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Fortschr Neurol Psychiatr 2012; 80(11): 627-634
DOI: 10.1055/s-0031-1299447
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Zur Pathogenese der Narkolepsie: Vom HLA-Typus als Risikoprofil zum Hypocretinmangel als Ursache

Pathogenesis of Narcolepsy: From HLA Association to Hypocretin Deficiency
G. Klein
1   Klinik I für Innere Medizin, Universitätsklinikum Köln
3   Klinik für Neurologie, Hospitalier de Luxembourg
,
L. Burghaus
2   Klinik und Poliklinik für Neurologie, Universitätsklinikum Köln
,
N. Diederich
2   Klinik und Poliklinik für Neurologie, Universitätsklinikum Köln
› Author Affiliations
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Publication History

Publication Date:
13 June 2012 (online)

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Zusammenfassung

Die Narkolepsie ist eine seltene, chronische Schlafkrankheit, die durch eine exzessive Tagesschläfrigkeit charakterisiert ist. Häufig assoziiert sind Kataplexie, Schlaflähmungen sowie hypnagoge oder hypnopompe Halluzinationen. Während der letzten 15 Jahre wurden deutliche Fortschritte beim Verständnis der Pathogenese dieser Erkrankung erreicht. Die wichtigste Erkenntnis hierbei war die Entdeckung der Neuropeptide Hypocretin-1 und -2 (Orexin A und B) im Jahre 1998. Hypocretin-Fasern und deren Rezeptoren sind weit verzweigt im gesamten ZNS vorhanden und spielen eine entscheidende Rolle in der Regulation des Schlaf-Wach-Rhythmus. Sie tragen auch zur Geruchswahrnehmung und zur Steuerung der Nahrungsaufnahme bei. Tiermodelle und Untersuchungen am Menschen belegen, dass das gestörte Hypocretin-System die entscheidende Ursache der Narkolepsie ist. Allerdings bleibt ungeklärt, warum es zum Verlust Hypocretin-produzierender Neurone im posterolateralen Hypothalamus kommt. Da das HLA-Allel DQB1*0602 mit der Narkolepsie assoziiert ist, wäre eine autoimmune Reaktion gegen Hypocretin-Neurone eine mögliche Erklärung. Neu entdeckte Genpolymorphismen sowie bisher unerkannte pathogenetische Mechanismen, die zur Verzahnung des Schlaf-Wach-Rhythmus mit dem Immunsystem beitragen, könnten ebenfalls die Entstehung der Erkrankung begünstigen. Zu nennen ist hier z. B. das „insuline-like growth factor“-bindende Protein 3 (IGFBP3). Dessen Überexpression verursacht eine Down-Regulation der Hypocretin-Produktion. In Zukunft mag der Ersatz der defizienten Neuropeptide durch Hypocretin-Analoga zur kausalen Therapie werden, wenn es gelingen sollte, eine adäquate Applikationsform zu finden. Zurzeit laufen diesbezügliche Tieruntersuchungen und beinhalten Studien zur Gentherapie und zu Zelltransplantationen sowie zu dem Einsatz von Hypocretin-Rezeptor-Agonisten.

Abstract

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.

Schlüsselwörter

Narkolepsie - Hypocretin - HLA-System

Key words

narcolepsy - hypocretin - HLA system
 

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