A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795). Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784). H1N1 Influenza
Type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. T-cells have been demonstrated to be cross-reactive to both a particular piece of the hemagglutinin flu protein of the pandemic 2009 H1N1 and the amidated terminal ends of the secreted hypocretin peptides.Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.A link between GlaxoSmithKlines H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults. In 2010, Finlands National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by molecular mimicry with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy. Pathophysiology
Loss of neurons
Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. Selective destruction of the HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology.
These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo. Animal models
Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience.The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder. Dog models
Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans.