SUMMARYThe aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genomewide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 AE 12.43 versus 21.49 AE 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 AE 13.79 versus 15.62 AE 14.94, P = 0.044). The mean diagnostic delay was 14.63 AE 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods 482 ª

An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons.

Summary Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease‐specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web‐based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post‐marketing medication side‐effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/373555 doi: bioRxiv preprint first posted online Jul. 22, 2018; Main Text 1 Type 1 narcolepsy (T1N) is a sleep disorder that affects 1/3,000 individuals across ethnic 2 groups 1-3 . Onset is typically in childhood through early adulthood. Symptoms are caused by the 3 destruction of hypocretin/orexin neurons, a small neuronal subpopulation of the hypothalamus 4 . 4Although the disease is considered autoimmune, the exact mechanism leading to hypocretin cell 5 death is still unclear. Indeed, T1N is strongly associated with alleles encoding the heterodimer 6 DQ0602 haplotype (HLA-DQA1*01:02~DQB1*06:02, 97% vs. 25%) across ethnic groups 5,6 . 7Other loci previously associated with the disease include T cell receptor (TCR) loci alpha (TRA) 8 and beta (TRB), receptors of HLA-peptide presentations, and other autoimmune associated 9 genes (CTSH, P2RY11, ZNF365, IFNAR1 and TNFSF4) [7][8][9][10] . 11Triggers of T1N point to the immune system, including influenza and Streptococcus Pyogenes 12 infections 9,11,12 , as well as immunization with Pandemrix®, an influenza-A vaccine developed 13 specifically against the H1N1 "swine flu" strain 13-20 suggest a strong environmental modifier of 14 disease risk for narcolepsy. Increased T1N incidence following the Pandemrix® vaccination was 15 first seen in Northern Europe [13][14][15][16][17][18][19][20] with 8-fold increase in incidence in (0.79/100,000 to 16 6.3/100,000) in children. The specificity was striking, as increased T1N was later detected in all 17 countries where Pandemrix® was used, whereas countries using other pH1N1 vaccine brands 18 did not detect vaccination-associated increases in incidence [13][14][15][16][17][18][19][20][21][22] . is defined by antigen presentation, mediated through specific T cell receptor chains, and 27 modulated by influenza-A as a critical trigger. 28. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/373555 doi: bioRxiv preprint first posted online Jul. 22, 2018; examined using LD Score Regression 33 , the shared heritability was largest with type-1 diabetes Genetics of vaccination-triggered narcolepsy. We have previously shown that both influenza 21 infections and, in rare cases, immunization with Pandemrix® can trigger narcolepsy 13,18,19,42,43 . 22The baseline for narcolepsy in unvaccinated vs. Pandemrix® vaccinated individuals was 23 0.7/100,000 vs. 9/100,000 person years with on average 10-fold increase in risk 13,18,19,[42][43][44] was not peer-reviewed) is t...