Abstract
Background: Febrile seizures (FS) are the most common seizures in childhood, yet their clinical, biochemical, and genetic risk factors are still being clarified. This study aimed to provide a comprehensive evaluation of FS from clinical, laboratory, and genetic perspectives. Methods: In this prospective cohort study, 124 children aged 6 months to 5 years presenting with FS and 93 febrile controls without seizures were evaluated. Clinical features, laboratory parameters (including trace elements and hormonal markers), and genetic analysis using a 37-gene epilepsy panel were assessed. Multivariate logistic regression analysis was performed to identify independent predictors of FS, complex FS, and recurrent seizures. Results: Children with FS had significantly lower serum sodium, vitamin D, and zinc levels compared to controls. Multivariate analysis identified low sodium and low vitamin D levels as independent risk factors for FS. In the subgroup analysis, lower sodium and vitamin D levels and elevated ferritin levels were independently associated with complex FS. Lower serum zinc levels were significantly associated with seizure recurrence. Genetic analyses revealed pathogenic or likely pathogenic variants in 15.7% of patients with FS, predominantly involving SCN1A and PCDH19 genes. Patients with pathogenic variants also exhibited significantly lower levels of zinc, and selenium compared to genetically negative patients. Conclusions: This study highlights that metabolic disturbances, particularly involving sodium, vitamin D, and zinc, play a crucial role in FS occurrence, complexity, and recurrence. Ferritin may serve as a more sensitive indicator of inflammatory processes influencing seizure severity compared to CRP. Furthermore, genetic predispositions, especially SCN1A and PCDH19 variants, may underlie susceptibility in a subset of children. Routine evaluation of biochemical markers and consideration of genetic testing in selected cases may enhance individualized management strategies for FS.