May 4, 2009 - Research

Genetic Study Strengthens Case For Autoimmune Cause of Narcolepsy

Stanford researchers are also studying narcoleptic dogs.

Ten years ago, the daytime drowsiness, irregular nighttime sleep and sudden loss of muscle tone and strength associated with narcolepsy were traced to the lack of a protein called hypocretin.   Further research showed that narcoleptics’ brains are missing the cells that produce this important wakefulness-promoting hormone.

Scientists didn’t know exactly why the hypocretin-secreting cells were missing in the brains of narcoleptics, but they did have a hunch.   More than 90% of people with narcolepsy carry a particular variation in an immune molecule that helps the body distinguish itself from foreign invaders like bacteria and viruses.   This led some researchers to suggest that narcolepsy is an autoimmune disease.

But 20% of people without narcolepsy also carry the immune molecule variation, indicating that there must be other genetic and/or environmental factors at work.  Now a new report, published online yesterday in the journal Nature Genetics, adds more evidence to the autoimmune theory of narcolepsy by showing that variations in another immune-related gene are also associated with this condition that affects about one out of every 2,000 people.

In a sample of approximately 1,800 people (about 800 with narcolepsy and 1,000 without), all with European ancestry and all carrying the immune molecule variation found in most narcoleptics, researchers led by Stanford’s Emmanuel Mignot found that variations in the TRA@ gene, which encodes a receptor found on specialized immune cells called T cells, are associated with narcolepsy.

The scientists confirmed their findings in a second group of Caucasians, as well as in Asian (Japanese and Korean) and African American samples, although the size of the African American sample was too small for statistically significant data to be gathered. In a statement, Mignot said that he thinks it is likely that the T cell receptor variations identified in this study and the immune molecule variation previously found in narcoleptics interact to kill hypocretin-secreting cells, but that more research will be needed to understand exactly how this happens.   He went on to say that once these interactions are understood, scientists might be able to identify people at risk for narcolepsy and perhaps stop development of the disease.

In addition to shedding light on the biology of narcolepsy, the authors of the study think their findings will help researchers studying other autoimmune diseases such as multiple sclerosis and type 1 diabetes.

“I’m sure immunologists are going to be very excited.   If we can work out what happens specifically in patients with narcolepsy, we’ll be able to better understand the role of T cells in other autoimmune diseases that are more complicated and difficult to detect,” Mignot said in a statement.

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