THE EFFECT OF UGT1A6 POLYMORPHISM AT TWO LOCI ON THE CLINICAL RESPONSE TO VALPROIC ACID IN EPILEPTIC CHILDREN

Background and Aim: Valproic acid (VPA) is a widely used antiepileptic drug. The main pathway of its elimination is through conjugation by UDP-glucuronosyltransferases with several polymorphic forms. In this study, we aimed to examine the effect of polymorphism in UGT1A6 enzyme-coding gene at two loci, namely, 541A>G and 552A>C on clinical outcome in Egyptian children with idiopathic epilepsy. Clinical outcome investigations involved VPA serum level, seizure control and incidence of adverse drug reactions (ADR). Methods: Genetic polymorphisms were detected in 48 patients receiving VPA monotherapy by PCR-RFLP. Steady state concentrations at trough level were determined by homogenous enzyme immunoassay technique. Patients were monitored for ADR, seizure frequency as well as seizure severity (SS). Results: Variant genotype group (AC & CC) had lower concentration to dose ratios (CDR) than those with (AA) genotype for UGT1A6 552A>C (p=0.029). Variant allele carriers had significantly lower CDR than wild allele carriers for both 541A>G and 552A>C (p= 0.047 and p= 0.001, respectively). Wild genotype for 552A>C had higher SS scores on Chalfont scale (p=0.020) and showed significantly higher incidence of fatigue than variant genotypes (p=0.047).  Children carrying variant genotype for 541 A>G showed a significantly higher incidence of difficulty in concentration reflected upon school work than wild genotype carriers (p=0.025). Neither loci could be found to affect seizure control. Conclusion: UGT1A6 polymorphisms may increase VPA metabolism in Egyptian epileptic children affecting both seizure severity as well as susceptibility to ADR. Further study with a larger sample size is strongly recommended.