Originally created 08/06/99

Narcolepsy gene found



BOSTON -- Scientists believe they have discovered a genetic flaw deep within the brain that causes narcolepsy, the bizarre disorder that makes people fall asleep without warning.

An estimated 135,000 Americans have narcolepsy, and until now its cause has been a mystery. Experts say the latest discovery should offer solid clues for finding better treatments.

Two groups of scientists, working independently, found that narcoleptics' overwhelming urge to fall asleep may result from a glitch in signals sent between cells in the hypothalamus, a part of the brain that regulates appetite and other basic drives.

The genetic foul-up was documented only in dogs and mice. But researchers say they are confident that a similar defect will be shown to be at fault in some human cases, although the origins of the disease are almost certainly far more complex in people than in animals.

"Clearly, these two papers will revolutionize the field of sleep research," predicted Juliette Faraco of Stanford University, a geneticist who co-authored one of the studies.

The Stanford research, directed by Dr. Emmanuel Mignot, is being published in Friday's issue of the journal Cell. Another study reaching similar conclusions was conducted by Dr. Masashi Yanagisawa of the University of Texas Southwestern Medical Center in Dallas. It will be published in Cell on Aug. 20.

Other researchers have found genes that control circadian rhythm, the daily cycle of sleeping and waking. But Faraco said the new research is the first discovery of a gene that directly regulates sleep itself.

For the latest discoveries, the Texas team bred mice that were missing one gene and would keel over asleep while racing on their running wheels. The Stanford team worked with Doberman pinschers and Laborator retrievers that have an inherited form of narcolepsy.

Like these animals, people with narcolepsy are overcome by uncontrollable urges to sleep, often at inconvenient times, such as when driving. Unlike folks taking ordinary naps, they fall immediately into the deepest stage of sleep, called REM. Some may suffer sleep paralysis, a terrifying inability to move shortly after awakening. Others have especially vivid dreams.

One common feature is called cataplexy, which is when people suddenly lose consciousness and fall down. Strong emotions, such as anger, surprise or laughter, often trigger this disconcerting collapse.

Narcoleptic dogs get cataplexy, too, during moments of tail-wagging excitement. "You show them a doggy biscuit and ker-flop, they go down on the ground," said Faraco.

The Stanford team traced the condition in these dogs to a gene that makes a receptor -- a bit of material on the surface of brain cells that allow them to get signals from other cells. This particular receptor hears messages that are transmitted by a protein called hypocretin-2.

When the gene is broken -- either because it is missing some code or has extra bits -- it makes a receptor that fails to recognize hypocretin-2, so the signal never gets through.

"This work implicates hypocretin in sleep regulation, which gives us a wonderful new handle on how we might approach sleep control" with new medicines, said Dr. Charlotte McCutchen of the National Institute of Neurological Disorders and Stroke, which financed the research.

Instead of treating narcolepsy with stimulates such as amphetamines, which have unwanted side effects, she said, it soon may be possible to find drugs that work solely on the brain's hypocretin system. Medicines could be designed to both prevent sleep in narcoleptics and induce it in insomniacs.

Last year, Yanagisawa discovered that a protein dubbed orexin-B stimulates the appetite. Now it turns out that orexin-B and hypocretin-2 are the same thing.

To study the protein's effects on appetite, Yanagisawa produced gene-altered mice that cannot make orexin-B. The scientists hooked up infrared cameras to watch their eating habits at night, when they are most active.

"We saw this very bizarre change in behavior," Yanagisawa said. "The mice would be grooming, running and burrowing and then all of a sudden they would fall over and stay there for one or two minutes."

At first the scientists suspected epileptic seizures. But further testing showed the mice had fallen into deep REM sleep. Like the Stanford dogs, these mice had cataplexy, caused by their brains' inability to receive signals sent by a potent protein called hypocretin-2 or orexin-B.