Abnormal fatty acid metabolism in narcolepsy type 1 and other hypersomnia

Narcolepsy type 1 (NT1) (previously called narcolepsy with cataplexy) is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and abnormal rapid eye movement (REM) sleep. In addition, NT1 patients are a higher risk of obesity. Researchers at Tokyo Metropolitan Institute of Medical Science and colleagues noted that a previous study revealed that a genetic variant (rs5770917) located in carnitine palmitoyltransferase 1B (CPT1B) gene was associated with not only NT1 but also other hypersomnia through a genome-wide association study. CPT1B is a rate-limiting enzyme in β-oxidation of long-chain fatty acid. Long-chain fatty acids are transported into mitochondria through the carnitine shuttle, in which the rate-limiting step is catalyzed by CPT1B. Therefore, in the present study, the researchers analyzed individual acylcarnitines using electrospray ionization tandem mass spectroscopy and conducted RNA sequencing-based whole transcriptome analysis, finding that abnormal fatty acid metabolism is involved in the pathophysiology of other hypersomnia as well as NT1.

image: Statistically significant P values are marked with bold.
The ratio of C0/(C16+C18) is calculated as a CPT1 activity marker, where free carnitine (C0) is a substrate of CPT1 and C16+C18 is the sum of long-chain acylcarnitines that are products of CPT1. Decreases in CPT1 activity lead to decreased CPT1 product (C16+C18), denominator, resulting in the increase of the ratio.
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Credit: TMIMS

Acylcarnitine analysis-low CPT1 activity-

Levels of individual acylcarnitines in 57 NT1 patients, 51 other hypersomnia patients and 61 healthy controls were determined using electrospray ionization tandem mass spectroscopy. As hypothesized by the researchers, levels of several long-chain acylcarnitines with a carbon chain length of 16 or 18 were significantly lower in not only the NT1 group but also in the other hypersomnia group (Table 1). In addition, lower CPT1 activity was identified to be an independent risk factor for both sleep disorders.

Then, it was examined whether rs5770917 in CPT1B gene affects CPT1 activity, because rs5770917 is significantly correlated with lower expression levels of CPT1B gene. No significant correlation between rs5770917 and CPT1 activity was detected in general. However, there was an interaction between BMI (non-obese <25kg/m2 and obese ≥25kg/m2) and rs5770917 (risk+, risk-), and non-obese NT1 patients without the risk allele had higher CPT1 activity.

 

RNA sequencing-based whole transcriptome analysis-low expression levels of carnitine shuttle related genes-