STUDY OBJECTIVES: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. SETTINGS: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). DESIGN: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. MEASUREMENTS AND RESULTS: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. CONCLUSIONS: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

Center for Sleep Sciences and Medicine and Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Palo Alto CA

Center for Sleep Sciences and Medicine and Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Palo Alto CA and Institute of Human Genetics Technische Universität München Munich Germany and Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Danish Center for Sleep Medicine Department of Clinical Neurophysiology Glostrup Hospital University of Copenhagen Denmark

Danish Center for Sleep Medicine Department of Clinical Neurophysiology Glostrup Hospital University of Copenhagen Denmark and Norwegian Resource Center for ADHD TS and Narcolepsy Oslo University Hospital Ullevål Norway

Department of Biomedical and Neuromotor Sciences University of Bologna and IRCCS Institute of Neurological Sciences Bologna Italy

Department of Neurology Charles University Prague 1st Faculty of Medicine Czech Republic

Department of Pathology Stanford University School of Medicine Stanford CA

Department of Pulmonary Medicine the Peking University People's Hospital Beijing China

Institute of Human Genetics Technische Universität München Munich Germany and Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Stanford Genome Technology Center Stanford University Palo Alto CA

See more in PubMed

Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355:39–40. PubMed

Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553–62. PubMed

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. Nat Med. 2000;6:991–7. PubMed

Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013;23:767–73. PubMed PMC

Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70:410–7. PubMed

Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7:e33723. PubMed PMC

Han F, Faraco J, Dong XS, et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 2013;9:e1003880–e. PubMed PMC

Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLADQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens. 1998;51:96–100. PubMed

Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686–99. PubMed PMC

Han F, Lin L, Li J, et al. HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens. 2012;80:328–35. PubMed

Alaez C, Lin L, Flores AH, et al. Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1 in Mexican patients: a relationship between HLA and gender is suggested. BMC Med Genet. 2008;9:79. PubMed PMC

Roh EY, Park MH, Park H, et al. Association of HLA-DR and -DQ genes with narcolepsy in Koreans: comparison with two control groups, randomly selected subjects and DRB1*1501-DQB1*0602--positive subjects. Hum Immunol. 2006;67:749–55. PubMed

Hong SC, Lin L, Lo B, et al. DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans. Hum Immunol. 2007;68:59–68. PubMed

Hohjoh H, Terada N, Honda Y, Juji T, Tokunaga K. Negative association of the HLA-DRB1*1502-DQB1*0601 haplotype with human narcolepsy. Immunogenetics. 2001;52:299–301. PubMed

Tafti M, Hor H, Dauvilliers Y, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 2014;37:19–25. PubMed PMC

Weiner Lachmi K, Lin L, Kornum BR, et al. DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status. Hum Immunol. 2012;73:405–10. PubMed PMC

Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733–6. PubMed

Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003;74:1667–73. PubMed PMC

Hong SC, Lin L, Jeong JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep. 2006;29:1429–38. PubMed

Heier MS, Evsiukova T, Vilming S, Gjerstad MD, Schrader H, Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep. 2007;30:969–73. PubMed PMC

Martinez-Rodriguez JE, Sabater L, Graus F, Iranzo A, Santamaria J. Evaluation of hypothalamic-specific autoimmunity in patients with narcolepsy. Sleep. 2007;30:27–8. PubMed

Knudsen S, Jennum PJ, Alving J, Sheikh SP, Gammeltoft S. Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population. Sleep. 2010;33:169–76. PubMed PMC

Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13:1035–48. PubMed

Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol. 2008;7:649–62. PubMed

Singh M, Drake CL, Roth T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep. 2006;29:890–5. PubMed

Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain. 2006;129:1609–23. PubMed

Aldrich MS, Chervin RD, Malow BA. Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep. 1997;20:620–9. PubMed

Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med. 2013;9:789–95. PubMed PMC

Nevsimalova S, Roth B, Zouhar A, Zemanova H. The occurrence of narcolepsy—cataplexy and periodic hypersomnia in early childhood. In: Koella WP, Obal F, Schulz H, Visser P, editors. Sleep ‘86. New York: Gustav Fisher Verlag; 1988. pp. 399–401.

Dong XS, Ma SF, Cao CW, et al. Hypocretin (orexin) neuropeptide precursor gene, HCRT, polymorphisms in early-onset narcolepsy with cataplexy. Sleep Med. 2013;14:482–7. PubMed

Olafsdottir BR, Rye DB, Scammell TE, Matheson JK, Stefansson K, Gulcher JR. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology. 2001;57:1896–9. PubMed

Faraco J, Mignot E. Genetics of narcolepsy. In: Pack AI, editor. Genetics of sleep and its disorders. Philadelphia, PA: Saunders Elsevier; 2011. pp. 217–28.

Hor H, Bartesaghi L, Kutalik Z, et al. A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am J Hum Genet. 2011;89:474–9. PubMed PMC

Eguibar JR, Cortes Mdel C. [The myelin mutant taiep as a model for abscence crisis] Gac Med Mex. 2010;146:11–8. PubMed

Prieto GJ, Urba-Holmgren R, Holmgren B. Sleep and EEG disturbances in a rat neurological mutant (taiep) with immobility episodes: a model of narcolepsy-cataplexy. Electroencephalogr Clin Neurophysiol. 1991;79:141–7. PubMed

Eguibar JR, Cortes Mdel C, Lara-Lozano M. Presynaptic dopaminergic agonists increased gripping-generated immobility episodes in the myelin-mutant taiep rat. Neurosci Lett. 2010;483:189–92. PubMed

Winkelmann J, Lin L, Schormair B, et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet. 2012;21:2205–10. PubMed PMC

Dalal MA, Schuld A, Pollmacher T. Undetectable CSF level of orexin A (hypocretin-1) in a HLA-DR2 negative patient with narcolepsy-cataplexy. J Sleep Res. 2002;11:273. PubMed

Guilleminault C, Grumet C. HLA-DR2 and narcolepsy: not all narcolepticcataplectic patients are DR2. Hum Immunol. 1986;17:1–2. PubMed

Knudsen S, Biering-Sorensen B, Kornum BR, et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology. 2012;79:102–3. PubMed

Kanbayashi T, Shimohata T, Nakashima I, et al. Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications. Arch Neurol. 2009;66:1563–6. PubMed

Wang C, Krishnakumar S, Wilhelmy J, et al. High-throughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci U S A. 2012;109:8676–81. PubMed PMC

Pedroso JL, Povoas Barsottini OG, Lin L, Melberg A, Oliveira AS, Mignot E. A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient. Sleep. 2013;36:1257–9. PubMed PMC

Diaz-Pena R, Lopez-Vazquez A, Lopez-Larrea C. Old and new HLA associations with ankylosing spondylitis. Tissue Antigens. 2012;80:205–13. PubMed

van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:323–39. PubMed

Kooy-Winkelaar Y, van Lummel M, Moustakas AK, et al. Gluten-specific T cells cross-react between HLA-DQ8 and the HLA-DQ2alpha/DQ8beta transdimer. J Immunol. 2011;187:5123–9. PubMed

Kwok WW, Nepom GT. Structural and functional constraints on HLA class II dimers implicated in susceptibility to insulin dependent diabetes mellitus. Baillieres Clin Endocrinol Metab. 1991;5:375–93. PubMed

Kwok WW, Kovats S, Thurtle P, Nepom GT. HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation. J Immunol. 1993;150:2263–72. PubMed

Treatment cost of narcolepsy with cataplexy in Central Europe