Abstracts

Rationale: The mechanism behind valproic acid-related liver failure is not clear. Human DNA polymerase iscomposed of two subunits; the catalytic subunit encoded by polymerase ? (POLG) andaccessory subunit encoded by POLG2. More than 80 pathogenic mutations mapped to the genefor the catalytic subunit (POLG) are known to result in Alpers Syndrome,myocerebrohepatopathy and other infantile hepatocerebral syndromes with mtDNA depletion.Only mutations in POLG for the mitochondrial DNA helicase TWINKLE have been associatedwith genetically proven valproic acid-related liver failure. Also a few other pathogenic POLGmutations have been reported to be associated with liver failure in patients with a phenotypeconcerning for Alpers Syndrome. The clinical significance of nonpathogenic variants in the POLGgene and the risk of developing liver failure with valproic acid (VPA) use are still unclear. Wereviewed our clinical records for children treated with VPA who had POLG mutations ofuncertain significance. Methods: Retrospective chart review of patients with mutations of uncertain significance in the POLGgene and treated by valproic acid. Results: Two patients were found to have variants of uncertain significance in the POLG gene. Theywere treated with valproic acid for seizure management. Patient 1 is a 12-month-old femaleinfant who presented with infantile spasms. Patient 2 is a 4-year-old male with refractorygeneralized epilepsy. Neither of them had a phenotype concerning for Alpers Syndrome. Bothof them were treated with valproic acid at the time of the genetic testing. Molecular studies onthe first patient showed a probable pathogenic variant (c.803G>C), and the second patient had a c331G>A p.Gly 111Arg variation in the POLG gene. Patient 1 was treated with valproic acid for 6 months with doses up to 38mg/kg/day and maximum serum trough levels reaching up to130mg/L. Patient 1 also received carnitine. Patient 2 received valproic acid for 25 months withdoses up 30 mg/kg/day with significant improvement in his seizure frequency. Neither patienthad changes in liver functions or signs of hepatotoxicity. Conclusions: Valproic acid appears to be a safe therapeutic option for seizure management in patientswithout a phenotype concerning for Alpers who happen to have a POLG mutation of uncertainsignificance.