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Impaired histaminergic neurotransmission in children with narcolepsy type 1
Patricia Franco1,2,3, Yves Dauvilliers2,4,5, Clara Odilia Inocente1
1Integrative Physiology of the Brain Arousal System, CRNL, INSERM-U1028, CNRS, UMR5292, University Lyon1, Lyon, France.
Insights
Children with narcolepsy type 1 (NT1) show altered brain histamine (HA) levels, with higher HA and lower tele-methylhistamine (t-MeHA) in cerebrospinal fluid (CSF). This suggests impaired histaminergic neurotransmission, supporting potential HA-based narcolepsy treatments.
Area of Science:
- Neuroscience
- Sleep Medicine
- Biochemistry
Background:
- Narcolepsy type 1 (NT1) is a neurological sleep disorder often starting in childhood, characterized by excessive daytime sleepiness and cataplexy.
- The primary cause of NT1 is the loss of hypocretin (orexin) neurons in the hypothalamus.
- The role of brain histamine (HA) in pediatric narcolepsy remains under investigation.
Purpose of the Study:
- To investigate the levels of brain histamine (HA) and its metabolite tele-methylhistamine (t-MeHA) in the cerebrospinal fluid (CSF) of children with narcolepsy type 1 (NT1).
- To explore the relationship between HA, t-MeHA, and narcolepsy pathophysiology in pediatric patients.
Main Methods:
- Collected CSF samples from 24 children diagnosed with NT1 and 21 age- and sex-matched healthy controls.
- Quantified CSF levels of HA and t-MeHA using liquid chromatography-tandem mass spectrometry.
- Measured CSF hypocretin-1 levels in NT1 patients and analyzed correlations with HA, t-MeHA, and clinical factors.
Main Results:
- Children with NT1 exhibited significantly higher CSF HA levels (771 vs 234 pmol/L) and lower t-MeHA levels (879 vs 1924 pmol/L) compared to controls.
- The t-MeHA/HA ratio was markedly reduced in NT1 children (1.1 vs 8.2), indicating decreased HA turnover.
- NT1 patients showed higher BMI z-scores and obesity rates, with decreased CSF HA associated with increased BMI z-score in this group.
Conclusions:
- Pediatric narcolepsy type 1 is associated with altered CSF histamine levels, characterized by elevated HA and reduced t-MeHA.
- These findings suggest impaired histaminergic neurotransmission in NT1.
- The results support the potential therapeutic application of histaminergic agents for treating narcolepsy in children.
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.
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