Serum metabolomics identifies ganglioside dysregulation and pyruvate dehydrogenase complex-related metabolic disturbances in pediatric drug-resistant epilepsy.

Introduction: Despite advances in epilepsy management, the exact causes of epilepsy remain unclear, and diagnostic biomarkers are still lacking. Besides, about one-third of cases involve drug-resistant epilepsy (DRE). Methods: This study employed untargeted metabolomics to identify potential metabolic signatures in the sera of pediatric patients with epilepsy using liquid chromatography-high-resolution mass spectrometry. Results: Our results revealed several disrupted energetic pathways and metabolites indicative of oxidative stress and mitochondrial dysfunction in both controlled epilepsy (CE) and DRE groups. Seventy-five metabolites were significantly elevated in CE compared to healthy controls (HC), including ethenoadenosine, 6-methyladenine, and fatty acyl-carnitine conjugates and intermediates. Additionally, 144 metabolites were decreased in CE relative to HC, including various fatty acyl-CoA intermediates, GM3 ganglioside, and amino acids. Key disrupted pathways in CE included pyrimidine and purine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, pyruvate metabolism, and glycolysis/gluconeogenesis. In DRE, 25 metabolites were significantly reduced compared to non-DRE (NDRE), notably S-acetyldihydrolipoamide, 2-(alpha-hydroxyethyl)-thiamine diphosphate (HE-TDP), and S-adenosylmethionine (SAM). Metabolites involved in glycerophospholipid biosynthesis were decreased, along with lower levels of GM2 ganglioside. The most affected pathways in DRE included the tricarboxylic acid (TCA) cycle, pyruvate metabolism, glycolysis/gluconeogenesis, and cysteine and methionine metabolism. Conclusion: The observed alterations in S-acetyldihydrolipoamide, HE-TDP, and SAM support their further investigation as candidate monitoring biomarkers and as metabolites potentially involved in therapeutically relevant pathways in DRE. The alterations observed in HE-TDP, SAM, GM2, PS, and PE generate the hypothesis that pathways involving thiamine-dependent energy metabolism, methylation, ganglioside metabolism, and mitochondrial membrane function may be relevant to DRE. However, the present observational study did not evaluate supplementation, causality, efficacy, or safety. Consequently, any therapeutic application remains speculative and would require mechanistic validation, preclinical assessment, and appropriately designed clinical trials.