Impaired histaminergic neurotransmission in children with narcolepsy type 1.

Abstract

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. We included 24 children with NT1 (12.3±3.6years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2±4.2years, 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. Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234pmol/L, P<0.001), lower t-MeHA levels (879 vs 1924pmol/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. 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.