[Pathogenesis of narcolepsy: from HLA association to hypocretin deficiency].

Narcolepsy is a rare and chronic sleep disorder, characterised by excessive daytime sleepiness. Frequently associated signs are cataplexy, sleep paralysis and hypnagogic or hypnopompic hallucinations. Advances in understanding the pathogenesis of the disease have essentially been elucidated during the last fifteen years. The most significant finding has been the discovery of hypocretin-1 and -2 in 1998. Hypocretin-containing cells have widespread projections throughout the entire CNS and play a crucial role in the regulation of the sleep-wake cycle. They also contribute to olefaction and to the regulation of food intake. Animal models and human studies concordantly show that the disturbed hypocretin system is the probable cause of narcolepsy. However, it remains unclear why there is neuronal death of hypocretin-producing cells in the lateral hypothalamus. As the HLA-allele DQB1*0602 is associated with narcolepsy and hypocretin deficiency, an autoimmune reaction against hypocretin-producing neurons has been vigorously discussed. Newly discovered gene polymorphisms as well as previously unknown pathogenetic mechanisms, linking the sleep-wake cycle with the immune system, may also contribute to the pathogenetic cascade. Worthy of mention in this context is, e.g., the "insulin-like growth factor"-binding protein 3 (IGFBP3), whose overexpression causes a down-regulation of the hypocretin production. Substitution of the deficient neuropeptides by hypocretin agonists may become the causal treatment strategy of the future, if an adequate administration route can be found. Presently, animal trials, including genetic therapy, cell transplantations or the administration of hypocretin receptor agonists, are underway.
AuthorsG Klein, L Burghaus, N Diederich
JournalFortschritte der Neurologie-Psychiatrie (Fortschr Neurol Psychiatr) Vol. 80 Issue 11 Pg. 627-34 (Nov 2012) ISSN: 1439-3522 [Electronic] Germany
Vernacular TitleZur Pathogenese der Narkolepsie: Vom HLA-Typus als Risikoprofil zum Hypocretinmangel als Ursache.
PMID22696207 (Publication Type: English Abstract, Journal Article, Review)
Copyright© Georg Thieme Verlag KG Stuttgart · New York.
Chemical References
  • HCRT protein, human
  • HLA Antigens
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Neurotransmitter Agents
  • Orexins
  • Animals
  • Disease Models, Animal
  • HLA Antigens (genetics, physiology)
  • Humans
  • Hypothalamus, Middle (metabolism, physiology)
  • Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, cerebrospinal fluid, deficiency, genetics, physiology)
  • Narcolepsy (diagnosis, drug therapy, epidemiology, genetics, physiopathology)
  • Neuropeptides (antagonists & inhibitors, cerebrospinal fluid, deficiency, genetics, physiology)
  • Neurotransmitter Agents (physiology)
  • Orexins

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