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

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

• Literatur

• 1 Caffe C. Maladie du sommeil. Journal des connaissances medicales et pharmaceutiques 1862; 29: 323
• 2 Westphal C. Eigentümliche mit Einschlafen verbundene Anfälle. Archiv für Psychiatrie und Nervenkrankheiten 1877; 7: 631-635
• 3 Fischer A. Epileptoide Schlafzustände. Archiv für Psychiatrie und Nervenkrankheiten 1878; 8: 203
• 4 Foot A. Narcolepsy (sudden periodic sleep seizures). Dubl J Med Sci 1866; 82: 165
• 5 Gelineau J. De la narcolepsie. Gaz des Hop 1880; 53: 535-637
• 6 Yoss R, Daly D. Criteria for the diagnosis of the narcolepsy syndrome. Proc Mayo Clin 1957; 3: 320-328
• 7 Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Archives of general psychiatry 1960; 3: 421-428
• 8 Knecht CD, Oliver JE, Redding R et al. Narcolepsy in a dog and a cat. Journal of the American Veterinary Medical Association 1973; 162: 1052-1053
• 9 Juji T, Satake M, Honda Y et al. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue antigens 1984; 24: 316-319
• 10 de Lecea L, Kilduff TS, Peyron C et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America 1998; 95: 322-327
• 11 Sakurai T, Amemiya A, Ishii M et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573-585
• 12 Economo C. Encephalitis lethargica. Klin Wochenschr 1917; 30: 581-585
• 13 Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalography and clinical neurophysiology 1949; 1: 455-473
• 14 Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953; 118: 273-274
• 15 Hublin C, Partinen M, Kaprio J et al. Epidemiology of narcolepsy. Sleep 1994; 17: S7-S12
• 16 Wilner A, Steinman L, Lavie P et al. Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. A study at the serological and genomic level. Human immunology 1988; 21: 15-22
• 17 Ohayon MM, Priest RG, Zulley J et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 2002; 58: 1826-1833
• 18 Mayer G. Taschenatlas spezial: Narkolepsie. Stuttgart: Thieme; 2006
• 19 Narkolepsie. LFSusFd, 1992. DbdTUMn. Symptomatologie und sozialmedizinische Folgen der Narkolepsie. Dissertation bei der Technischen Universität München; 1992
• 20 Heidbreder A, Mueller T, Young P. Klinische Aspekte der Narkolepsie. Klin Neurophysiol 2008; 39: 249-255
• 21 Anic-Labat S, Guilleminault C, Kraemer HC et al. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999; 22: 77-87
• 22 Yoss RE, Daly DD. Narcolepsy. Archives of internal medicine 1960; 106: 168-171
• 23 Parkes JD, Fenton G, Struthers G et al. Narcolepsy and cataplexy. Clinical features, treatment and cerebrospinal fluid findings. The Quarterly journal of medicine 1974; 43: 525-536
• 24 Hishikawa Y. Sleep paralysis. In: Guilleminaut C, Dement WC, Passpouant P, (eds) Narcolepsy. New York: Spectrum; 1976: 97-124
• 25 Roth B. Narcolepsy and Hypersomnia. Basel: Karger; 1980
• 26 Cheyne JA, Rueffer SD, Newby-Clark IR. Hypnagogic and hypnopompic hallucinations during sleep paralysis: neurological and cultural construction of the night-mare. Consciousness and cognition 1999; 8: 319-337
• 27 Ribstein M. Hypnagogic hallucinations. In: Guilleminault C, Dement WC, Passouant P, (eds) Narcolepsy. New York: Spectrum; 1976
• 28 Hishikawa Y, Wakamatsu H, Furuya E et al. Sleep satiation in narcoleptic patients. Electroencephalography and clinical neurophysiology 1976; 41: 1-18
• 29 Montplaisir J, Billiard M, Takahashi S et al. Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Biological psychiatry 1978; 13: 73-89
• 30 Broughton R, Dunham W, Newman J et al. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalography and clinical neurophysiology 1988; 70: 473-481
• 31 Aldrich MS, Hollingsworth Z, Penney JB. Dopamine-receptor autoradiography of human narcoleptic brain. Neurology 1992; 42: 410-415
• 32 Aldrich MS, Prokopowicz G, Ockert K et al. Neurochemical studies of human narcolepsy: alpha-adrenergic receptor autoradiography of human narcoleptic brain and brainstem. Sleep 1994; 17: 598-608
• 33 Kish SJ, Mamelak M, Slimovitch C et al. Brain neurotransmitter changes in human narcolepsy. Neurology 1992; 42: 229-234
• 34 Fruhstorfer B, Mignot E, Bowersox S et al. Canine narcolepsy is associated with an elevated number of alpha 2-receptors in the locus coeruleus. Brain research 1989; 500: 209-214
• 35 Strittmatter M, Isenberg E, Grauer MT et al. CSF substance P somatostatin and monoaminergic transmitter metabolites in patients with narcolepsy. Neuroscience letters 1996; 218: 99-102
• 36 Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Progress in neurobiology 1997; 52: 27-78
• 37 Planelles D, Puig N, Beneto A et al. HLA-DQA, -DQB and -DRB allele contribution to narcolepsy susceptibility. European journal of immunogenetics: official journal of the British Society for Histocompatibility and Immunogenetics 1997; 24: 409-421
• 38 Mignot E, Tafti M, Dement WC et al. Narcolepsy and immunity. Advances in neuroimmunology 1995; 5: 23-37
• 39 Chabas D, Taheri S, Renier C et al. The genetics of narcolepsy. Annual review of genomics and human genetics 2003; 4: 459-483
• 40 Lin L, Faraco J, Li R et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365-376
• 41 Mignot E, Lin L, Rogers W et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. American journal of human genetics 2001; 68: 686-699
• 42 Goel N, Banks S, Mignot E et al. DQB1*0602 predicts interindividual differences in physiologic sleep, sleepiness, and fatigue. Neurology 2010; 75: 1509-1519
• 43 Hallmayer J, Faraco J, Lin L et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature genetics 2009; 41: 708-711
• 44 Langdon N, Welsh KI, van Dam M et al. Genetic markers in narcolepsy. Lancet 1984; 2: 1178-1180
• 45 Matsuki K, Grumet FC, Lin X et al. DQ (rather than DR) gene marks susceptibility to narcolepsy. Lancet 1992; 339: 1052
• 46 Hohjoh H, Terada N, Miki T et al. Haplotype analyses with the human leucocyte antigen and tumour necrosis factor-alpha genes in narcolepsy families. Psychiatry and clinical neurosciences 2001; 55: 37-39
• 47 Okun ML, Giese S, Lin L et al. Exploring the cytokine and endocrine involvement in narcolepsy. Brain, behavior, and immunity 2004; 18: 326-332
• 48 Himmerich H, Beitinger PA, Fulda S et al. Plasma levels of tumor necrosis factor alpha and soluble tumor necrosis factor receptors in patients with narcolepsy. Archives of internal medicine 2006; 166: 1739-1743
• 49 Billiard M, Laaberki M, Reygrobellet C et al. Elevated antibodies to streptococcal antigens in narcoleptic subjects. Sleep Res 1989; 18
• 50 Billiard M. Narcolepsy-cataplexy. Schweizer Archiv für Neurologie und Psychiatrie 1989; 140: 249-253
• 51 Aran A, Lin L, Nevsimalova S et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009; 32: 979-983
• 52 Cvetkovic-Lopes V, Bayer L, Dorsaz S et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. The Journal of clinical investigation 2010; 120: 713-719
• 53 Peraita-Adrados R, Ezpeleta D, Balas A et al. Narcolepsy-cataplexy syndrome associated with DRB1*0806-DQB*0602 haplotype in a Caucasian patient. Sleep research online: SRO 1999; 2: 29-31
• 54 Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Annals of neurology 1992; 32: 3-10
• 55 Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region. Journal of neuroimmunology 2001; 117: 9-20
• 56 Pablos JL, del Rincon E, Francisco F et al. Narcolepsy in systemic lupus erythematosus. The Journal of rheumatology 1993; 20: 375-376
• 57 Baba T, Nakashima I, Kanbayashi T et al. Narcolepsy as an initial manifestation of neuromyelitis optica with anti-aquaporin-4 antibody. Journal of neurology 2009; 256: 287-288
• 58 Black 3rd JL , Silber MH, Krahn LE et al. Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 2005; 28: 427-431
• 59 Tanaka S, Honda Y, Inoue Y et al. Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep 2006; 29: 633-638
• 60 Honda M, Arai T, Fukazawa M et al. Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy. Neurology 2009; 73: 511-517
• 61 Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 2009; 32: 993-998
• 62 Kawashima M, Tamiya G, Oka A et al. Genomewide association analysis of human narcolepsy and a new resistance gene. American journal of human genetics 2006; 79: 252-263
• 63 Miyagawa T, Kawashima M, Nishida N et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nature genetics 2008; 40: 1324-1328
• 64 Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50: S16-S22
• 65 WHO. Statement of the WHO. WHO; 2011 http://www.who.int/vaccine_safety/topics/influenza/pandemic/h1n1_safety_assessing/narcolepsy_statement/en/index.html
• 66 Force NNT. Interim Report. 31.01.2011
• 67 Han F, Lin L, Warby SC et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Annals of neurology 2011; 70: 410-417
• 68 Caillol M, Aioun J, Baly C et al. Localization of orexins and their receptors in the rat olfactory system: possible modulation of olfactory perception by a neuropeptide synthetized centrally or locally. Brain research 2003; 960: 48-61
• 69 Peyron C, Tighe DK, van den Pol AN et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. The Journal of neuroscience: the official journal of the Society for Neuroscience 1998; 18: 9996-10015
• 70 Trivedi P, Yu H, MacNeil DJ et al. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438: 71-75
• 71 Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends in neurosciences 2000; 23: 359-365
• 72 Silber MH, Rye DB. Solving the mysteries of narcolepsy: the hypocretin story. Neurology 2001; 56: 1616-1618
• 73 Hara J, Beuckmann CT, Nambu T et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001; 30: 345-354
• 74 van den Pol AN, Gao XB, Obrietan K et al. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. The Journal of neuroscience: the official journal of the Society for Neuroscience 1998; 18: 7962-7971
• 75 Chemelli RM, Willie JT, Sinton CM et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 437-451
• 76 Chemelli RM, Sinton CM, Yanagisawa M. Polysomnographic characterization of orexin-2 receptor knockout mice. Sleep 2000; 23: 296-297
• 77 Willie JT, Chemelli RM, Sinton CM et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 2003; 38: 715-730
• 78 Peyron C, Faraco J, Rogers W et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature medicine 2000; 6: 991-997
• 79 Thannickal TC, Moore RY, Nienhuis R et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469-474
• 80 Honda M, Eriksson KS, Zhang S et al. IGFBP3 colocalizes with and regulates hypocretin (orexin). PloS one 2009; 4: e4254
• 81 De La Herran-Arita AK, Zomosa-Signoret VC, Millan-Aldaco DA et al. Aspects of the narcolepsy-cataplexy syndrome in O/E3-null mutant mice. Neuroscience 2011; 183: 134-143
• 82 Mignot E, Lammers GJ, Ripley B et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Archives of neurology 2002; 59: 1553-1562
• 83 Nishino S, Ripley B, Overeem S et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39-40
• 84 Dalal MA, Schuld A, Haack M et al. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology 2001; 56: 1749-1751
• 85 Bassetti C, Gugger M, Mathis J et al. Cerebrospinal fluid levels of hypocretin (orexin) in Hypersomnolent patients without cataplexy. Actas Fisiolog 2001; 7: 205
• 86 Khatami R, Maret S, Werth E et al. Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 2004; 363: 1199-1200
• 87 Gerashchenko D, Murillo-Rodriguez E, Lin L et al. Relationship between CSF hypocretin levels and hypocretin neuronal loss. Experimental neurology 2003; 184: 1010-1016
• 88 Oka Y, Inoue Y, Kanbayashi T et al. Narcolepsy without cataplexy: 2 subtypes based on CSF hypocretin-1/orexin-A findings. Sleep 2006; 29: 1439-1443
• 89 Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacological reviews 2009; 61: 162-176
• 90 Mieda M, Willie JT, Hara J et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proceedings of the National Academy of Sciences of the United States of America 2004; 101: 4649-4654
• 91 Liu M, Thankachan S, Kaur S et al. Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. The European journal of neuroscience 2008; 28: 1382-1393
• 92 Mignot E, Nishino S. Emerging therapies in narcolepsy-cataplexy. Sleep 2005; 28: 754-763
• 93 Deadwyler SA, Porrino L, Siegel JM et al. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. The Journal of neuroscience: the official journal of the Society for Neuroscience 2007; 27: 14239-14247
• 94 Herold KC, Hagopian W, Auger JA et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. The New England journal of medicine 2002; 346: 1692-1698
• 95 Herold KC, Gitelman S, Greenbaum C et al. Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin Immunol 2009; 132: 166-173
• 96 Keymeulen B, Vandemeulebroucke E, Ziegler AG et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. The New England journal of medicine 2005; 352: 2598-2608