Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

• MeSH
• autoimunita genetika   MeSH
• autoimunitní nemoci * epidemiologie   genetika   MeSH
• chřipka lidská * epidemiologie   genetika   MeSH
• lidé MeSH
• narkolepsie * chemicky indukované   genetika   MeSH
• vakcíny proti chřipce * škodlivé účinky   MeSH
• virus chřipky A, podtyp H1N1 * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• vakcíny proti chřipce * MeSH

Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.

• Klíčová slova
• cell transplantation, gene therapy, hypocretin, narcolepsy, orexin, orexin agonists,
• MeSH
• genetická terapie MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• narkolepsie farmakoterapie   genetika   MeSH
• orexiny terapeutické užití   MeSH
• transplantace buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• knihovny malých molekul MeSH
• orexiny MeSH

The aim of our study was to analyze the distribution of HLA-DQB1 in Czech patients with central hypersomnias and differences between diagnostic groups of narcolepsy type 1 (NT1), type 2 (NT2), idiopathic hypersomnia (IH) and no central hypersomnia subjects (no-CH). Statistical analysis of DQB1 genotyping was performed on the cohort of 716 patients (375 men, 341 women) with reported excessive daytime sleepiness. DQB1*06:02 allele was present in 94% of the NT1 patients. The decrease of DQB1*06:03 allele was also confirmed. No other DQB1*06 allele nor any other DQB1 allele group was differently distributed in the NT1. In the cohort of NT2 patients DQB1*06:02 allele was present in 43%. Allele group DQB*05 was detected with a significantly higher frequency in this diagnostic unit. Any differences in presence of DQB1*05 alleles in NT2 patients were not reported so far. The cohort of patients with IH did not show any difference in allele distribution of DQB1 alleles/allele groups comparing to healthy controls. DQB1*06:02 allele was significantly increased in the no hypersomnia group. No other DQB1 allele/allele group had any difference in distribution in patients comparing to healthy controls. The different distribution of DQB1*06:02 and other DQB1 alleles/allele groups was detected in analyzed diagnostic groups. These results indicate that DQB1 contributes to the genetic predisposition to NT1, NT2, IH and no-CH in different manners.

• Klíčová slova
• Central hypersomnias, HLA-DQB1, Idiopathic hypersomnia, Narcolepsy,
• MeSH
• alely MeSH
• bdění MeSH
• dítě MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• HLA-DQ beta řetězec genetika   MeSH
• idiopatická hypersomnie genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• narkolepsie genetika   MeSH
• orexiny metabolismus   MeSH
• poruchy iniciace a udržování spánku genetika   MeSH
• poruchy nadměrné spavosti genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spánek MeSH
• studie případů a kontrol MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• HLA-DQ beta řetězec MeSH
• HLA-DQB1 antigen MeSH Prohlížeč
• orexiny MeSH

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.

• Klíčová slova
• DNMT1, HLA, MHC, MOG, cataplexy, exome sequencing, hypocretin, narcolepsy, orexin,
• MeSH
• alely MeSH
• glykoprotein v myelinu oligodendrocytů genetika   MeSH
• HLA-DQ beta řetězec genetika   MeSH
• internacionalita MeSH
• intracelulární signální peptidy a proteiny mozkomíšní mok   nedostatek   genetika   MeSH
• kataplexie genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mutace genetika   MeSH
• mutační analýza DNA MeSH
• narkolepsie genetika   MeSH
• neuropeptidy mozkomíšní mok   nedostatek   genetika   MeSH
• orexiny MeSH
• represorové proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DMAP1 protein, human MeSH Prohlížeč
• glykoprotein v myelinu oligodendrocytů MeSH
• HCRT protein, human MeSH Prohlížeč
• HLA-DQ beta řetězec MeSH
• HLA-DQB1 antigen MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• MOG protein, human MeSH Prohlížeč
• neuropeptidy MeSH
• orexiny MeSH
• represorové proteiny MeSH

The occurrence of sleep disorder in three half sibling Lipizzaner is described. Sleepiness, swaying, stumbling, carpal joints buckling and falling down onto the carpal joints had been present since early foal age in all of them. Clinical signs had gradually reduced since the age of 2 years in cases 1 and 3. Sleepiness was induced by going out from the stable in adulthood. A physostigmine test was performed in all three affected horses and produced positive results in cases 1 and 3. The result of the test in case 2 was unclear due to the almost continuous sleepiness of the foal. Hypocretin-1 concentration in the cerebrospinal fluid was established using a standardised radioimmunoassay in case 1 (317.85 pg/mL), case 2 (303.43 pg/mL) and five adult control horses (275.2 ± 47.9 [SD] pg/mL) and was considered as normal in all horses. The sire of the affected horses has had 19 other registered offspring who did not show clinical signs of sleep disorder and also dams of all three cases produced healthy foals. Based on the demographic and clinical data together with the responses to the physostigmine challenges, the diagnosis of familial equine narcolepsy was made.

• MeSH
• fysostigmin MeSH
• intracelulární signální peptidy a proteiny mozkomíšní mok   MeSH
• koně MeSH
• narkolepsie diagnóza   genetika   veterinární   MeSH
• nemoci koní diagnóza   genetika   MeSH
• neuropeptidy mozkomíšní mok   MeSH
• orexiny MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• fysostigmin MeSH
• intracelulární signální peptidy a proteiny MeSH
• neuropeptidy MeSH
• orexiny MeSH

A group of 153 probands with narcolepsy included 38 subjects (24.8%) with a familial incidence of excessive daytime sleepiness (EDS). In 15 cases (9.8%), at least one additional family member suffered from narcolepsy-cataplexy; only EDS was present in the remaining 23 cases (15.0%). One thousand eighty-two relatives were evaluated. The percentage of first degree relatives affected with narcolepsy-cataplexy was 2.28% (1.20% if only clinically confirmed cases were accounted); the adequate value for second degree relatives was 1.49%. The occurrence of EDS exceeded these values several times (4.28% in first degree relatives, 6.57% in second degree relatives). The vertical mode of transmission was found in most families. Human leukocyte antigen (HLA) typing was performed in six families with multiple-case incidence of narcolepsy. Forty-one blood samples were analyzed (12 patients with narcolepsy, 7 with only EDS, 2 with sleep apnea syndrome, and 20 healthy relatives). HLA DR2+ and DQB1*0602+ were found in only 8 out of 12 narcoleptic patients with cataplexy and in six out of seven patients with isolated attacks of sleepiness. These findings support the hypothesis that there is a common genetic basis for narcolepsy associated with cataplexy and "monosymptomatic" forms of narcolepsy and suggest the existence of non-major histocompatibility complex (MHC) susceptibility factors for narcolepsy.

• MeSH
• dospělí MeSH
• genotyp MeSH
• HLA-DQ antigeny imunologie   MeSH
• HLA-DR antigeny imunologie   MeSH
• kataplexie etiologie   genetika   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• narkolepsie komplikace   genetika   imunologie   MeSH
• rodokmen MeSH
• vertikální přenos infekce MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• HLA-DQ antigeny MeSH
• HLA-DR antigeny MeSH

The authors examined HLA antigens in 124 narcoleptics. In addition to narcolepsy, 122 patients suffered also from cataplexy. The two patients without cataplexy suffered also from sleep paralysis and hypnagogic hallucinations. These two symptoms were also present in many of the other patients. HLA group DR2 was found in 120 patients including all six symptomatic cases. In four patients HLA DR2 was not present. Two of these were fully pronounced narcolepsy-cataplexy cases whereas the two other did not suffer from cataplexy. Since several other cases with negative DR2 have already been published it is necessary to admit the existence of DR2-negative narcolepsy, albeit very rare. Among 5 patients with isolated sleep paralysis HLA DR2 was present in one familial and 1 sporadic case. The authors further discuss some aspects of the classification of narcolepsies in the light of recent HLA studies as well as their delimitation from idiopathic hypersomnia.

• MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DR2 antigen MeSH
• kataplexie genetika   MeSH
• lidé MeSH
• mapování chromozomů MeSH
• narkolepsie genetika   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• poruchy nadměrné spavosti genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA-DR antigeny MeSH
• HLA-DR2 antigen MeSH

• MeSH
• bdění MeSH
• lidé MeSH
• narkolepsie genetika   MeSH
• poruchy nadměrné spavosti genetika   MeSH
• poruchy spánku a bdění genetika   MeSH
• rodokmen MeSH
• spánek REM MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

• MeSH
• elektroencefalografie MeSH
• lidé MeSH
• narkolepsie genetika   MeSH
• poruchy spánku a bdění genetika   MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH