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.
In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.
We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean¡SD age 20¡10 yrs, 69% male) and 117 controls (22¡6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (DV9E)/carbon dioxide tension (DPCO 2 ) L?min KEYWORDS: Chemoresponsiveness, human leukocyte antigen DQB1, hypercapnia, hypoxia, narcolepsy H ypoxic and hypercapnic sensing are processed through neuromuscular circuits resulting in an increase or decrease of tidal volume, respiratory frequency and minute ventilation (V9E). Such chemosensory reflexes operate to influence sleep apnoea, chronic obstructive pulmonary disease (COPD), heart failure, and acute adaptation to high altitude [1]. A variation in chemosensitivity across various inbred rodent strains and familial clustering of ventilatory traits in humans provides a strong rationale for gene and protein isolation efforts to unravel molecular mechanisms for these traits operating in health and disease [2].Hypocretin (orexin) is a hypothalamic neurotransmitter, which, when given intracerebroventricularly in mice, promotes both wakefulness and ventilation [3,4]. Both hypocretin knockout and hypocretin neuron-ablated mice show attenuation of respiratory excitation during fightor-flight responses [5]. Particular to chemoresponsiveness, hypocretin/orexin knockout mice have attenuated hypercapnic ventilatory responses [6]; supplementation of hypocretin-1 or -2 partially restores an attenuated response to hypercapnia, while administration of hypocretin receptor-1 antagonist will reduce hypercapnic responsiveness in wild type mice [7]. Post-hypoxic long-term facilitation, a physiological feature that is presumed to reduce sleep apnoea, is absent in hypocretin/orexin knockout mice [8].The human model of hypocretin deficiency is narcolepsy with cataplexy [9,10]. This disorder is also associated with the gene marker, human leukocyte antigen (HLA)-DQB1*0602 [11]. This disease is also considered to be associated with a higher expression of sleep-disordered breathing [12,13]. Our primary hypothesis was that an impaired chemoresponsiveness would be present
627Childhood Narcolepsy/Hypersomnia-Han et al on the pediatric population could help address issues related to puberty, genetic predisposition, and environmental triggers, and possibly shed light on factors that might delay diagnosis. We report on findings from a pediatric cohort of patients who presented with primary hypersomnia to a sleep clinic in Beijing, China over a period of ~10 years. All were evaluated in a standard fashion and classified as narcolepsy with or without cataplexy or idiopathic hypersomnia. Our purpose was to describe age of onset and clinical features of primary hypersomnia among a mainland Chinese cohort of children, and to compare the findings to the literature. METHODS PatientsPatients were children, defined as < 18 years of age, successively presenting with hypersomnia seen over a period of ~10 years (September, 1998 to May, 2009) at People's Hospital, Beijing University, Beijing. A total of 417 children (63%) were drawn from a population of 671 adults and children with hypersomnia. The hospital has a pulmonary medicine departmentbased sleep center, which sees both children and adults, and receives referrals from all of mainland China. It is estimated that 70% of the diagnosed narcolepsy patients in mainland China are seen at this center at People's Hospitals.12 A prior report focused on the impact of a narcolepsy recognition strategy in a pediatric neurology clinic, 13 whereas this report retrospectively describes a cohort with a broader symptom profile, evaluated using a stan- INTRODUCTIONNarcolepsy-cataplexy (NC) occurs worldwide. In China, there is a population prevalence of 0.034% in patients in South China presenting to sleep centers in Hong Kong 1,2 and a prevalence of 0.014% in Korean adolescents with similar clinical and biological presentations.3-5 Studies in North America and Europe estimates are similar. As the origin and mechanisms that produce narcolepsy are not well understood, comparisons of clinical presentations in collections of several characterized patient groups can inform future studies of clinical and genetic epidemiology.Narcolepsy-cataplexy is said to present in the second to third decade of life, with 70% to 80% of patients reporting onset between 10-20 years of age. Large sample size observations from the United States, Canada, Europe, and Japan report that half of adult patients with narcolepsy report narcolepsy onset prior to 15 years old, and only exceptionally at 5 or younger.6-9 Studies in the 1980s-1990s reported a median delay > 10 years between onset and diagnosis, 10 whereas a more recent report suggests the delay can be only a few years, particularly in children.11 A focus 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) ...
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. Conclusion 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.
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