What causes narcolepsy?

The exact cause of all forms of narcolepsy remain unknown but for a sizable group on sufferers 2010 proved to be an interesting year. Scientists and the medical community have for the last decade believed that the reduction of a neuropeptide called orexin or hypocretin (it's the same, but was discovered by two groups at the same time and given different names) is a major culprit in causing narcolepsy.

In 2010 the University of Lucerne and Geneva found what was causing the reduction in orexin; it's an auto immune response to something called a tribble, or to be exact a trib 2 antibody. These anti trib 2 antibodies kill areas of the brain that produce orexin/hypocretin, the stuff that regulates sleep. This in turn triggers narcolepsy and particularly narcolepsy with cataplexy.

Scientists have suspected for years that an anti-self immune response, known as autoimmunity, played a major role in narcolepsy. The problem was no one had been able to find what was causing the abnormal response. Until the scientist in Switzerland genetically engineered mice to overproduce tribbles. They found that orexin producing cells made a large amount of a specific type of tribble - Trib 2. The researchers then tested people and found that those with narcolepsy, but not other people, had a lot of antibodies against Trib 2.

The results indicate that Trib 2 specific antibodies target orexin/hypocretin producing neurons in the hypothalamus and kill them. If it runs its full course the Trib 2 antibodies kill all the neurons and this leads to orexin/hypocretin deficiency.

While important for many patients, these findings do not explain why some can have narcolepsy and still retain hypocretin production. The autoimmunity is important but it isn’t behind all forms of narcolepsy.
 

Sleep-wake cycle and the role of hypocretin

  • It is known that severe disruption of the normal sleep-wake cycle is responsible for the symptoms in narcolepsy. Abnormalities of REM or dream sleep are particularly important
  • A neuropeptide known as hypocretin or orexin is normally responsible for controlling the sleep-wake cycle by maintaining stable wakefulness and preventing the onset of sleep during the day
  • The cells containing hypocretin are found in an area of the brain known as the hypothalamus and extend to other parts of the brain that are known to be involved in wake and sleep regulation
  • Most narcolepsy sufferers, however, have undectectable or low levels of hypocretin which leads to the disruption of the sleep-wake cycle
  • The low number of cells containing hypocretin has been proved to be caused by the body's immune system that normally attacks infections destroying the hypocretin cells by mistake and that narcolepsy is a so-called autoimmune disease.
  • It is rare for narcolepsy to run in families although a normal variation in a subjects chromosomes may confer a higher risk of developing the disease