new studies, Howard Hughes Medical Institute investigator Dr. Masashi Yanagisawa at the University of Texas Southwestern Medical Center examined mice that were genetically engineered to lack a hormone called orexin. He had discovered the gene for orexin a year ago, and found that it appeared to affect how much rats ate.
The mice that lacked orexin had a few subtle changes in their eating habits, but it was their dramatic shift in activity that caught Yanagisawa’s attention.
“The mice were running around or grooming themselves . . . and then all of a sudden--boom!--they stopped,” he said. “Oftentimes, they would fall over to the side like they were dead. One or two minutes later, they would go back to normal behavior, as if nothing happened.”
After a few other tests, Yanagisawa said, it became clear that the mice had narcolepsy. “Orexin normally regulated the sleep cycle in the mice,” he said, and the removal of the orexin led to irregular sleep.
He said that this tied in with his earlier work on regulating hunger. After all, he reasoned, if you need to eat, it’s important not to curl up and fall asleep. Low levels of orexin would promote sleep, and high levels promote wakefulness.
The journal released the Texas study early, to coincide with the Stanford study on dogs.
Researchers at the Stanford Center for Narcolepsy studied Dobermans and Labradors that were members of families in which some animals had narcolepsy and some did not. The goal was to find the gene that caused the sleepy behavior.
Zooming in on the exact gene took 10 years.
In a finding independent of the Texas work, the Stanford group found that the culprit gene held instructions for a receptor in the brain to which orexin attaches. When the receptor was defective, the dogs snoozed.
Experts agree that the situation is more complicated in humans, where probably only a few narcoleptics completely lack orexin or the receptor, as is the case with animals.
Dr. Emmanuel Mignot, who led the Stanford studies, speculates that the orexin system is involved in the human version of narcolepsy, but maybe in subtle ways: Perhaps the receptors develop properly and then are damaged.
Neurology professor Clifford Saper of the Harvard Medical School and his colleagues found that modafinil, the newest narcolepsy drug, works by interacting with the receptors. For the drug to work, at least some receptors must be present to begin with.
Perhaps, Saper said, people with narcolepsy are sleepy because they have only a few orexin receptors, and modafinil works by buffing up those that are present.
Now, with the genes identified, researchers hope to design drugs more specifically targeted to the cause.
Narcolepsy affects about 200,000 Americans, though many may not be diagnosed, according to the nonprofit National Sleep Foundation. Narcoleptics’ sleepiness is caused by the body yearning for more REM sleep--the dreaming part of sleep, characterized by rapid eye movements.
Since narcoleptics have unusual patterns of this deep sleep, they always feel like they need more and can slip into it at any time, often with little or no warning.
“When [most people] wake up, [they] feel refreshed,” said Carella, a narcoleptic. “When I wake up, I’m as tired as when I went to sleep.”
Extreme sleepiness, even after a full night’s sleep, and the associated “sleep attacks” are the most prevalent symptoms of narcolepsy. Others are rarer: the inability to move shortly after waking or dozing off, vivid and frightening hallucinations while asleep or “zoning,” and cataplexy--the sudden loss of muscle control, usually triggered by strong emotions or laughter.
Some people report “automatic behavior” in which they go through daily routines with no awareness that they have done so, and associated memory losses. One member of the Narcolepsy Network said that a two-year portion of her life virtually disappeared: “I know I must have paid bills, eaten, gone to work. . . . I just don’t remember it.”
Narcoleptics often are misunderstood, Carella said, and are called lazy or unmotivated. She hopes that the new findings will lead to a cure, and maybe even to a little understanding.
“We know now that it’s genetic. I sat and cried when they told me,” she said. “I’ve waited for 25 years to hear that.”
