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The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin\/orexin ligand and its receptor. Mutations in hypocretin\u2010related genes are rare in humans, but hypocretin ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is probably due to the post\u2010natal cell death of hypocretin neurones. Although a close association between human leucocyte antigen (HLA) and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proved. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune\u2010mediated neurological disorders, such as Guillain\u2013Barre syndrome, MA2\u2010positive paraneoplastic syndrome and neuromyelitis optica (NMO)\u2010related disorder. The findings in symptomatic narcoleptic cases may have significant clinical relevance to the understanding of the mechanisms of hypocretin cell death and choice of treatment option. The discoveries in human cases lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid hypocretin\u20101 levels for \u2018narcolepsy with cataplexy\u2019 and \u2018narcolepsy due to medical condition\u2019). As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.<\/jats:p>","DOI":"10.1111\/j.1748-1716.2009.02012.x","type":"journal-article","created":{"date-parts":[[2009,6,25]],"date-time":"2009-06-25T14:34:09Z","timestamp":1245940449000},"page":"209-222","source":"Crossref","is-referenced-by-count":61,"title":["Hypocretin\/orexin and narcolepsy: new basic and clinical insights"],"prefix":"10.1111","volume":"198","author":[{"given":"S.","family":"Nishino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Okuro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Kotorii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Anegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Ishimaru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Matsumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Kanbayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,1,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/49.3.257"},{"key":"e_1_2_12_3_1","first-page":"61","article-title":"Comparative analysis of the structure and function of TNF\u2010alpha and TNF\u2010beta","volume":"56","author":"Aggarwal B.B.","year":"1992","journal-title":"Immunol Ser"},{"key":"e_1_2_12_4_1","first-page":"1","volume-title":"Loss, Grief and Care: Psychosocial Aspects of Narcolepsy","author":"Alaila S.L.","year":"1992"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.39.11.1505"},{"key":"e_1_2_12_6_1","first-page":"620","article-title":"Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy","volume":"20","author":"Aldrich M.S.","year":"1997","journal-title":"Sleep"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1252"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/27.8.1465"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00415-009-0139-4","article-title":"Narcolepsy as an initial manifestation of neuromyelitis optica with anti\u2010aquaporin 4 antibody","volume":"256","author":"Baba T.","year":"2008","journal-title":"J Neurol"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-194807000-00001"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199310001-00003"},{"key":"e_1_2_12_12_1","first-page":"201","article-title":"Elevated antibodies to streptococcal antigens in narcoleptic subjects","volume":"18","author":"Billiard M.","year":"1989","journal-title":"Sleep Res"},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1093\/sleep\/25.7.719","article-title":"Search for neuron\u2010specific and non\u2010neuron\u2010specific antibodies in narcoleptic patients with and without HLA DQB1*0602","volume":"25","author":"Black J.L.","year":"2002","journal-title":"Sleep"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.04.026"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000175219.01544.c8"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81973-X"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000168173.71940.ab"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4000911"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60237-2"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.322"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1999.276.4.R1018"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005053-193003000-00001"},{"key":"e_1_2_12_23_1","doi-asserted-by":"crossref","unstructured":"Von Economo C.1931.Encephalitis lethargica: its sequelae and treatment. 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