Cause of Narcolepsy Found by Researchers
California researchers report that they have found the long-sought cause of narcolepsy, a mysterious sleep disorder that affects at least 125,000 Americans.
The condition is caused by the death of a few cells deep within the brain, researchers from UCLA and Stanford report today.
The results suggest that it may be possible to treat victims of the disorder, which is characterized by overwhelming sleepiness, and could lead to new ways of attacking other sleep disorders, experts said.
Teams at UCLA and Stanford studied preserved brains from narcoleptics and independently found that all were missing cells from the hypothalamus that secrete a hormone called hypocretin. Also known as orexin, the hormone previously has been shown to be involved in the regulation of sleep.
The brains showed clear evidence that the cells had been destroyed, perhaps by a toxin or more likely by an autoimmune attack, said Dr. Jerome M. Siegel of UCLA and the Sepulveda Veterans Affairs Medical Center.
“The findings end a 120-year search for the cause of narcolepsy and open new paths for treating this incurable disease,” he said.
“This is probably the most significant narcolepsy research in the history of the disease,” said Robert L. Cloud, executive director of the Narcolepsy Network.
Narcolepsy affects about one in every 2,000 people, usually striking during their teens or 20s and lasting throughout their lives. Victims suffer from uncontrollable sleepiness, often while working, in class or even driving. Many also suffer from cataplexy, a loss of muscle tone triggered by sudden strong emotions, such as laughter and impulsive anger.
The traditional treatments have been central nervous system stimulants, such as Ritalin and Dexedrine, to combat sleepiness and antidepressants to control cataplexy, but neither approach is very effective, Cloud said.
In the last two years, the wakefulness-promoting drug modafinil, which is not a central nervous system stimulant, has become the drug of choice to treat narcolepsy, but it still leaves much to be desired, he said. And ongoing clinical trials have shown that a drug called GHB--the same GHB that is known as the “date-rape” drug--is 90% to 95% effective in controlling cataplexy.
Researchers hope that the new discovery will lead to treatments that are more effective and have fewer side effects.
The crucial advance leading to the new findings occurred two years ago when Dr. Masashi Yanagisawa of the University of Texas Southwestern Medical Center discovered orexin. Orexin helps to control appetite, and researchers immediately seized on it as the basis for a potential anti-obesity drug.
Since that discovery, “the speed of research has been breathtaking,” Siegel said.
Yanagisawa genetically engineered mice that did not produce orexin and discovered that the mice suffered classic narcolepsy symptoms. He reported that finding last summer.
Simultaneously, Dr. Emmanuel Mignot of Stanford reported that narcolepsy in dogs is caused by a genetic defect in the protein that serves as a brain receptor for orexin--which sleep scientists call hypocretin.
“That was our first foot in the door to understanding the pathways of narcolepsy,” said geneticist Juliette Faraco, who works in Mignot’s lab.
Mignot immediately began looking at humans to see if they suffered similar genetic defects, but was unsuccessful.
In the absence of a genetic defect, his group looked at the hypocretin-secreting cells themselves, using preserved narcoleptic brains collected by the late Dr. Michael Aldrich of the University of Michigan.
Siegel had the same idea and also used brains furnished by Aldrich.
To their surprise, Siegel and Mignot found that the critical cells were missing. In each brain they studied, from 85% to 99% of those so-called Hcrt cells were gone, having shriveled up and died. They also observed a phenomenon called gliosis, a type of scarring that indicated that the cells had undergone a degenerative process.
Preserved brains from people who did not have narcolepsy, in contrast, showed no evidence of damage to Hcrt cells. Mignot reports his results in today’s Nature Medicine, and Siegel in an upcoming issue of the journal Neuron.
There was no damage to any of the other types of cells in the hypothalamus, however, indicating that the Hcrt cells had been specifically targeted.
“That is a really important observation,” said neuroscientist Cheryl Kitt of the National Institute of Neurological Diseases and Stroke. “There are only a very few neurological disorders that show such a specific loss of cells.”
One example is Parkinson’s disease, which is marked by the loss of dopamine-secreting cells in the substantia nigra. Parkinson’s is caused by a genetic defect, but it can be produced by chemicals that kill those same cells.
“There’s good news here for narcoleptics,” Siegel said. Although the cells that secrete hypocretin are dead, the receptors for the hormone remain functional. That suggests that administration of the peptide could lead to control of narcolepsy symptoms, he said.
Pharmaceutical companies are doing safety trials of hypocretin in animals in hopes of using it as an anti-obesity drug, Kitt said. That should speed the process of testing it in narcolepsy patients. Although no one was willing to predict when that would happen, Kitt speculated that it could occur “very quickly.”
For more information on narcolepsy, visit https://narcolepsynetwork.org or https://www.med.stanford.edu/school/psychiatry/narcolepsy/.
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Brain Cells Key to Sleep Control
Studying preserved brains from narcoleptics, researchers have found that they lack cells in the hypothalamus that secrete a hormone called hypocretin, which is linked to sleep control.
Source: American Medical Assn. Encyclopedia of Medicine
