Center for Narcolepsy

News

Recent findings made by the center are highlighted, together with a brief explanation. For pdf files, please go to the publications section on this site.

Alberto K. De la Herrán-Arita, Birgitte Rahbek Kornum, Josh Mahlios, Wei Jiang3, Ling Lin1, Tieying Hou, Claudia Macaubas, Mali Einen, Giuseppe Plazzi, Catherine Crowe, Evan W. Newell, Mark M. Davis, Elizabeth D. Mellins, and Emmanuel Mignot.  CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci Transl Med 18 December 2013, Vol. 5, Issue 216, p. 216ra176 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007762. Pulished in the journal of Science Translational Medicine 2013. In this breakthrough study we identified circulating immune T cells that react to hypocretin, together with a specific protein target of the autoimmune attack, conclusively demonstrating the autoimmune basis for the disease in a process called molecular mimicry.

Han F, Faraco J, Dong XS, Ollila HM, Lin L, et al. (2013) 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 9(10): e1003880. doi:10.1371/journal.pgen.1003880 Published in PLoS Genet. 2013. In this important study done in collaboration with China, we identify new susceptibility genes for the disease, including the beta chain of the T cell receptor, ZNF365, and IL10RB-IFNAR1.  We also identify HLA DQB1*03:01 as a major factor modulating age of disease onset  of narcolepsy (associated with onset nearly two years sooner). Most interestingly, we found  that frequencies of selected HLA-associated markers differed significantly in cases with onset after the recent influenza pH1N1 pandemic.   We suggest that monitoring the genetic architecture of autoimmune disorders across time could help pinpoint to the appearance of novel environmental triggers.  

Faraco J, Lin L, Kornum BK, Kenny EE, Trynka G,  Einen M, Rico TJ, Lichtner P, Dauvilliers Y, Arnulf I, Lecendreux M, Javidi S, Geisler P, Mayer G, Pizza F, Poli F, Plazzi G, Overeem S Lammers GJ,  Kemlink D, Sonka K, Nevsimalova S, Rouleau G, Desautels A, Montplaisir J, Frauscher B, Ehrmann L, Högl B, Jennum P, Bourgin P, Peraita-Adrados R, Iranzo A, Bassetti C, Chen WM, Concannon P, Thompson SD, Damotte V, Fontain B, Breban M, Gieger C, Klopp N, Deloukas P, Wijmenga C, Hallmayer J, Onengut-Gumuscu S, Rich SS, Winkelmann J, Mignot E. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. Plos Genetics, 2013;9(2):e1003270. doi: 10.1371/journal.pgen.1003270. Epub 2013 Feb 14.  This world-wide collaborative study identifies two new narcolepsy susceptibility genes related to autoimmunity.  Published in PLoS Genet. 2013.

Andlauer O, Moore H, Jouhier L, Drake C, Peppard PE, Han F, Hong SH, Poli F, Plazzi G O’Hara R, Haffen E, Roth T, Young T, Mignot E.  Nocturnal REM sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA neurology, 2013 Jul;70(7):891-902. doi: 10.1001/jamaneurol.2013.1589. The study shows that short REM latency on nocturnal sleep polysomnography can be used instead of the Multiple Sleep Latency Test (MSLT) to diagnose narcolepsy and predict hypocretin/orexin deficiency.  Published in JAMA Neurol. 2013.

Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, Melberg A, Cornelio F, Urban AE, Pizza F, Poli F, Grubert F, Wieland T, Graf E, Hallmayer J, Strom TM, Mignot E. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy.  Hum Mol Genet. 2012 May 15;21(10):2205-10.  See also Pedroso JL, Barsottini OGP, Lin L, Melberg A, Oliveira ASB, Mignot E. A Novel de novo Exon 21 DNMT1 Mutation Causes Cerebellar Ataxia, Deafness and Narcolepsy in a Brazilian Patient. Sleep, 2013 Aug 1;36(8):1257-9, 1259A. doi: 10.5665/sleep.2898. In this collaboration with Italy and Germany, we discovered that a rare and devastating disorder is due to mutations in the enzyme DNMT1. DNMT1 is an enzyme known to methylate DNA and stop the activity of some genes. The disorder is characterized by narcolepsy plus an onset of deafness at age 20-35. Symptoms progress to include cerebellar ataxia, and dementia by age 40-50. We are now working with colleagues around the world (Italy, Sweden, Brazil, England) to better understand this complex disease. Although not funded, we consider this to be a “research” emergency as we believe a way treat this disease is within reach. More research is urgently needed in this important area as many younger carriers of the mutation have been identified who are currently unaffected and it is possible that existing medications could prevent or delay the symptoms. Published in Hum Mol Genet. 2012 and Sleep, 2013.

Andlauer O, Moore H 4th, Hong SC, Dauvilliers Y, Kanbayashi T, Nishino S, Han F, Silber MH, Rico T, Einen M, Kornum BR, Jennum P, Knudsen S, Nevsimalova S, Poli F, Plazzi G, Mignot E. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy.  Sleep, 2012 Sep 1;35(9):1247-55F. In this collaborative study, we found that some cases of narcolepsy without cataplexy, especially those with multiple entries to Rapid Eye Movement (REM) sleep on sleep tests, have low hypocretin-1 in the cerebrospinal fluid after a lumbar puncture (hypocretin/orexin deficiency as the cause of their narcolepsy).  This was especially frequent in African Americans, making the diagnosis unusually difficult in this ethnic group. Published in Sleep, 2012.

Mignot E.  A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes. Neurotherapeutics, 2012 Oct;9(4):739-52. A summary of the treating philosophy at the Stanford Center for Narcolepsy including treatment recommendations for narcolepsy and hypersomnia. Written to assist clinicians and patients alike; not based on evidence-based clinical trials but clinical experience. Published in Neurotherapeutics, 2012.

Han F, Lin L, Li J, Dong SX, An P, Zhao L, Liu NY, Li QY, Yan H, Gao ZC, Faraco J, Strohl KP, Liu X, Miyadera H, Mignot E. HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens. 2012 Oct;80(4):328-35.   This work proposes a new model explaining HLA predisposition in narcolepsy based on Human Leukocyte Antigen (HLA) data in China.  Published in Tissue Antigens, 2012.   

Plazzi G, Pizza F, Palaia V, Franceschini C, Poli F, Moghadam KK, Cortelli P, Nobili L, Bruni O, Dauvilliers Y, Lin L, Edwards MJ, Mignot E, Bhatia KP.   Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011 Dec;134(Pt 12):3480-92. doi: 10.1093/brain/awr244. Epub 2011 Sep 19. In this important study, our colleagues in Bologna, Italy, show that narcolepsy in children often have an unusual and severe presentation (rapid obesity, premature puberty, general or facial twitching or weakness), which makes it more difficult to diagnose. Published in Brain, 2011.

Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX, An P, Zhao L, Wang LH, Li QY, Yan H, Gao ZC, Yuan Y, Strohl KP, Mignot E. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China.   Ann Neurol. 2011 Sep;70(3):410-7. In this seminal study in collaboration with China, our collaborators demonstrate that the incidence of narcolepsy in children is seasonal, typically occurring in the spring and summer (about 4-6 months after the winter), and that a 300% increased in incidence occurred after the 2009 Influenza H1N1 (“swine flu”) pandemic season.  Importantly, this increase occurred independent of flu vaccination, suggesting that the recently reported cases following Pandemrix, an adjuvanted H1N1 vaccine, are at least partially due to exposure to the H1N1 antigen.  We believe that a specific H1N1 or influenza related antigen produces a cross immune reaction with hypocretin cells, creating narcolepsy after a few months in some genetically susceptible individuals.   Additional factors are probably needed, explaining why some vaccines such as the AS03 adjuvanted Pandemrix increased risk but not other, weaker vaccines  such as the US non-adjuvanted vaccines (although this needs to be studied).  Even after Pandemrix, however, only 1/16,000 children developped narcolepsy (1/4,000 in DQB1*06:02 positive children), indicating a low risk after vaccination and the need for other factors. Published in Ann Neurol. 2011 Sep;70(3):410-7. See also Han F, Lin L, Li J, Dong XS, Mignot E. Ann Neurol. 2012 Nov 9. doi: 10.1002/ana.23799.

Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, Axtell RC, Kuipers H, Weiner K, Hamacher A, Kassack MU, Han F, Knudsen S, Li J, Dong X, Winkelmann J, Plazzi G, Nevsimalova S, Hong SC, Honda Y, Honda M, Högl B, Ton TG, Montplaisir J, Bourgin P, Kemlink D, Huang YS, Warby S, Einen M, Eshragh JL, Miyagawa T, Desautels A, Ruppert E, Hesla PE, Poli F, Pizza F, Frauscher B, Jeong JH, Lee SP, Strohl KP, Longstreth WT Jr, Kvale M, Dobrovolna M, Ohayon MM, Nepom GT, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Peppard P, Young T, Jennum P, Steinman L, Tokunaga K, Kwok PY, Risch N, Hallmayer J, Mignot E. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011 Jan;43(1):66-71. The study describes a novel narcolepsy gene, P2YR11, a receptor for ATP involved in triggering immune cell (and maybe other cell) death. The gene is located within the genetic region of a methylation enzyme called DNA methylase 1 (DNMT1) also involved in cell death and narcolepsy.  Published in Nature Genetics, January 1, 2011.  Published in Nat Genet. 2011.

Dauvilliers Y, Montplaisir J, Cochen V, Desautels A, Einen M, Lin L, Kawashima M, Bayard S, Monaca C, Tiberge M, Filipini D, Tripathy A, Nguyen BH, Kotagal S, Mignot E.  Post-H1N1 Narcolepsy-Cataplexy Sleep 2010 33(11):1428-30.  For discussion see also Mignot E, Dauvillers Y, Montplaisir J. Comment on the Letter to the Editor by Dr. Marcus on the association between narcolepsy and H1N1 exposure Sleep 2011, Vol. 34, 689-690. Following the H1N1 (swine flu) outbreak of 2009/2010, researchers in Europe, Canada and the United States noted an apparent increase in new narcolepsy cases. This letter to the Editor of Sleep suggests that exposure through theH1N1 vaccine containing adjuvant ASO3 (used in Europe, not the United States) or infection with H1N1 virus, may trigger narcolepsy in rare cases, and suggests the need for systematic study and replication. It was published to warn the scientific community.  Published in Sleep, November 1, 2010.

Dauvilliers Y, Montplaisir J, Cochen V, Desautels A, Einen M, Lin L, Kawashima M, Bayard S, Monaca C, Tiberge M, Filipini D, Tripathy A, Nguyen BH, Kotagal S, Mignot E.  Post-H1N1 Narcolepsy-Cataplexy Sleep 2010 33(11):1428-30.  Following the H1N1 (swine flu) outbreak of 2010, researchers in Europe, Canada and the United States noted an apparent increase in new narcolepsy cases. This letter to the Editor of Sleep suggests that exposure H1N1 vaccine containing adjuvant ASO3 (used in Europe, not the United States) or infection with H1N1 virus, may trigger narcolepsy in rare cases, and suggests the need for systematic study and replication. Published in Sleep, November 1, 2010.

Kawashima M, Lin L, Tanaka S, Jennum P, Knudsen S, Nevsimalova S, Plazzi G, Mignot E. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep. 2010 33(7):869-74. This study extends upon a previous report by Cvetkovic-Lopes identifying autoantibodies directed against the TRIB2 protein in Narcolepsy cases. Here, autoantibodies were found to be present more often in narcolepsy cases only close to disease onset, and rarely found in cases without cataplexy, or long after disease onset. Published in Sleep July 1, 2010.

Aran A, Lin L. Nevsimalova S, Plazzi G, Hong SC, Weiner K, Zeitzer J, Mignot E. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009 32:979-983. Markers indicating recent Streptococcal infections were elevated in narcolepsy cases close to disease onset. This suggests that Streptococcal infections may play a role in triggering the onset of the disease.  Published in Sleep, August 1, 2009.

Hallmayer J, Faraco J, Lin L, Hesselson S, Winklemann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong S, Honda Y, Honda M, Högl B, Longstreth Jr WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan J, Desautels A, Erhardt C, Hesla PE, Poll F, Frauscher B, Jeong JH, Sung-Pil Lee SP, Ton TGN, Kvale M, Kolesar LB, Dobrovolna M, Nepom GT, Salomon D, Wichmann HE, Rouleau  GA, Gieger C, Levinson  DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga  K, Kwock PY, Risch N, Mignot E. Narcolepsy is strongly associated with the TCR alpha locus. Nature Genet, 41(6):708-11 This genome wide association demonstrated that variants at the T cell receptor alpha locus are associated with susceptibility to narcolepsy across ethnic groups. These findings provide strong evidence for an autoimmune pathology in the disease. Published in Nature Genetics, June 2009.

Yokogawa T, Marin W, Faraco J, Pezeron G, Appelbaum L, Rosa F, Mourrain P, Mignot E. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol. 2007, Oct 16;5(10):e277.  This report established that zebrafish, a widely used vertebrate model organism, display sleep behaviors and have a functional hypocretin neuropeptide system.  Unlike in mammals, however, hypocretin neurons interact with different cell types in the fish, and act to promote sleep rather than wakefulness. Hypocretins in fish act to consolodate sleep in fish as they do in mammals, and fish without hypocretin receptors have disrupted sleep as seen in narcolepsy in humans, rodents and dogs.  Published in Public Library of Science, Biology, October 16, 2007.

Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol., 59(10): 1553-1562.  This large study established the use of CSF hypocretin measurement as a diagnostic tool for narcolepsy, with levels below 110pg/mL being diagnostic. Published in The Archives of Neurology, October 2002.

Mignot E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M, Grumet F, Fernandez-Vina M, Honda M, Risch N. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001 Mar;68(3):686-99. American Journal of Human Genetics, March 1st, 2001. The first systematic HLA study on narcolepsy across three different ethnic groups.

Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6;98(3):365-76.
Canine narcolepsy is caused by mutations in the hypocretin (orexin) receptor 2 gene. First publication implicating the hypocretin system in narcolepsy, published in Cell August 6th, 1999.

Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E.Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000 Jan 1;355(9197):39-40
Human narcolepsy is associated with undetectable hypocretin-1 levels in the cerebrospinal fluid. First publication implicating the hypocretin system in human narcolepsy, published in The Lancet, January 1st 2000.

Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000 Sep;6(9):991-7.
Most cases of human narcolepsy cases are not caused by hypocretin gene mutations. Only one hypocretin mutation was found, in a case with unsually early narcolepsy onset at 6 months of age. This finding demonstrates that hypocretin mutations can cause narcolepsy in humans as they do in animals. This manuscript also extends on the human CSF study by showing that human narcolepsy brain tissues have no hypocretin-1 and 2 peptides. It also reports that human narcolepsy cases have no preprohypocretin transcripts in their hypothalami, an area containing the hypocretin cells. First publication indicating that human narcolepsy is caused by a destruction of hypocretin-containing cells, published in Nature Medicine, September 1st 2000.

 

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