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Abstract
Background and Objectives 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.
Methods 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).
Results 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.
Discussion 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.
Classification of Evidence This study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.
Glossary
- AHI=
- apnea-hypopnea index;
- ANOVA=
- analysis of variance;
- BCAA=
- branched-chain amino acid;
- BMI=
- body mass index;
- EDS=
- excessive daytime sleepiness;
- ESS=
- Epworth Sleepiness Scale;
- FDR=
- false discovery rate;
- ICSD-3=
- International Classification of Sleep Disorders, 3rd edition;
- LDL=
- low-density lipoprotein;
- lysoPC=
- lysophosphatidylcholines;
- MSLT=
- Multiple Sleep Latency Test;
- NT1=
- narcolepsy type 1;
- OPLS-DA=
- orthogonal partial least squares discriminant analysis;
- ORX=
- orexin;
- PC=
- phosphatidylcholine;
- PC aa=
- phosphatidylcholine diacyl;
- PC ae=
- phosphatidylcholine acyl-akyl;
- PLMS=
- periodic leg movements during sleep;
- PSG=
- polysomnography;
- QC=
- quality control;
- VIP=
- variable influence on prediction
Footnotes
Go to Neurology.org/N for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
Class of Evidence: NPub.org/coe
- Received April 12, 2021.
- Accepted in final form November 12, 2021.
- © 2022 American Academy of Neurology
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