Effect of CPS14217C>A genotype on valproic-acid-induced hyperammonemia

Abstract Background: In order to clarify the factors causing hyperammonemia and to predict occurrences during treatment with valproic acid (VPA), we investigated the effect of the genetic polymorphism of carbamoyl‐phosphate synthase 1 ( CPS1 4217C>A) on susceptibility of hyperammonemia, together with the effect of coadministration of other anticonvulsants. Methods: Seventy‐nine patients with epilepsy were enrolled, and five of them had hyperammonemia. Univariate and multivariate logistic regression analyses were performed. Results: The aspartate aminotransferase level in the patients with hyperammonemia was significantly higher than that in those without hyperammonemia. The risk of hyperammonemia was significantly influenced by the number of anticonvulsants concomitantly administered with VPA. Also, the distribution of the CPS1 4217C>A genotype differed depending on whether the patients had hyperammonemia or not. No significant effects of CPS1 4217 genotypes and the number of anticonvulsants coadministered with VPA on the serum concentrations of VPA were observed. The multivariate logistic regression analysis showed that the concomitant administration of two or more anticonvulsants with VPA and the heterozygous or homozygous carrier state of the A allele of the CPS1 4217C>A polymorphism were independent risk factors for developing hyperammonemia. Conclusions: These findings suggested that in epileptic patients undergoing VPA therapy, CPS1 4217A polymorphism and the number of coadministered anticonvulsants would be considered as risk factors for hyperammonemia, even if the serum VPA concentrations were controlled.