Metabolomic and molecular genetic markers of epilepsy in children with obesity

Epilepsy is one of the important problems of modern neurology. Various epileptic syndromes can be comorbid with other pathologies, in particular, with excess weight. Currently, various aspects of the etiopathogenesis of epileptic seizures against the background of obesity are actively studied.

Objective. The aim of the work is to identify the main metabolic and molecular genetic changes in epilepsy in children associated with obesity in order to develop a personalized approach to the diagnosis of this pathological condition.

Materials and methods. The study included 22 patients aged from 1 year to 16 years (mean age 11.7 years): 16 patients with various epileptic syndromes against the background of obesity and 6 patients of the comparison group. The study of the profile of 60 organic acids in urine was carried out by high performance liquid chromatography and tandem mass spectrometry. Whole exome sequencing was performed in 5 patients using a Helicon G50 genetic analyzer.

Results. In the group of patients with epilepsy against the background of obesity, the upper reference limit of a number of markers of the Krebs cycle (fumaric and 2-ketoglutaric acids), bacterial dysbiosis and lactic acid levels were exceeded. Also, in the sample of patients, in contrast to the comparison group, an increase in the levels of a number of markers of mitochondrial dysfunction was found. Whole exome sequencing of 5 patients with epilepsy against the background of obesity did not reveal known pathological mutations.

Conclusion. Thus, we have identified a number of metabolic markers associated with epilepsy in children against the background of obesity. Molecular genetic testing of a number of patients did not reveal significant pathological mutations. The results of the study confirm the importance of a personalized approach to the diagnosis and treatment of this pathological condition and further study of metabolomic and molecular genetic markers of this pathological condition.

1. Li Y.X., Guo W., Chen R.X., Lv X.R., Li Y. The relationships between obesity and epilepsy: A systematic review with meta-analysis. PLoS One 2024; 19(8): e0306175. DOI: 10.1371/journal.pone.0306175

2. Beghi E. The Epidemiology of Epilepsy. Neuroepidemiology 2020; 54(2): 185–191. DOI: 10.1159/000503831

3. Fisher R.S., Acevedo C., Arzimanoglou A., Bogacz A., Cross J.H., Elger C.E., et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55(4): 475–482. DOI: 10.1111/epi.12550

4. Pong A.W., Xu K.J., Klein P. Recent advances in pharmacotherapy for epilepsy. Curr Opin Neurol 2023; 36(2): 77–85. DOI: 10.1097/WCO.0000000000001144

5. Novak A., Vizjak K., Rakusa M. Cognitive Impairment in People with Epilepsy. J Clin Med 2022;11(1): 267. DOI: 10.3390/jcm11010267

6. Villanueva V., Artal J., Cabeza-Alvarez C.I., Campos D., Castillo A., Flórez G., et al. Proposed Recommendations for the Management of Depression in Adults with Epilepsy: An Expert Consensus. Neurol Ther 2023; 12(2): 479–503. DOI: 10.1007/s40120–023–00437–0

7. Sidhu H.S., Srinivasa R., Sadhotra A. Evaluate the effects of antiepileptic drugs on reproductive endocrine system in newly diagnosed female epileptic patients receiving either Valproate or Lamotrigine monotherapy: A prospective study. Epilepsy Res 2018; 139: 20–27. DOI: 10.1016/j.eplepsyres.2017.10.016

8. Gotlib D., Ramaswamy R., Kurlander J.E., DeRiggi A., Riba M. Valproic Acid in Women and Girls of Childbearing Age. Curr Psychiatry Rep 2017; 19(9): 58. DOI: 10.1007/s11920–017–0809–3

9. Lai W., Shen N., Zhu H., He S., Yang X., Lai Q., et al. Identifying risk factors for polycystic ovary syndrome in women with epilepsy: A comprehensive analysis of 248 patients. J Neuroendocrinol 2023; 35(3): e13250. DOI: 10.1111/jne.13250

10. Zhou K., Yang H., Chen R., Wang W., Qu Z. Causal relation-ship among obesity and body fat distribution and epilepsy subtypes. Front Neurol 2022; 13: 984824. DOI: 10.3389/fneur.2022.984824

11. Buro A.W., Salinas-Miranda A., Marshall J., Gray H.L., Kirby R.S. Obesity and neurodevelopmental and mental health conditions among adolescents aged 10–17years: The National Survey of Children’s Health 2017–2018. J Paediatr Child Health 2022; 58(10): 1753–1759. DOI: 10.1111/jpc.16081

12. Lee D.H., Kim S.Y., Park J.E., Jeon H.J., Park J.H., Kawachi I. Nationwide trends in prevalence of underweight, over-weight, and obesity among people with disabilities in South Korea from 2008 to 2017. Int J Obes (Lond) 2022; 46(3): 613–622. DOI: 10.1038/s41366–021–01030-x

13. Lee Y., Ahn Y., Cucullo L. Impact of Physical Activity and Medication Adherence on the Seizure Frequency and Quality of Life of Epileptic Patients: A Population Study in West Texas. Biomed Res Int 2022; 2022: 4193664. DOI: 10.1155/2022/4193664

14. Chen M., Wu X., Zhang B., Shen S., He L., Zhou D. Associations of overweight and obesity with drug-resistant epilepsy. Seizure 2021; 92: 94–99. DOI: 10.1016/j.seizure.2021.07.019

15. Nazish S. Obesity and metabolic syndrome in patients with epilepsy, their relation with epilepsy control. Ann Afr Med 2023; 22(2): 136–144. DOI: 10.4103/aam.aam_139_22

16. Pfeifer M.T., Kostev K., Doege C. Sex-related associations between body mass index and the incidence of epilepsy. Epilepsy Behav 2022; 136: 108926. DOI: 10.1016/j.yebeh.2022.108926

17. Ziegler S.G., Kim J., Ehmsen J.T., Vernon H.J. Inborn errors of amino acid metabolism — from underlying pathophysiology to therapeutic advances. Dis Model Mech 2023; 16(11): dmm050233. DOI: 10.1242/dmm.050233

18. Coman D., Kranc K.R., Christodoulou J. Fumarate Hydratase Deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, 1993–2024.

19. Rasgado L.A., Reyes G.C., Díaz F.V. Modulation of brain glutamate dehydrogenase as a tool for controlling seizures. Acta Pharm 2015; 65(4): 443–452. DOI: 10.1515/acph-2015–0033

20. Desguerre I., Hully M., Rio M., Nabbout R. Mitochondrial disorders and epilepsy. Rev Neurol (Paris) 2014; 170(5): 375–380. DOI: 10.1016/j.neurol.2014.03.010