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Background: The narcolepsy severity scale (NSS) was developed to measure the severity and consequences of symptoms in patients with narcolepsy. The scale has been validated in France, though no other studies have further validated this instrument. The current study aimed to present psychometric properties and describe the score distribution of the Chinese-NSS.Methods: One hundred twenty-two patients with narcolepsy (41 females and 81 males; mean age 26.14 ± 15.40 years) participated in the study. All patients completed the Chinese-NSS. Cronbach's α, item-total score correlations, exploratory factor analysis (EFA), and correlations between NSS total scores and clinical or sleep parameters were then calculated.Results: EFA yielded a three-factor model. Internal consistency was acceptable (Cronbach'sα = 0.799). The NSS total score had significant correlations with the Epworth sleepiness score (0.447), pediatric daytime sleepiness scale (0.318), the insomnia severity index (0.592), Beck depression inventory (0.593), EurQol five dimensions-utility (0.457), EurQol five dimensions -VAS (- 0.323), the sleep disturbance scale for children (0.440), the children depression inventory (0.553), and the pediatric quality of life inventory (0.555) total scores, demonstrating acceptable convergence as predicted.Conclusions: The current study is the first validation study of the narcolepsy severity scale in an Asian population. The findings validated the Chinese-narcolepsy severity scale in a Chinese population with acceptable psychometric properties. There are minor differences between our results and those of the original study due to cultural differences. [ABSTRACT FROM AUTHOR]

Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7×10−9 OR 0.77), ZNF365 (rs10995245 max P = 1.2×10−11 OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2×10−9 OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10−9 beta −1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8×10−10 OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases. [ABSTRACT FROM AUTHOR]

The executive function profile in patients with narcolepsy type 1 (NT1) has been mentioned; however, limited research exists on children and adolescent patients with NT1.This study aims to assess executive function in children and adolescent patients with NT1 in China, examine potential influencing factors and evaluate the short-term treatment effect on executive function. 53 NT1 patients (36 males, age 12.2 ± 3.4 years) and 37 healthy controls (23 males, age 12.2 ± 2.5 years) underwent self-reported measures assessing subjective sleepiness, depression, anxiety and sleep quality. A comprehensive neuropsychological test was administered to assess executive function domains, including processing speed, inhibitory control, cognitive flexibility and working memory. These assessments were repeated in NT1 patients after three-day regular drug treatment. NT1 patients exhibited higher levels of excessive daytime sleepiness, depression, anxiety, and poor sleep quality compared to healthy controls. Patients showed impaired processing speed, inhibitory control and cognitive flexibility (p < 0.05), whereas working memory was unaffected (p > 0.05). Regression analysis revealed that parameters from sleep monitoring, such as sleep efficiency and sleep latency, were correlated with executive function performance after controlling for age, gender, and education years. The short-term treatment led to improvements in inhibitory control, cognitive flexibility, and working memory. The findings showed that executive function was impaired among children and adolescent patients with NT1, which was associated with objective sleep parameters. Furthermore, this study emphasizes the necessity of neuropsychological assessments and early interventions among children and adolescent NT1 patients. • Symptoms exacerbated mood, impair sleep quality and executive function during daytime in children and adolescent patients with NT1. • Pediatric NT1 patients exhibited impaired processing speed, inhibition control and cognitive flexibility, whereas working memory remained unaffected. Short-term pharmacological intervention could improve the impaired executive function. [ABSTRACT FROM AUTHOR]

ABSTRACT Narcolepsy-cataplexy syndrome is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. It is strongly associated with the genetic marker, human leucocyte antigen (HLA) DQB1*06:02. A deficit in the endogenous hypocretin/orexin system due to neuronal degeneration in the lateral hypothalamus, induced by an autoimmune-mediated process, is the primary pathophysiology associated with the human disease. The important finding of an association with hypocretin genes in animal models of narcolepsy has led to the establishment of cerebrospinal fluid hypocretin measurements as a new diagnostic test for human narcolepsy. This is a fascinating story of translation of basic science research into clinical practice in sleep medicine during the past decade. Recent advances have shed light on the associations between respiratory medicine and narcolepsy-cataplexy research. The first is that upper airway infections, including H1N1 and/or streptococcal infections, may initiate or reactivate an immune response that leads to loss of hypocretin-secreting cells and narcolepsy in genetically susceptible individuals. The second is that an increased incidence of sleep disordered breathing among narcoleptic subjects may relate to the impairment of central control of breathing, linked to hypocretin deficiency or carriage of HLADQB1*06:02, in animals and human subjects with narcolepsy, respectively, indicating neural dysfunction in an area where respiratory and sleep-wake systems are closely interrelated. [ABSTRACT FROM AUTHOR]

Abstract: 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⩽110pg/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. [Copyright &y& Elsevier]

To develop and psychometrically test the pediatric narcolepsy severity scale (P-NSS) for pediatric with narcolepsy type 1 (NT1). Item pool was formed based on literature review, clinical judgement of the expert panel and input of the narcoleptic patients and their parents. Psychometric properties were evaluated after applying the P -NSS in a sample of 200 patients (8–18 years age) with narcolepsy. Analyses included item analysis, validity analysis and reliability analysis. P -NSS consisted four factors with a total of 17 items. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) revealed four distinct and theoretically coherent factors, explaining 63.4% of the total variance. The fitting results of the CFA model were χ2/dƒ = 2.235, GFI = 0.876, AGFI = 0.822, RMSEA = 0.079, TLI = 0.908, CFI = 0.927. P -NSS score is correlated with Pediatric Daytime Sleepiness Scale (r = 0.512, P < 0.01), Epworth Sleepiness Scale for Children and Adolescents (r = 0.355, P < 0.01) and Narcolepsy quality-of-life instrument with 21 questions (r = −0.512, P < 0.01). Cronbach's α coefficient for P -NSS and four dimensions were from 0.732 to 0.915. The split-half reliability was 0.882 (P < 0.01). P -NSS is proved to be a reliable and valid measure for Chinese children with NT1. It may serve in China as a valuable and easily accessible outcome measure for using in narcolepsy trials, the clinic with improved responsiveness and long term follow-up. • It is necessary to assess the severity of symptoms of pediatrics with NT1. • Symptom severity assessment is essential for clinical decision-making and follow-up management in narcoleptics. • There are few tools assessing the severity of symptoms in children with NT1. • Pediatric narcolepsy severity scale is a valid measure of symptom severity for pediatric patients with NT1. [ABSTRACT FROM AUTHOR]

Summary: The hypocretin neurons in the lateral hypothalamus are connected not only to brain alertness systems but also to brainstem nuclei that regulate blood pressure and heart rate. The premise is that regulation of blood pressure and heart rate is altered and affected by methylphenidate, a stimulant drug in children with narcolepsy with cataplexy. The changes in 24‐hr ambulatory systolic and diastolic blood pressure and heart rate were compared among pre‐treated narcolepsy with cataplexy patients (40 males, 10 females), with mean age 10.4 ± 3.5 years (M ± SD, range 5–17 years) with values from 100 archival age–sex–body mass index matched controls. Patients had a lower diurnal systolic blood pressure (−6.5 mmHg; p = 0.000) but higher heart rate (+11.0 bpm; p = 0.000), particularly evident in the waketime, while diastolic blood pressure was comparable. With methylphenidate (18 mg sustained release at 08:00 hours), patients with narcolepsy with cataplexy had higher systolic blood pressure (+4.6 mmHg, p = 0.015), diastolic blood pressure (+3.3 mmHg, p = 0.005) and heart rate (+7.1 bpm, p = 0.028) during wake time, but nighttime cardiovascular values were unchanged from pre‐treated values; amplitude variation in cardiovascular values was unchanged over 24 hr. In conclusion, children with narcolepsy with cataplexy had downregulation blood pressure profile but a higher heart rate, and lesser non‐dipping profiles. Daytime methylphenidate treatment increases only waketime blood pressure and further elevated heart rate values. [ABSTRACT FROM AUTHOR]

To assess the impact of symptom severity on health-related quality of life (HRQoL) in people with narcolepsy type 1 (NT1). A total of 174 people with NT1 were enrolled. They completed the Narcolepsy Severity Scale (NSS) and EQ-5D-3L consisting of five dimensions (EQ-5D utility values) and a visual analog scale (EQ-5D VAS). The relationship between severity of symptoms and HRQoL dimensions was evaluated by Pearson correlation analyses. Logistic regression was used to identify significant predictors of HRQoL. Nomogram was established based on results of independent predictors of factors on logistic regression analyses. The mean score for NSS, EQ-5D utility values, and EQ-5D VAS were 29.8 (10.08), 0.78 (0.09), and 64.30 (19.84) in people with NT1, respectively. NSS score showed a significant correlation with self-care (r = 0.157, p <.05), usual activities (r = 0.236, p <.01), pain/discomfort (r = 0.174, p <.05), anxiety/depression (r = 0.2, p <.01), and EQ-5D utility values (r = −.261, p <.01). EDS (excessive daytime sleep), cataplexy, hallucinations, paralysis, and disrupted nocturnal sleep (DNS) were significantly associated to EQ-5D VAS (r ranged from −0.154 to −0.354, p <.05). EDS (OR = −0.297) and DNS (OR = −0.16) were predictors of HRQoL. NSS score (OR = −0.360) and treatment (OR = 0.215) were predictors of the metrics of HRQoL. The C-indices of the nomogram were 0.726. The severity of symptoms could disrupt self-care and usual activities, and increase pain/discomfort and anxiety/depression. HRQoL might be improved by alleviating symptom severity. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence of core attention-deficit/hyperactivity disorder (ADHD) symptoms in Chinese narcolepsy type 1 (NT1) patients and to explore mood, quality of life, and executive function in narcolepsy patients with or without ADHD and the response to Methylphenidate Hydrochloride Extended-release tablets (ER-MPH) treatment.Method: A total of 267 pediatric NT1 patients (194 males and 73 females, 5-17 years old) were evaluated for ADHD symptoms by a psychiatrist using the DSM-IV diagnostic criteria of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI Kid) from February 2011 to July 2013 at Peking University People's Hospital. All patients underwent Stanford Sleep Inventory (SSI) evaluation and polysomnography followed by multiple sleep latency tests (MSLT) before ER-MPH treatment. Neuropsychological evaluations, including the Inventory of Subjective Life Quality (ISLQ), Depression Self-resting Scale for Children (DSRS-C), Screening for Child Anxiety-related Emotional Disorders (SCARED) and Barratt Impulsiveness Scale (BIS), were performed before and after 16 weeks of ER-MPH treatment. Executive abilities were assessed by the Behavior Rating Inventory of Executive Function-parent version (BRIEF-P). The narcolepsy symptoms, evaluated by the Pediatric Sleep Questionnaire (PSQ), and ADHD symptoms were assessed before and after treatment in NT1 patients with ADHD.Result: Seventy-seven of 267 (28.8%) NT1 patients had ADHD symptoms, with 73 patients being inattentive type (ADHD-I) and 4 patients being combined type (ADHD-C). Despite similar objective sleep parameters, NT1 patients with ADHD symptoms experienced higher anxiety levels, more impulsive behaviors, lower health-related quality of life and worse executive functions than those without ADHD (p<0.05). Methylphenidate treatment was effective in improving daytime sleepiness in NT1 patients with ADHD (PSQ, 16.7 ± 2.1 vs 13.5 ± 1.9, p<0.05) but was ineffective on ADHD symptoms (ADHD-RS, 25.3 ± 9.1 vs 26.4 ± 8.9, p>0.05).Conclusion: A high prevalence of ADHD (28.8%) was identified in children and adolescents with NT1. Comorbid ADHD symptoms were associated with increased levels of mood disorders and lower quality of life. ER-MPH treatment could reduce daytime sleepiness but not ADHD symptoms in narcolepsy patients with ADHD, suggesting that new treatment strategies are needed for this group of patients. [ABSTRACT FROM AUTHOR]

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1 ∗ 01:02-DQB1 ∗ 06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1 ∗ 01:03-DPB1 ∗ 04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10 −6 ) and HLA-DPA1 ∗ 01:03-DPB1 ∗ 04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10 −4 ) and predisposing effects of HLA-DPB1 ∗ 05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10 −05 ). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10 −17 ) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10 −5 ). HLA-class-II-independent associations with HLA-A ∗ 11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10 −4 ), HLA-B ∗ 35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10 −5 ), and HLA-B ∗ 51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10 −5 ) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. [ABSTRACT FROM AUTHOR]

Background: There are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force.Methods: A total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries.Results: Most of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries.Conclusion: The results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents. [ABSTRACT FROM AUTHOR]

Objective: To evaluate reliability and validity of the Chinese version of Narcolepsy Severity Scale (NSS) in adult patients with narcolepsy type 1 (NT1).Methods: One hundred and fifty-one adult patients (≥18 years) with NT1 were recruited. All filled out the 15-item Chinese version of NSS. Item analysis included critical ratio and correlation analysis. The validity of NSS was assessed by exploratory factor analysis, discriminant validity and convergent validity. Reliability of NSS was assessed by Cronbach's α coefficient, spilt-half reliability and test-retest reliability.Results: Critical value of all 15 items ranged from 3.01 to 13.36. Each item was significantly correlated with the total score by a correlation coefficient (r) ranging from 0.219 to 0.700. Three common domains were extracted and 15 items explained 54.86% of the total variance. There was a shift in domains compared to the English version likely due to cultural differences. Cronbach's α coefficient for the total scale of 15 items was 0.821 and for three factors was 0.726, 0.748 and 0.760 respectively. The NSS had good correlation with Epworth sleepiness scale scores, Insomnia severity index scores and moderate correlation with mean the sleep latency of polysomnographic recording, and European Quality of Life-5 Dimensions Questionnaire. The Chinese version of NSS showed good spilt-half reliability and test-retest reliability.Conclusion: The Chinese version of NSS shows satisfactory psychometric properties with good validity and reliability. It is applicable to evaluate the severity and consequences of symptoms in Chinese adult patients with NT1. [ABSTRACT FROM AUTHOR]

A meta-analysis was conducted to review the prevalence and associated moderators of depression or depressive symptoms in patients with narcolepsy. An extensive search of the literature yielded 1104 articles and abstracts, of which 31 studies were included in the meta-analysis. Meta-analysis revealed that the overall pooled prevalence of depression or depressive symptoms in patients with narcolepsy was 32% (95% Confidence Interval, 28–36%) with high between-study heterogeneity (Q = 249.77, df = 30, p < 0.001, τ2 = 0.0087, I2 = 88%). An analysis of 13 studies with healthy control groups indicated that narcolepsy was associated with a significantly increased risk of depression or depressive symptoms (Odds Ratio 3.48, 95% Confidence Interval 2.73–4.45; Q = 41.23, df = 12, p < 0.001, τ2 = 0.0087, I2 = 70.9%). The prevalence of depression or depressive symptoms in patients with narcolepsy was significantly affected by study design (Q = 5.05, p = 0.02) and recruitment setting (Q = 5.98, p = 0.01), and was marginally affected by age group (Q = 3.44, p = 0.06). The results indicate that narcolepsy patients should be closely monitored for depression and depressive symptoms and that early screening should be considered. However, these conclusions should be tempered because of high variability between studies. The estimates across studies are very inconsistent, indicating the need for larger, multicenter studies, with stringent case definitions. [ABSTRACT FROM AUTHOR]

Background: Narcolepsy type 1 (NT1) is considered to be an autoimmune disease, and streptococcal infection may be an environmental trigger. However, previous studies from Asian narcolepsy patients did not reveal elevated anti-streptolysin O [ASO]. The aim is to investigate whether large sample Chinese patients with NT1 have an increase in antistreptococcal antibody titers.Methods: A total of 214 narcolepsy patients and 360 healthy controls were recruited. All patients were DQB1∗0602 positive with clear-cut cataplexy or had low CSF hypocretin-1. Participants were tested for ASO and anti DNAse B [ADB]. These patients were divided into five groups according to disease duration, including 29 patients less than 3 months; 25 from 3 months to 1 year; 40 from 1 to 3 years; 61 from 3 to 10 years and 59 patients over 10 years. Comparison was also made between children and adults with age matched controls, respectively.Results: There were no significant differences between patients and healthy controls in regard to both ASO ≥200 IU (19.2% vs. 16.9%, p = 0.50) and ADB≥480IU (9.8% vs. 10.3%, p = 0.86). For children narcolepsy patients, ASO positive rates (19.8% vs. 18%, p = 0.68) and ADB positive rates (10.4% vs. 12%, p = 0.72) had no differences compared to age matched controls. No difference was observed in adult narcolepsy patients either, with ASO positive rates (18.5% vs. 13.8%, p = 0.39) and ADB positive rates (9.3% vs. 5.3%, p = 0.42) compared to age matched controls, respectively. ASO and ADB positive rates had no significant differences among different disease duration groups (p = 0.55 and 0.9, respectively).Conclusion: Streptococcus infection reflected by increase of ASO and ADB levels was not found in Chinese patients with type 1 narcolepsy, additional triggers for narcolepsy need to be addressed in this population. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were to document the trajectory of weight gain and body mass index (BMI) in children with type 1 narcolepsy, and to analyze basal metabolic rate (BMR).Methods: A total of 65 Chinese children with type 1 narcolepsy with a disease duration ≤12 months were included. In addition, 79 healthy age-matched students were enrolled as controls. Height and body weight were measured every six months for up to 36 months to calculate BMI growth. BMR was measured using COSMED K4b2 indirect calorimetry in 34 patients and 30 healthy controls at six months. At the end of 36 months, the BMR was compared among 18 patients and 16 healthy controls.Results: The children with type 1 narcolepsy showed higher BMIs at follow-up assessments. At the end of the study, 38.46% of the patients were obese and an additional 26.15% were overweight. The patients' BMI growth at six, 12, 18, 24 and 30 months of follow-up was significantly higher, but not at month 36. The patients' basal energy expenditure was significantly lower than that of the controls at six months but not at 36 months.Conclusion: BMI increased rapidly in children with type 1 narcolepsy after disease onset, but BMI growth decreased gradually with prolonged disease. Decreased BMR is an important cause underlying rapid weight gain. The gradual restoration of BMI growth and BMR in narcolepsy emphasizes the importance of compensatory metabolic mechanisms in this disease. [ABSTRACT FROM AUTHOR]

Type 1 narcolepsy, an autoimmune disease affecting hypocretin (orexin) neurons, is strongly associated with HLA-DQB1*06:02. Among polymorphisms associated with the disease is single-nucleotide polymorphism rs2305795 (c.*638G>A) located within the P2RY11 gene. P2RY11 is in a region of synteny conserved in mammals and zebrafish containing PPAN, EIF3G and DNMT1 (DNA methyltransferase 1). As mutations in DNMT1 cause a rare dominant form of narcolepsy in association with deafness, cerebellar ataxia and dementia, we questioned whether the association with P2RY11 in sporadic narcolepsy could be secondary to linkage disequilibrium with DNMT1. Based on genome-wide association data from two cohorts of European and Chinese ancestry, we found that the narcolepsy association signal drops sharply between P2RY11/EIF3G and DNMT1, suggesting that the association with narcolepsy does not extend into the DNMT1 gene region. Interestingly, using transethnic mapping, we identified a novel single-nucleotide polymorphism rs3826784 (c.596-260A>G) in the EIF3G gene also associated with narcolepsy. The disease-associated allele increases EIF3G mRNA expression. EIF3G is located in the narcolepsy risk locus and EIF3G expression correlates with PPAN and P2RY11 expression. This suggests shared regulatory mechanisms that might be affected by the polymorphism and are of relevance to narcolepsy. [ABSTRACT FROM AUTHOR]

Abstract: 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 ∼2000bp promoter region was first sequenced in 181 patients and 153 controls, and rare polymorphisms including three nonsynonymous amino acid changes were identified. Next the 557bp 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 6years, 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. [Copyright &y& Elsevier]

We report a 5-year-old boy with epilepsy and narcolepsy-cataplexy. He developed myoclonic seizures at the age of 4 years, which manifested as head shaking to the left. Approximately 6 months later, narcolepsy-cataplexy with excessive daytime sleepiness occurred. Although a short-time electroencephalography (EEG) and 24-hour ambulatory EEG monitoring found epileptiform discharges, no seizures were determined. Oxcarbazepine was used and led to increased attacks. Video EEG testing finally confirmed the diagnosis of epilepsy; therefore, valproate was given and seizures were controlled completely. Typical cataplexy triggered by laughing, together with the positive multiple sleep latency tests confirmed a diagnosis of narcolepsy-cataplexy. Human leukocyte antigens DQB1*0602 was positive, and the hypocretin level in cerebrospinal fluid was found to be decreased. Combination of valproate, methylphenidate, and clomipramine treatment improved the symptoms of both narcolepsy-cataplexy and seizure. The coexistence of both disorders in this single patient indicated that there might be a common mechanism between epilepsy and narcolepsy-cataplexy. [ABSTRACT FROM PUBLISHER]

A correction to the article "Common variants in P2RY11 are associated with narcolepsy" that was published in the December 19, 2010 issue is presented.