Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy

Kaisa Teele Oja; Mihkel Ilisson; Karit Reinson; Kai Muru; Tiia Reimand; Hedi Peterson; Dmytro Fishman; Tõnu Esko; Toomas Haller; Jaanika Kronberg; Monica H Wojcik; Adam Kennedy; Gregory Michelotti; Anne O'Donnell-Luria; Eve Õiglane-Šlik; Sander Pajusalu; Katrin Õunap

doi:10.1101/2023.03.29.23287640

Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy

medRxiv [Preprint]. 2023 Mar 30:2023.03.29.23287640. doi: 10.1101/2023.03.29.23287640.

Authors

Kaisa Teele Oja^{1

2}, Mihkel Ilisson², Karit Reinson^{1

2}, Kai Muru^{1

2}, Tiia Reimand^{1

2}, Hedi Peterson³, Dmytro Fishman³, Tõnu Esko⁴, Toomas Haller⁴, Jaanika Kronberg⁴, Monica H Wojcik^{5

6

7}, Adam Kennedy⁸, Gregory Michelotti⁸, Anne O'Donnell-Luria^{5

6}, Eve Õiglane-Šlik^{9

10}, Sander Pajusalu^{1

2}, Katrin Õunap^{1

2}

Affiliations

¹ Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
² Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
³ Institute of Computer Science, Faculty of Science and Technology, University of Tartu, Tartu, Estonia.
⁴ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
⁵ Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
⁷ Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
⁸ Metabolon, 615 Davis Drive, Suite 100, Morrisville, NC, USA.
⁹ Department of Pediatrics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu.
¹⁰ Children's Clinic of Tartu University Hospital, Tartu University Hospital.

Abstract

Introduction: Epilepsy is a common central nervous system disorder characterized by abnormal brain electrical activity. We aimed to compare the metabolic profiles of plasma from patients with epilepsy across different etiologies, seizure frequency, seizure type, and patient age to try to identify common disrupted pathways.

Material and methods: We used data from three separate cohorts. The first cohort (PED-C) consisted of 31 pediatric patients with suspicion of a genetic disorder with unclear etiology; the second cohort (AD-C) consisted of 250 adults from the Estonian Biobank (EstBB), and the third cohort consisted of 583 adults ≥ 69 years of age from the EstBB (ELD-C). We compared untargeted metabolomics and lipidomics data between individuals with and without epilepsy in each cohort.

Results: In the PED-C, significant alterations (p-value <0.05) were detected in sixteen different glycerophosphatidylcholines (GPC), dimethylglycine and eicosanedioate (C20-DC). In the AD-C, nine significantly altered metabolites were found, mainly triacylglycerides (TAG), which are also precursors in the GPC synthesis pathway. In the ELD-C, significant changes in twenty metabolites including multiple TAGs were observed in the metabolic profile of participants with previously diagnosed epilepsy. Pathway analysis revealed that among the metabolites that differ significantly between epilepsy-positive and epilepsy-negative patients in the PED-C, the lipid superpathway (p = 3.2*10-4) and phosphatidylcholine (p = 9.3*10-8) and lysophospholipid (p = 5.9*10-3) subpathways are statistically overrepresented. Analogously, in the AD-C, the triacylglyceride subclass turned out to be statistically overrepresented (p = 8.5*10-5) with the lipid superpathway (p = 1.4*10-2). The presented p-values are FDR-corrected.

Conclusion: Our results suggest that cell membrane fluidity may have a significant role in the mechanism of epilepsy, and changes in lipid balance may indicate epilepsy. However, further studies are needed to evaluate whether untargeted metabolomics analysis could prove helpful in diagnosing epilepsy earlier.

Keywords: epilepsy; lipidomics; metabolomics; phosphatidylcholines.

Publication types

Preprint