Table of Contents
ISRN Neurology
Volume 2013, Article ID 261497, 4 pages
Research Article

Increased Occurrence of Valproic Acid-Induced Hyperammonemia in Carriers of T1405N Polymorphism in Carbamoyl Phosphate Synthetase 1 Gene

1Laboratory of Perioperative Genomics and Anesthetic Preoperative Evaluation Clinic, Department of Anesthesiology, Pennsylvania State University College of Medicine, MS Hershey Medical Center, H187, 500 University Drive, Hershey, PA 17033, USA
2Department of Experimental and Clinical Pharmacology, Warsaw Medical University, Krakowskie Przedmiescie 26/28, 00-927 Warsaw, Poland
3Department of Neurology, Pennsylvania State University MS Hershey Medical Center, H187, 500 University Drive, Hershey, PA 17033, USA
42nd Department Neurology, National Institute of Psychiatry and Neurology, Ulica Sobieskiego 9, 02-957 Warsaw, Poland

Received 7 June 2013; Accepted 6 July 2013

Academic Editors: N. Bresolin and T. Kato

Copyright © 2013 Piotr K. Janicki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Numerous cases of severe and life-threatening hyperammonemia (HA) related to the treatment of epileptic seizures with valproic acid (VPA) have been previously reported in the medical literature. The aim of this prospective, multicenter study was to verify the putative association between T1405 polymorphism and occurrence of VPA-induced HA in the cohort of 142 adult Caucasian patients with epilepsy treated with VPA for at least 1 year and with normal liver functions. The nonsynonymous T1405N polymorphism genotyping was performed by real-time TaqMan PCR genotyping. In addition to plasma ammonia level, concentrations of liver enzymes and total VPA were measured in plasma with standard laboratory methods. HA (defined as ammonia plasma level >65 μmol/L) was observed in total of 11 (7.7%) of patients treated with VPA, and the carrier status for the investigated polymorphism was significantly ( , odds ratio 5.4 with 95% confidence interval of 1.58–18.43) associated with the occurrence of HA. The results of this study support a notion that in the Caucasian patients with epilepsy undergoing VPA therapy, a T1405N (4217C > A, rs1047891) nonsynonymous variant was a significant risk factor for the occurrence of HA, even in patients with normal plasma levels of VPA.