Serum methylmalonic acid levels and epilepsy prevalence: Association analysis, exploratory mediation, and clinical corroboration

OBJECTIVE: This study aimed to investigate the association between methylmalonic acid (MMA) and epilepsy prevalence and to explore potential inflammatory and nutritional pathways underlying this association. METHODS: This study included adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Weighted multivariable logistic regression was used to assess the association between MMA and epilepsy prevalence, and restricted cubic spline (RCS) analysis was performed to explore potential nonlinearity. Subgroup and mediation analyses were conducted to evaluate heterogeneity and the mediating effects of the systemic inflammation response index (SIRI) and albumin (ALB). An independent clinical cohort was used for preliminary clinical corroboration, and serum MMA and inflammatory/neuronal markers were measured by enzyme-linked immunosorbent assay. RESULTS: A total of 9996 participants were included. Higher MMA was significantly associated with epilepsy prevalence (continuous MMA: odds ratio [OR] = 1.377, 95% confidence interval [CI]: 1.017-1.865; highest versus lowest tertile [T3 vs. T1]: OR = 1.593, 95% CI: 1.024-2.477). RCS analysis suggested a nonlinear association, with an apparent inflection point around ln(MMA) = 4.8. The association was more pronounced in participants aged < 60 years (p for interaction = 0.006). Exploratory mediation analysis indicated that SIRI and ALB accounted for 3.875% and 6.340% of the observed association respectively (both p < 0.001). Findings from the clinical cohort were consistent with the NHANES results. Patients with epilepsy had higher serum MMA levels, and MMA levels were significantly correlated with both inflammatory and neuronal injury markers. CONCLUSION: Elevated MMA levels were associated with epilepsy prevalence in NHANES. The preliminary findings from the independent clinical cohort showed consistent patterns. Further prospective studies are needed to clarify the temporal relationship between MMA and epilepsy.