Causes

Narcolepsy is a neurological sleep disorder. It is not caused by mental illness or psychological problems. It is most likely the end result of a number of genetic abnormalities that affect specific biologic factors in the brain, coupled with an environmental trigger such as a virus.

Researchers are attempting to come up with a unifying theory involving genetic factors, autoimmunity, and deficiencies in hypocretin, a brain peptide that is important in regulating sleep. Most of the research conducted on narcolepsy uses dogs that have genetic factors that cause narcolepsy, but such studies are helping researchers find the biologic bases to this strange and distressing condition.

Hypocretin and Other Chemicals in the Brain

Hypocretin. Hypocretin (also called orexin) is a peptide that modulates activity in the hypothalamus (the region in the brain associated with sleep, well being, and appetite). Hypocretin specifically has properties that promote wakefulness and inhibits REM sleep. Hypocretin may also have other actions that affect feeding behavior and increase activity in the autonomic (sympathetic) nervous system and systems that regulate motor control. Deficiencies in this peptide have been observed in most patients with narcolepsy who also have cataplexy. Deficiencies might set off the following chemical responses that may produce sleep attacks:

• Lower levels of histamine, a chemical that promotes wakefulness
• Low levels of epinephrine (commonly known as adrenaline), a hormone important in alertness and arousal
• Increase in acetylcholine, which affects REM sleep
• Changes in the enzyme monoamine oxidase, which is believed to be important in preventing arousal
• Changes in dopamine, an important neurotransmitter (chemical messenger in the brain) that helps regulate sleep
• Lower levels of leptin, a hormone associated with obesity when levels decline; (people with narcolepsy tend to be overweight.
• Higher-than-normal secretion of growth-hormone during the day, which may play a role in sudden falling-asleep episodes

Genetic Factors

Narcolepsy has a genetic component and tends to run in families. Experts estimate that around 8 – 10% of people with narcolepsy have a close relative who has the disorder. A 2006 study reported that the risk for narcolepsy among male first-degree relatives (parents or sibling) was 105 times higher than the general population; the risk for female first-degree relatives was 54 times higher. Other studies suggest that people who have a first-degree relative with narcolepsy are 20 – 40 times more likely to have narcolepsy than other people.

However, most experts agree that genetics are not the only factor involved in narcolepsy. Narcolepsy most likely involves a combination of genetics and one or more environmental triggers such as infection, trauma, hormonal changes, immune system problems or stress. Researchers are looking for specific genetic mutations that may make individuals susceptible to this disorder.

Autoimmunity

It has been theorized that narcolepsy may be an autoimmune disease, in which the immune system may be tricked into perceiving its own proteins to be antigens. (Antigens are foreign substances targeted for attack by immune factors in the body.)

An antigen is a substance that can provoke an immune response.

Important autoimmune diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. In such diseases, the immune system overproduces potent factors called cytokines, which cause inflammation and injury in the susceptible cells and tissues affected by the disease. Most autoimmune diseases also tend to afflict those with particular genetically determined molecules of the immune system called human leukocyte antigens (HLAs).

Experts suggest that an immune attack in narcolepsy may occur against cells containing the brain peptide hypocretin (orexin), resulting in deficiencies that are now believed to be major components of the narcolepsy process. HLAs, particularly a subgroup known as (HLA)DQB1-0602, have been strongly associated with narcolepsy and low levels of hypocretin. Narcolepsy patients who carry this HLA group tend to have a specific syndrome of symptoms that include cataplexy and periodic limb movement disorder. However, between 20% and 40% of people without narcolepsy carry these HLA types.

An important research report, published in 2004 in The Lancet, provided the first concrete evidence that autoimmunity may play a role in narcolepsy. The study’s research team seem to have identified an autoantibody associated with narcolepsy. The researchers injected mice with antibodies taken from patients with narcolepsy. All patients carried the (HLA)DQB1-0602 genotype. Mice were also injected with antibodies from healthy patients. Only the antibodies from patients with narcolepsy produced narcolepsy-type neuromuscular responses.

The results suggested that the antibodies triggered an autoimmune response that affected the hypocretin system. Scientists hope that this autoantibody may prove to be a diagnostic biomarker and that a blood test can eventually be developed to accurately diagnose narcolepsy. In addition to new diagnostic tests, this research may pave the way for immunomodulatory drugs that could prevent hypocretin depletion. However, other research has yet to conclusively establish a link between narcolepsy and autoimmunity.