Patricia Franco1,2,3, Yves Dauvilliers2,4,5, Clara Odilia Inocente1, Aurore Guyon1,2,3, Carine Villanueva6, Veronique Raverot7, Sabine Plancoulaine8, Jian-Sheng Lin1. 1. Integrative Physiology of the Brain Arousal System, CRNL, INSERM-U1028, CNRS, UMR5292, University Lyon1, Lyon, France. 2. National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), Bron, France. 3. Pediatric Sleep Unit, Mother- Children Hospital, Hospices Civils de Lyon, University Lyon1, Lyon, France. 4. Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, CHU Montpellier, Montpellier, France. 5. Inserm, U1061, Univ Montpellier 1, Montpellier, France. 6. Department of Endocrinology, Mother- Children Hospital, Hospices Civils de Lyon, University Lyon1, France. 7. Laboratoire de Hormonologie, Groupement Est, Hospices Civils de Lyon, University Lyon1, Lyon, France. 8. INSERM, UMR1153, Centre of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Villejuif, Paris-Descartes University, Paris, France.
Abstract
OBJECTIVE: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.
OBJECTIVE:Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcolepticpatients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcolepticpatients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS:Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcolepticchildren and support the use of a histaminergic therapy in the treatment against narcolepsy.
Authors: Philipp O Valko; Yury V Gavrilov; Mihoko Yamamoto; Hasini Reddy; Johannes Haybaeck; Emmanuel Mignot; Christian R Baumann; Thomas E Scammell Journal: Ann Neurol Date: 2013-12 Impact factor: 10.422