Open AccessImpaired histaminergic neurotransmission in children with narcolepsy type 1
Author(s) -
Franco Patricia,
Dauvilliers Yves,
Inocente Clara Odilia,
Guyon Aurore,
Villanueva Carine,
Raverot Veronique,
Plancoulaine Sabine,
Lin JianSheng
Publication year - 2019
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13057
Subject(s) - cataplexy , narcolepsy , histaminergic , orexin , medicine , endocrinology , cerebrospinal fluid , gastroenterology , psychology , histamine , neuropeptide , neurology , psychiatry , receptor
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.