Introduction: The goal of the antiepileptic therapy is the complete control of seizures with adverse drug reactions as limited as possible. This becomes even more important in children and adolescents with longstanding therapy, where the effectiveness of the treatment and the possible manifestation of adverse drug reactions are even more crucial. Polymorphisms of genes involved in the metabolism and transport of antiepileptic drugs influence the effect of therapy and in the manifestation of collateral effects. In this dissertation, we evaluated genetic markers in children and adolescents with epilepsy, which may be associated with the effectiveness of therapy and the manifestation of collateral effects.
Methods: We included 165 children and adolescents with epilepsy treated at the Department of Child, Adolescent and Developmental Neurology, Children's Hospital, University Medical Centre Ljubljana, Slovenia. Family and personal history were taken. Molecular genetics analysis with qPCR to test for known polymorphisms of the genes CYP3A4, CYP2C9, CYP2C19, ABCB1, ABCC2, ABCG2 and SCN1A were performed. Statistical analysis with genetics and clinical data were performed. A control group of 95 presumably healthy participants was used.
Results: Patients treated with valproic acid with genotype TT of the polymorphism ABCB1 rs1128503 have 4 times more frequently present cognitive impairment compared to patients with genotype CT. The association of this variant with cognitive impairment due to valproic acid treatment has not been previously reported. Patients treated with valproic acid with genotype AG of polymorphism ABCC2 rs2273697 have 3 times more frequently present cognitive impairment compared to those with genotype GG. This corroborated the reported higher valproic acid concentrations in patients with AA genotype in comparison to GG genotype. Patients with genotype GG of the polymorphism CYP2C19 rs4244285 have 2.6 times more frequently present adverse drug reactions behavioural disorder compared to genotype AA, while patients with genotype AA have 2.8 times more frequently behavioural disorder compared with cognitive impairment. This variant has been previously reported in correlation with other adverse drug reactions of the valproic acid treatment, such as obesity and hypeinsulinism in female patients with epilepsy, but not in association with behavioural disorders. Patients treated with carbamazepine or oxcarbazepine with genotype AG of the polymorphism ABCC2 rs717620 have 3 times more frequently behavioural disorders compared to genotype GG which has not been previously reported. We have shown that in patients with G allele of the polymorphism SCN1A rs2298771, mainly at the homozygous state, the antiepileptic treatment is more efficient, which has not been previously reported. At the same time, it is associated with predisposition to develop epilepsy, already reported in Asian populations.
Conclusions: The results of our and similar studies could be the foundation of the future recommendations for the individualised treatment of the epilepsy that will have sufficient efficiency and limited adverse drug reactions.
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