Recently, it has been recognized that rare mutations in the urea cycle genes encoding CPS1 and OTC might have detrimental consequences in patients being treated with valproic acid. Severe cases of urea cycle disorders (UCDs) are primarily recognized in newborn infants. These infants may develop lethargy, poor feeding, and emesis on initiation of protein in their diet.41 If unrecognized or untreated, accumulation of ammonia may cause cerebral edema, followed by coma and possibly death. Additionally, cases of severe hyperammonemia have been reported after the administration of valproic acid in pediatric populations.42 In cases of partial UCD deficiencies, increased levels of accumulating ammonia might be triggered by dehydration, stress, or administration of valproic acid.43 The FDA-approved drug label includes a contraindication of valproic acid in patients with known UCDs as well as provides information regarding those who should be considered for additional evaluation.23 Although there are genetic variants in the CPS1 and OTC genes that are associated with UCDs, genotyping for these variants before the initiation of valproic acid therapy is not recommended at this time. This is perhaps due to
