Metabolic Profile Identified to Distinguish Patients With Narcolepsy Type 1

Yves Dauvilliers, MD, PhD

Data from a recent study suggest a distinct metabolite profile can differentiate patients with narcolepsy type 1 (NT1) from patients that do not have the disorder, using body mass index (BMI) as a function. Investigators propose that identified metabolites may also offer targets for treatment of obesity in this patient population. 

A total of 117 patients with NT1 and a mean age of 38.4 years (standard deviation [SD], 17.1) were included in the study, 41 of whom were obese (BMI >30 kg/m2) and 32 of whom were overweight (BMI ≥25 and ≤30 kg/m2). Also included were 116 patients with a mean age of 35.5 years (SD, 11.9) in a BMI control group, who had been referred for evaluation of hypersomnolence, suspected sleep-disordered breathing, or a systematic sleep study in health subjects. Within the control group, 57 participants were obese and 8 were overweight.

Investigators, led by Yves Dauvilliers, MD, PhD, professor of neurology and physiology, University of Montpellier; and coordinator, National Reference Network for Orphan Disease: Narcolepsy and Rare Hyperinsomnias, Sleep Unit, department of neurology, Gui de Chauliac Hospital, Montpellier, France, found that sarcosine, glutamate, nonaylcarnitine (C9), 5 long chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls all showed increased concentration levels in patients with NT1, driving the difference between them and the control group, irrespective of BMI. There was little overlap in metabolite concentrations that were significantly affected by NT1 and BMI category. 

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When performing a quantitative enrichment analysis, common metabolic pathways implicated in the NT1, and control differences were revealed in both normal BMI and obese comparisons. This included glycine and serine, arachidonic acid, and tryptophan metabolisms. 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). 

As part of the NT1 metabolic phenotype, relationships between metabolic concentrations seen in the control group and sleep parameters—namely sleep duration, sleep latency, and periodic leg movement—were lost, according to investigators, having identified this during linear metabolite endophenotype regression analyses. Investigators employed a targeted liquid chromatography-mass spectrometry metabolomic approach in the study, measuring 141 circulating, low molecular weight metabolites. Venous blood samples were collected from participants in drug-free conditions who fasted since 8 PM the night before in a sleep laboratory, following a polysomnography recording. 

“Our results support a metabolomics signature of NT1, with sarcosine, glutamate, tryptophan, serotonin, acylcarnitines (eg, C9), some long chain lysoPCs and phosphatidylcholines (eg, PC aa C34:4) being the main metabolites driving these differences, and showing increased concentrations in NT1,” Dauvilliers et al wrote. “Our linear metabolite endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between sleep parameters and metabolite concentrations observed in the controls were lost in the NT1 patients.”

Investigators noted study limitations, included the absence of a large group of health controls; however, the both the control group and the patient group were heterogeneous. Additionally, metabolites related to carbohydrate, bile acid, sterol and steroid metabolism, nor peptides such as ghrelin or leptin were identified, as the metabolomics analytical platform was targeted to measures a specific set of metabolite classes. 

“These results represent the most comprehensive metabolic profiling of NT1 as a function of BMI and suggest some potential diagnostic biomarkers for NT1 metabolic disturbances, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine (C9), and PC aa C34:4,” Dauvilliers et al wrote. “If confirmed, these metabolic pathways are possible targets for treatment of obesity in NT1.”

REFERENCE

Dauvilliers Y, Barateau L, Middleton B, Van Der Veen D, Skene DJ. Metabolomic signature of patients with narcolepsy. Neurology. Published online November 29, 2021. doi:10.1212/WNL.0000000000013128