Hypocretin (orexin) neuropeptide precursor gene, HCRT, polymorphisms in early-onset narcolepsy with cataplexy.

BACKGROUND: To test if the hypocretin (orexin) neuropeptide precursor (HCRT) gene, HCRT, mutations are implicated in the development of narcolepsy with cataplexy deficiency in young children. METHODS: The entire HCRT gene and ~2000 bp promoter region was first sequenced in 181 patients and 153 controls, and rare polymorphisms including three nonsynonymous amino acid changes were identified. Next the 557 bp region of exon 2 harboring the three nonsynonymous changes was sequenced in an additional 298 early-onset subjects and in 148 control samples. RESULTS: A previously known common polymorphism (rs760282) and nine rare novel polymorphisms were identified in subjects and controls without significant differences. Two nonsynonymous exon 2 substitutions (+977 H54A, +979 G55R) were detected in two subjects with early onset at 7 and 6 years, respectively, but were not found in any controls. These substitutions are not likely to vastly change peptide binding to hypocretin receptors. One additional exon 2 substitution (+1019, K68R) was found in two patients and one control. Additional sequencing that focused on exon 2 showed additional subjects and controls with the +1019 K68R polymorphism and without significant differences between the subjects and the control. Segregation of two of these three nonsynonymous single nucleotide polymorphisms (SNPs) were observed from unaffected parents to offspring. CONCLUSIONS: Sequencing of a large number of early-onset narcolepsy subjects revealed three novel nonsynonymous substitutions within the preprohypocretin protein, two of which were only found in patients with early-onset narcolepsy but are not likely to be functionally significant, especially in heterozygote subjects.

TCRA, P2RY11, and CPT1B/CHKB associations in Chinese narcolepsy.

OBJECTIVES: Polymorphisms in the TCRA and P2RY11, two immune related genes, are associated with narcolepsy in Caucasians and Asians. In contrast, CPT1B/CHKB polymorphisms have only been shown to be associated with narcolepsy in Japanese, with replication in a small group of Koreans. Our aim was to study whether these polymorphisms are associated with narcolepsy and its clinical characteristics in Chinese patients with narcolepsy. METHODS: We collected clinical data on 510 Chinese patients presenting with narcolepsy/hypocretin deficiency. Patients were included either when hypocretin deficiency was documented (CSF hypocretin-1≤110 pg/ml, n=91) or on the basis of the presence of clear cataplexy and HLA-DQB1∗0602 positivity (n=419). Genetic data was compared to typing obtained in 452 controls matched for geographic origin within China. Clinical evaluations included demographics, the Stanford Sleep Inventory (presence and age of onset of each symptom), and Multiple Sleep Latency Test (MSLT) data. RESULTS: Chinese narcolepsy was strongly and dose dependently associated with TCRA (rs1154155C) and P2RY11 (rs2305795A) but not CPT1B/CHKB (rs5770917C) polymorphisms. CPT1B/CHKB polymorphisms were not associated with any specific clinical characteristics. TCRA rs1154155A homozygotes (58 subjects) had a later disease onset, but this was not significant when corrected for multiple comparisons, thus replication is needed. CPT1B/CHKB or P2RY11 polymorphisms were not associated with any specific clinical characteristics. CONCLUSIONS: The study extends on the observation of a strong multiethnic association of polymorphisms in the TCRA and P2RY11 with narcolepsy, but does not confirm the association of CPT1B/CHKB (rs5770917) in the Chinese population.

Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China.

OBJECTIVE: Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of narcolepsy in northern Europe following H1N1 vaccination. METHODS: The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998-2010). Self-reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi-square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history. RESULTS: The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7-fold increase from trough to peak. Studying year-to-year variation, we found a 3-fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross-correlation indicated a significant 5- to 7-month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences. INTERPRETATION: In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample.

Presentations of primary hypersomnia in Chinese children.

OBJECTIVE: To retrospectively describe childhood presentations of primary hypersomnia with an emphasis on narcolepsy-cataplexy in a Chinese population. METHODS: A total of 417 children (< 18 years old) successively presenting with complaints of hypersomnia without anatomic cause or sleep apnea risk were evaluated using the Stanford Sleep Inventory, human leukocyte antigen (HLA) DQB1*0602 typing, and MSLT recordings. CSF hypocretin-1 was measured in 47 cases to document hypocretin deficiency. A subgroup ("narcolepsy/hypocretin deficiency") with likely hypocretin deficiency (low hypocretin-1 or HLA positive with clear-cut cataplexy) was further examined for presentations prior to, around, or after puberty. RESULTS: Narcolepsy with (n = 361) or without (n = 17) cataplexy presented at an earlier age and with increased male predominance when compared to idiopathic hypersomnia (n = 39, P < 0.01). Nearly 70% of those with narcolepsy/hypocretin deficiency (n = 271) had disease onset before age 10 y, and 15% had onset before age 6, an unusually young age distribution. Onset was prior to puberty in 78% of cases. Clinical features were similar in presentations across puberty groups except for sleep paralysis, which increased in frequency with age/puberty. Mean sleep latency (MSL) decreased and the number of sleep onset REM periods (SOREMPs) increased with age/puberty, but MSLT diagnosis criteria (MSL ≤ 8 min, ≥ 2 SOREMPs) were similarly positive across groups. Familial clustering was present in only 1.7% of probands. CONCLUSION: In children presenting with a complaint of primary hypersomnia to a sleep clinic in China, 86% (361/417) meet criteria for narcolepsy with cataplexy. Puberty did not affect positivity on the MSLT as a diagnostic feature. Sleep paralysis was the only symptom that increased with increasing age. In addition, narcolepsy with cataplexy in our clinic population appeared to begin at a younger age than usually reported in other studies.

Noninvasive positive pressure ventilation treatment for acute respiratory failure in SARS.

This study describes the blood gases features and short-term outcomes with noninvasive positive pressure ventilation (NPPV) treatment in the management of acute respiratory failure (ARF) during a severe acute respiratory syndrome (SARS) epidemic. Between April 22 and May 1, 2003, 120 patients meeting clinical criteria for SARS were admitted to a hospital for infectious diseases in Beijing, China. At 6 weeks after onset, 25% of patients (30/120) had experienced ARF. Of interest, 16 of these patients (53%) exhibited hypercapnia (PaCO (2) > 45 mm Hg), and 10 hypercapnic events occurred within 1 week of admission. The occurence of hypencapnia or CO (2) retention and was accompanied by myalgias. NPPV was instituted in 28 patients; one was intolerant of NPPV. In the remaining 27 patients, NPPV was initiated 1.2 +/- 1.6 days after ARF onset. An hour of NPPV therapy led to significant increases in PaO (2) and PaO (2)/FiO (2) and a decrease in respiratory rate ( p < 0.01). Endotracheal intubation was required in one third of the patients (9 of 27) who initially had a favorable response to NPPV. Remarkable pulmonary barotrauma was noticed in 7 of all 120 patients (5.8%) and in 6 of those (22%) on NPPV. The overall fatality rate at 13 weeks was 6.7% (8/120); it was higher (26.7%) in those needing NPPV. No caregiver contracted SARS. We conclude that NPPV is a feasible and appropriate treatment for ARF occurring as a result of a SARS infection.