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The Etiology of Narcolepsy Type 1 and Narcolepsy Type 2
Most people living with narcolepsy have low levels of CSF hypocretin (also known as orexin).1
In people living with narcolepsy who experience cataplexy (often called narcolepsy type 1), the disorder is usually caused by the selective loss of hypocretin neurons in the hypothalamus. The underlying cause of narcolepsy without cataplexy (often called narcolepsy type 2) is often not known.1
For some patients with narcolepsy type 2, the disorder may result from partial loss of hypocretin neurons.2,3
A retrospective study found that up to a third of patients with narcolepsy type 2 have intermediate to undetectable cerebrospinal fluid (CSF) hypocretin levels. These individuals are more likely to develop cataplexy and subsequently be diagnosed with narcolepsy type 1.1,4 The presence of cataplexy is generally thought to indicate more significant loss of hypocretin neurons.1,5,6
Data from a retrospective study evaluating CSF hypocretin-1 concentrations in patients with narcolepsy type 2 (n=171).4
Mice genetically modified to exhibit hypocretin neuron dysfunction have shown some features reminiscent of narcolepsy type 2 in humans.7
- The mice had increased REM sleep and reduced sleep latency, yet lacked cataplexy and had normal hypocretin cell counts.7
Is narcolepsy genetic?

The loss of hypocretin neurons is likely triggered by an autoimmune response in genetically predisposed people.6,8
- Genetic factors play a key role in the development of narcolepsy.6 Up to 98% of patients with narcolepsy have the human leukocyte antigen (HLA) gene variant HLA-DQB1*0602, compared with 12% to 38% of the general population.1,6
- In a study that analyzed blood samples from individuals with narcolepsy, autoreactive CD4+ memory T cells that target self-antigens expressed by hypocretin neurons were detected inall participants in the study, regardless of the hypocretin deficiency or the presence of HLA subtype DQB1*0602. Hypocretin-specific CD8+ T cells were also detected in some participants in the study.9
- Studies have shown an increased rate of narcolepsy onset following seasonal infections like streptococcus pyogenes, influenza A H1N1 infection, and the H1N1 Pandemrix® vaccine.10-12

Sleep-Wake State Instability
See how loss of hypocretin leads to unstable boundaries between sleep-wake states.
Go deeper »Manifestations
Understand signs and symptoms that reflect underlying sleep-wake state instability. Make the connection »- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
- Bassetti C, Adamantidis A, Burdakov D, et al. Narcolepsy – clinical spectrum, aetiopathophysiology, diagnosis, and treatment. Nat Rev Neurol. 2019;15(9):519-539.
- Thannickal T, Nienhuis R, Siegel J. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009;32(8):993-998.
- Andlauer O, Moore H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255F.
- Drakatos P, Leschziner G. Cataplexy with normal sleep studies and normal CSF hypocretin: an explanation? J Clin Sleep Med. 2016;12(3):449-450.
- Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
- Williams R, Tsunematsu T, Thomas A, Bogyo K, Yamanaka A, Kilduff T. Transgenic archaerhodopsin-3 expression in hypocretin/orexin neurons engenders cellular dysfunction and features of type 2 narcolepsy. J Neurosci. 2019;39(47):9435-9452.
- Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31.
- Latorre D, Kallweit U, Armentani E, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature. 2018;562(7725):63-68.
- Han F, Lin L, Warby S, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70(3):410-417.
- De la Herran-Arita A, Garcia-Garcia F. Narcolepsy as an immune-mediated disease. Sleep Disord. 2014; 2014:792687. doi: 10.1155/2014/792687
- Picchioni D, Hope C, Harsh J. A case-control study of the environmental risk factors for narcolepsy. Neuroepidemiology. 2017;29(3-4):185-192.