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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

Etiology Graph DESKTOP Etiology Graph MOBILE

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
DID YOU KNOW?

Is narcolepsy genetic?

Etiology Graphic
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
Etiology Graphic
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Sleep-Wake State Instability

See how loss of hypocretin leads to unstable boundaries between sleep-wake states.

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Manifestations
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  1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
  2. Bassetti C, Adamantidis A, Burdakov D, et al. Narcolepsy – clinical spectrum, aetiopathophysiology, diagnosis, and treatment. Nat Rev Neurol. 2019;15(9):519-539.
  3. Thannickal T, Nienhuis R, Siegel J. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009;32(8):993-998.
  4. Andlauer O, Moore H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255F.
  5. Drakatos P, Leschziner G. Cataplexy with normal sleep studies and normal CSF hypocretin: an explanation? J Clin Sleep Med. 2016;12(3):449-450.
  6. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  7. 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.
  8. Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31.
  9. 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.
  10. 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.
  11. De la Herran-Arita A, Garcia-Garcia F. Narcolepsy as an immune-mediated disease. Sleep Disord. 2014; 2014:792687. doi: 10.1155/2014/792687
  12. Picchioni D, Hope C, Harsh J. A case-control study of the environmental risk factors for narcolepsy. Neuroepidemiology. 2017;29(3-4):185-192.

Performance of routine tasks without awareness.

Sudden and brief loss of muscle tone, often triggered by strong emotions or certain situations. Narcolepsy with cataplexy is known as narcolepsy type 1.

Complete collapse to the ground; nearly all skeletal muscles are involved.

Only certain muscle groups are involved.

Biological clock mechanism that regulates the 24-hour cycle in the physiological processes of living beings. It is controlled in part by the SCN in the hypothalamus and is affected by the daily light-dark cycle.

Frequent awakenings and inappropriate transitions between states of sleep and wakefulness during nighttime sleep.

The inability to stay awake and alert during the day.

A neurotransmitter in the brain that supports wakefulness.

Vivid, realistic, and sometimes frightening dream-like events that occur when falling asleep.

Also known as orexin. A neuropeptide that supports wakefulness and helps suppress non-REM sleep and REM sleep.

Primary brain region for regulating the timing of sleep-wake states.

Unintentionally falling asleep due to excessive daytime sleepiness. Also known as “sleep attacks.”

Brief, unintentional lapses into sleep or loss of awareness.

A validated objective measure of the tendency to fall asleep in quiet situations.

People living with narcolepsy type 1 have low levels of hypocretin.

Narcolepsy without cataplexy; the cause of narcolepsy type 2 is unknown.

A state of sleep characterized by slower-frequency, more synchronized neuronal activity and decreased muscle tone. Deep stages help to restore the body.

A multiparameter test that monitors physiologic signals during sleep; used as a diagnostic tool in sleep medicine.

A state of sleep characterized by fast-frequency, desynchronized activity on EEG, vivid dreams, and loss of muscle tone. Normally occurs 60-90 minutes after sleep onset. Also known as “paradoxical sleep.”

Brief loss of control of voluntary muscles with retained awareness at sleep-wake transitions.

Sleep-onset REM period.

The VLPO as well as the median preoptic nucleus (MnPO) are located in the hypothalamus and contain essential neurons for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.8,11 Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep.8