Impaired histaminergic neurotransmission in children with narcolepsy type 1

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.

Keywords: histamine; hypocretin (orexin); narcolepsy; pediatrics; sleep.

Figure 1

Schematic graphics illustrating the pathway of histamine (HA) synthesis, release, and inactivation and our interpretation on the changes in the CSF HA and tele‐methylhistamine (t‐MeHA) levels seen with the narcoleptic children. HA is synthetized solely by histidine decarboxylase (HDC) and inactivated, once released from terminals, by HA‐N‐methyltransferase producing the direct metabolite t‐MeHA. Bar presentation of HA and t‐MeHA levels is based on the values given in Table 1. Our narcoleptic children showed a marked increase in CSF HA, which unlikely indicates an upregulation of HA synthesis or/and release because of an accompanied marked decrease in t‐MeHA. This concomitant increase in HA and decrease in t‐MeHA lead to a remarkable decrease in the t‐MeHA/HA ratio (7.2 folds), indicating an abnormal accumulation or impaired utilization of HA. On a more functional level, our observations strongly suggest that HA neurotransmission is prominently affected in narcoleptic children. The confirmation of such impaired dynamic of the brain HA system as a causative agent in narcolepsy awaits further development of direct neurochemical monitoring of HA transmission in the human brain

Figure 2

Histamine (HA) levels according to BMI z‐score in case and control children. BMI z‐score: body mass index z‐score, CSF HA levels: cerebrospinal fluid histamine levels; cases: narcoleptic children (cases) are represented by black diamond‐shaped figure (♦), control children by empty squares (□). A significant decrease in CSF HA levels was observed with the increase in BMI z‐score among cases (P = 0.007), while no association was observed among controls (P = 0.31) (multivariable regression model M1)

Figure 3

Tele‐methyl‐histamine (t‐MeHA) levels according to BMI z‐score in case and control children. BMI z‐score: body mass index z‐score, t‐MeHA levels: cerebrospinal fluid tele‐methyl‐histamine (t‐MeHA) levels; cases: narcoleptic children (cases) are represented by black diamond‐shaped figure (♦), control children by empty squares (□). A significant increase in CSF t‐MeHA was observed with the increase in BMI z‐score among controls (P = 0.006), while no association was observed among cases (P = 0.15) (multivariable regression model M1)

Figure 4

Tele‐methyl‐histamine (t‐MeHA) levels according to age in case and control children. T‐MeHA levels: cerebrospinal fluid tele‐methylhistamine (t‐MeHA) levels; cases: narcoleptic children (cases) are represented by black diamond‐shaped figure (♦), control children by empty squares (□). A significant decrease in CSF t‐MeHA was observed with age among controls (P = 0.005), while no association was observed among cases (P = 0.15) (multivariable regression model M1)