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Every individual with narcolepsy shows some degree of excessive daytime sleepiness, with a tendency to doze off when sedentary in school, at work, or even when driving. Most people with narcolepsy feel rested when they wake in the morning or after a nap, but within a few hours, they feel as sleepy as a healthy person would feel if awake for the entire night. Narcolepsy affects about 1 in 2.000 people in the United States and Europe.

In addition to excessive daytime sleepiness, most people with narcolepsy also have symptoms indicative of abnormal rapid eye movement (REM) sleep. REM sleep is normally characterized by dreaming and muscle paralysis that prevents an individual from acting out their dreams. In narcolepsy, REM sleep can occur at any time of day. A very distinctive symptom of narcolepsy is cataplexy: sudden muscle paralysis triggered by strong, generally positive emotions, such as when laughing or unexpectedly meeting a friend. The muscle weakness of cataplexy usually begins in the face and neck and then sometimes spreads to the trunk and limbs; in severe episodes, an individual may slump to the ground, conscious yet unable to speak or move for a minute or two.

Narcolepsy has been studied for almost 150 years, but only in the past 20 years has the underlying cause become clear. In 1998, two research groups independently discovered orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively), small neuropeptides produced solely by neurons in the lateral hypothalamus. Derived from a precursor protein (prepro-orexin), orexin A and orexin B have excitatory effects on postsynaptic neurons via the orexin 1 receptor (OX1R) and OX2R. Soon after, researchers found that narcolepsy is caused by a highly selective and severe loss of the orexin neurons that results in low levels of orexins in the brain and cerebrospinal fluid (CSF). This discovery spurred the recognition of two types of narcolepsy: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). The classic phenotype, NT1, is characterized by chronic sleepiness plus cataplexy, and CSF orexin levels in this disorder are very low or undetectable, owing to a severe loss of the orexin neurons. NT2 has generally less severe symptoms, and 90% of patients have normal CSF orexin levels. NT2 affects up to half of all narcolepsy patients and may be caused by a partial loss of the orexin neurons.

Narcolepsy is caused by the selective destruction of the orexin-producing neurons. What kills the orexin-producing neurons remains a major mystery, but several lines of evidence suggest that NT1 is an autoimmune disease mediated by T cells.

HLA alleles strongly influence the development of narcolepsy. More than 90% of individuals with NT1 bear the HLA class II allele DQB1*06:02. The DQB1*06:02 allele increases the risk of developing NT1 200-fold — the strongest known association of an HLA with any disease — and NT1 rarely develops in people lacking this allele. People who are homozygous for this allele have twice the risk of developing NT1 as those who are heterozygous.

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