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Chemical may be key to narcolepsy

2 studies show patients may lack hypocretin in brain

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WASHINGTON — A chemical that transmits signals in the brain — discovered just two years ago — may hold clues to the cause of the rare but dangerous disease narcolepsy.

Narcolepsy is marked by recurring episodes of daytime sleep in the victim, lasting from a few seconds to an hour. The disease can be merely inconvenient to some, but disabling and dangerous to others who may fall asleep while driving or operating machinery.

Stimulant drugs help some victims but can cause side effects. The cause of the disease has eluded researchers.

The discovery that a specific brain chemical is involved in narcolepsy could point the way for researchers to seek new treatments for the disease. There are about 125,000 narcolepsy patients in the United States. The disease usually strikes in the mid-teens to about age 25 and visits both sexes equally.

The two new studies are complimentary, "we both find that these cells are disappearing," said Dr. Emmanuel Mignot of Stanford University.

A team led by Mignot reports in the September issue of Nature Medicine that they found a lack of the chemical hypocretin in the brains of narcolepsy victims.

Hypocretins, which they noted were discovered just two years ago, are a type of neurotransmitter produced by the hypothamlus region of the brain. Prior studies have shown these signal transmitters to stimulate appetite and arousal.

"The finding that hypocretins are absent in most cases (of narcolepsy) . . . strongly supports a central role for hypocretin deficiency in the human disorder," they said.

The researchers added that their findings "suggest a loss of neurons that may be irreversible once the disease is fully established."

In a separate study in the journal Neuron, researchers at the University of California, Los Angeles, reported finding that narcolepsy patients had a dramatic, degenerative loss of a type of brain cell called Hcrt. Hcrt cells, or neurons, contain hypocretin and are located in the hypothalamus.

Those researchers, led by Dr. Jerome M. Siegel, found that the number of Hcrt neurons in narcoleptics was 85 percent to 95 percent less than the number found in non-narcoleptic brains. But they found no loss of other cells normally found intermixed with Hcrt cells.

"While it is clear that the degenerative loss of Hcrt cells is directly linked to narcolepsy, the cause of this cell loss remains to be determined," Siegel said.

Both teams suggested the possibility of autoimmune disease, and Siegel's group noted that the presence of gliosis, or scarring, indicates a degenerative process.

Mignot's group also noted that autoimmune processes, when the body attacks itself, have been suspected for years.

But those researchers found no recent inflammation that would indicate such a process, though it could have occurred much earlier.

"More surprisingly," they said, "we also did not detect significant residual gliosis and-or cellular loss in the region."

Mignot's team also looked for genetic changes that could have led to the loss of hypocretin, but found a mutation in only one narcolepsy patient, an unusual case occurring in a young child.