Causes of Narcolepsy

The role of narcoleptic Dobermans and "knockout" mice in researching narcolepsy

Advancement in the understanding of narcolepsy was aided by research done at the Stanford University Sleep Disorders Center Canine Colony (Nishino et al. 2000).
In a study involving 10 narcoleptic Doberman pinschers and 6 control Dobermans, it was discovered that the narcoleptic Dobermans suffered from Sleep Onset REM periods (SOREMPS) (Nishino et al. 2000).

These SOREMPS appeared in the narcoleptic canines within fifteen minutes of lights off. Their appearance experimentally verified the belief that narcolepsy is a disorder of REM sleep generation

The knockout mouse story

This story began interestingly enough with a search for a treatment for obesity (Siegal et al. 2001).
Peptides known as hypocretin-1 and hypocretin-2 (also called orexins in some literature) were selected as a target for research because the genes for hypocretin are expressed in the hypothalamus and the hypothalamus controls appetite.
Researchers created genetic knockout mice that did not produce either hypocretin peptide and found some reduced food intake but also a surprise result:

The knockout mice were experiencing cataplectic seizures, characteristic of narcolepsy! (Siegal et al 2001)
When hypocretin-2 alone was knocked out mice experienced sleep attacks, however when hypocretin-1 alone was knocked out, mice had fewer signs of narcolepsy, suggesting that at least in mice, hypocretin-2 is the primary culprit for cataplexy (Siegal et al 2000).
This study led to the discovery that a massive reduction in hypocretin-containing cells (Hcrt cells) is linked with narcolepsy (Kilduff 2000).

Humans with narcolepsy have since been found to have a 85%-95% reduction in the number of Hcrt-containing cells (Kilduff 2000)

Nature vs. Nurture?

Whether or not a person will have narcolepsy is partially dependent on genetics, but environmental factors play a role as well.
In a study of monozygotic twins, the percentage of twins who were both narcoleptic as opposed to simply one being narcoleptic was 25%-31%, while among first degree relatives the concordant rate of narcolepsy was 1%-2%, still higher than the average of 0.03%-0.16% within the overall population.

These results suggest a genetic component to the disorder, and indeed further studies have shown linkage of narcolepsy to chromosome 4p13-q21 as well as the human leukocyte antigen (HLA) gene DQ6/DQB1*0602 (Nakayama 2000).