title: Adverse events in a newborn on valproate therapy due to loss-of-function mutations in CYP2C9.
abstract: An increased risk of valproate-induced toxicity has been reported in children, particularly in those younger than 2 years of age. Significant variations in valproate pharmacokinetics and shifts in the metabolic pathways towards CYP2C9-dependent metabolism seem to play some role in the age-related differences in the incidence of adverse events. We present the case of a premature patient with moderate hemorrhage in the subependymal region (grade II - intraventricular hemorrhage without ventricular dilatation), several myoclonic episodes in her right upper arm (series of jerks lasting milliseconds), and epileptiform abnormalities on the EEG (localized spike-and-wave in the left frontal region with preserved background activity who was treated with valproate. Serious side effects, consisting of bone marrow depression, hyperammonemia, and serum alkaline phosphatase elevation, were observed seventeen days after the beginning of valproate therapy. The toxic symptoms were likely the consequence of a reduced ability to metabolize valproate. The patient was demonstrated to carry two loss-of-function mutations in CYP2C9 (CYP2C9*3/*3) resulting in exaggerated blood concentrations of valproate. The present case highlights the importance of assaying inborn errors in CYP2C9 gene in pediatric patients to avoid valproate-evoked serious side effects.
authors.affiliation: Heim Pál Children's Hospital, Madarász 22-24, H-1131 Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Heim Pál Children's Hospital, Madarász 22-24, H-1131 Budapest, Hungary ; 2nd Department of Pediatrics, Semmelweis University, Tűzoltó 7-9, H-1094 Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Bűdi
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117 Budapest, Hungary.
authors.forename: Manna
authors.initials: M
authors.lastname: Temesvári
authors.affiliation: Heim Pál Children's Hospital, Madarász 22-24, H-1131 Budapest, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szever
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117 Budapest, Hungary.
authors.forename: Pál Tamás
authors.initials: PT
authors.lastname: Szabó
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117 Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
keywords: Bone marrow depression; CYP2C9 genotype; Hyperammonemia; Pediatric patient; Valproate