Scientists believe they may have identified the cause of the debilitating sleep disorder narcolepsy in humans.
A new study shows a dramatic reduction - up to 95 percent - in the number of neurons containing a substance called hypocretins in the brains of people with narcolepsy compared to control brains.
Hypocretin peptides are neurotransmitters that play an important role in regulating sleep and appetite. The researchers hypothesize that the pronounced loss of these neurons could be caused either by a neurodegenerative process or an autoimmune response.
Narcolepsy is a disabling sleep disorder that affects 135,000 Americans.
Patients suffer from excessive daytime sleepiness; sudden brief episodes of muscle weakness or paralysis, also called cataplexy; paralysis while sleeping or upon waking up; and vivid dream-like images that occur at sleep onset.
The disorder is often difficult to diagnose, and there is presently no cure.
The study, led by Jerome M. Siegel, Ph.D., Professor of Psychiatry and Biobehavioral Sciences at the University of California at Los Angeles, and Chief of Neurobiology Research at the Veterans Administration in Sepulveda, is being published in the September 2000 issue of Neuron.
Dr. Siegel's work is supported in part by the National Institute of Neurological Disorders and Stroke (NINDS).
Recent studies have shown that there is a genetic component to narcolepsy in dogs and mice involving mutations of the hypocretin precursor or receptor genes.
However the authors point out that the genetics of human narcolepsy are well defined - most narcoleptics generally do not have first degree relatives with the disorder. When present in identical twins, in most cases only one twin is affected.
Because narcolepsy does not occur until later in life, after age 15 and into the 30's, the researchers hypothesized that a loss of hypocretin neurons after birth could be responsible for narcolepsy.
To test this theory they conducted a neuropathological study involving 16 human brains.
The researchers stained the hypothalamus region of four narcoleptic brains and 12 neurologically normal brains.
The staining revealed the presence of hypocretin neurons and melanin concentrating hormone (MCH) neurons, which are intermixed with hypocretin neurons in the normal brain.
The narcoleptic brains showed a dramatic loss of hypocretin cells, between 85 and 95 percent fewer than the normal brains. There was no marked difference in the number of MCH neurons, showing that it was the loss of hypocretin cells specifically that was significant in the narcoleptic group.
The narcoleptic brains also revealed signs of an inflammatory process called gliosis, which is linked to neuronal degeneration and may explain the loss of the hypocretin cells.
There has been other speculation that an autoimmune process might cause narcolepsy, although no clear evidence for this has been found in human studies.
Dr. Siegel and his colleagues state that autoimmune attacks on the hypocretin neurons or cellular sensitivities to environmental or biological toxins are "reasonable possibilities" for the cause of the degeneration.
The findings suggest that replacement of the missing hypocretin cells may reverse the symptoms of narcolepsy, and this has been recently demonstrated by Dr. Siegel's group in dogs. It is possible that administration of hypocretins to humans with narcolepsy may be an effective treatment.
A similar study led by NINDS grantee Emmanuel Mignot, MD, Ph.D. director of the Center for Narcolepsy at Stanford University Medical Center, will appear in the September 2000 issue of Nature Medicine.
Dr. Mignot's group looked at the role of hypocretins in six narcoleptic brains and also did genetic screening of 74 patients.
In the neuropathology tests, the researchers found that concentrations of hypocretins were "undetectable" in the brain tissue of narcoleptic patients. In the genetic testing, the researchers found a genetic mutation in the hypocretin system of one very severe early onset case of narcolepsy.
However, there was a very low frequency of genetic mutations in the other narcoleptic patients screened.
The authors conclude that, "although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system."
"The results of both of these studies provide dramatic insight into the neurobiology of a very perplexing sleep disorder, and may lead directly to new therapeutic approaches for narcolepsy," said Cheryl Kitt, Ph.D, program director for NINDS.
The NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system. The NINDS is now celebrating its 50th anniversary.