Narcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m²). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.

We used a targeted liquid chromatography–mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals).

Common metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC aa C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost.

These results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1.

This study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.

嗜睡症 1 型 (NT1) 是一种由食欲素神经元的不可逆破坏引起的孤儿脑疾病。代谢紊乱常见于体重指数 (BMI) 比一般人群高 10% 至 20% 的 NT1 患者，其中三分之一为肥胖（BMI >30 kg/m ²）。除了 NT1 中食欲素神经元的破坏外，肥胖和非肥胖 NT1 患者的代谢改变仍然未知。本研究的目的是确定 NT1 患者和对照组之间血浆代谢谱的可能差异，作为其 BMI 状态的函数。

我们使用靶向液相色谱-质谱代谢组学方法测量了 117 名 NT1 患者（包括 41 名肥胖个体）与 116 名 BMI 匹配的对照（包括 57肥胖者）。

确定了导致 NT1 患者和对照组之间差异的常见代谢物，无论 BMI 为何，即肌氨酸、谷氨酸、壬基肉碱 (C9)、5 种长链溶血磷脂酰胆碱酰基、1 种鞘脂、12 种磷脂酰胆碱二酰基和 11 种磷脂酰胆碱酰基-烷基，所有显示 NT1 中的浓度增加。受 NT1 (n = 42) 和 BMI 类别 (n = 40) 显着影响的代谢物浓度几乎没有重叠 (n = 5)。定量富集分析揭示了与正常 BMI 和肥胖比较中 NT1/对照差异有关的常见代谢途径，即甘氨酸和丝氨酸、花生四烯酸和色氨酸代谢。驱动这些差异的代谢物是谷氨酸、肌氨酸和鸟氨酸（甘氨酸和丝氨酸代谢）；谷氨酸和 PC aa C34：4（花生四烯酸代谢）；和谷氨酸、血清素和色氨酸（色氨酸代谢）。线性代谢物-内表型回归分析强调，作为 NT1 代谢表型的一部分，在对照组中观察到的睡眠参数（即慢波睡眠持续时间、睡眠潜伏期和周期性腿运动）与代谢物浓度之间的大多数关系都丢失了.

这些结果代表了 NT1 患者最全面的代谢谱作为 BMI 的函数，并提出了一些 NT1 代谢诊断生物标志物，即谷氨酸、肌氨酸、5-羟色胺、色氨酸、壬基肉碱和一些磷脂酰胆碱。如果得到证实，确定的代谢途径为 NT1 治疗肥胖提供了可能的目标。

这项研究提供了 II 类证据，表明不同的代谢特征可以区分 NT1 患者和没有疾病的患者。