Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Functional brown adipose tissue and sympathetic activity after cold exposure in humans with type 1 narcolepsy

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Cerebrospinal fluid biomarkers of neurodegeneration are decreased or normal in narcolepsy

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Breathing Disturbances Without Hypoxia Are Associated With Objective Sleepiness in Sleep Apnea

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Onset of Impaired Sleep and Cardiovascular Disease Risk Factors: A Longitudinal Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Sleep in cluster headache revisited: Results from a controlled actigraphic study

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Atypical sleep in critically ill patients on mechanical ventilation is associated with increased mortality

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Fang Han
  • Ling Lin
  • Barbara Schormair
  • Fabio Pizza
  • Giuseppe Plazzi
  • Hanna M Ollila
  • Sona Nevsimalova
  • Poul Jennum
  • Stine Knudsen
  • Juliane Winkelmann
  • Cristin Coquillard
  • Farbod Babrzadeh
  • Tim M Strom
  • Chunlin Wang
  • Michael Mindrinos
  • Marcelo Fernandez Vina
  • Emmanuel Mignot
View graph of relations

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.

Original languageEnglish
JournalSleep
Volume37
Issue number10
Pages (from-to)1601-8
Number of pages8
ISSN0161-8105
DOIs
Publication statusPublished - Oct 2014

ID: 45079398