Narcolepsy is a chronic, debilitating sleep disorder first described in the late 19th century which is characterized by excessive daytime sleepiness, cataplexy i.e. sudden transient muscular weakness, disturbed night sleep and sleep paralysis. Narcolepsy is caused by deficiencies in hypothalamic hypocretin (also known as orexin) neurotransmission, most likely through autoimmune-mediated postnatal cell death of hypocretin producing neurons. Hypocretin is a neuropeptide hormone that is responsible for for controlling appetite and sleep patterns.
Prevalence studies have shown that genetic factors play a role on narcolepsy but are neither necessary nor sufficient to cause narcolepsy. Twin studies show that only 25 – 30% of twins are concordant. Family studies show that the risk of developing narcolepsy for a first degree relative of a patient is only 1 – 2%. This is however 30 – 40 times higher than the estimated prevalence of narcolepsy in the general population, showing that genetic heritability does play a role. One of the most important predisposing genetic factors is the HLA-DQB1*06:02 allele on the DRB1*15:01 – DQA1*01:02 – DQB1*06:02 haplotype. Between 85 and 95% of narcolepsy patients with cataplexy carry this haplotype. Persons homozygous for HLA-DQB1*06:02 carry a greater risk than heterozygous persons, though persons heterozygous for HLA-DQB1*03:01 and HLA-DQB1*06:02 are also at increased risk. HLA-DQB1*05:01 and DQB1*06:01 are thought to be protective for narcolepsy. HLA-DQB1*06:02 has a larger P4 pocket which would facilitate binding of larger hydrophobic residues compared to HLA-DQB1*06:01 and this may help explain the opposite effects these two allele have on narcolepsy susceptibility.
The genetic risk of developing narcolepsy is not however fully explained by HLA-DQB1*06:02 as there are many patients with narcolepsy who do not carry HLA-DQB1*06:02, pointing to the possibility of non HLA gene involvement. Candidate genes include the different hypocretin system genes, though initial studies have not shown an association and TNFα gene polymorphisms.
Genetic testing for narcolepsy, particularly, HLA-DQB1*06:02 typing is useful as an aid to diagnosis in patients with cataplexy but the association is not specific as there are many narcolepsy patients with HLA-DQB1*06:02 and many HLA-DQB1*06:02 persons who do not have narcolepsy.
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