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

Piotr K Janicki,J Daniel Bowman,Iwona Kurkowska-Jastrzebska,Cathy Mcnew,Vinita Acharya,Dagmara Mirowska-Guzel,Marek Postula,Robert S Thompson,Dmitri Bezinover,Jayant Acharya

doi:10.1155/2013/261497

Abstract

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 (P = 0.009, 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.

Highlights

Valproic acid (VPA) has a clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression
Numerous cases of severe and life-threatening HA related to the VPA treatment mostly in children, adolescents, and adults [1] have been previously reported in the medical literature (>220 published reports in Medline since 1980 by search using VPA and HA as keywords in August 2012)
In the recent larger study, Yamamoto et al identified several other risk factors for HA in PWE, including VPA dose and use of hepatic enzyme inducers, genetic polymorphism was not analyzed in this study [6]

Summary

Introduction

Valproic acid (VPA) has a clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. Hyperammonemia (HA) has been generally associated with liver failure or rare genetic mutations in enzymes participating in the urea cycle. In some patients treated with VPA, severe HA has been observed in the absence of liver failure and resulting in vomiting, ataxia, behavioral changes, lethargy, somnolence, or, in extreme cases, coma. Numerous cases of severe and life-threatening HA related to the VPA treatment mostly in children, adolescents, and adults [1] have been previously reported in the medical literature (>220 published reports in Medline since 1980 by search using VPA and HA as keywords in August 2012). The exact mechanism of VPA-induced encephalopathy is unclear but relates to the accumulation of toxic VPA metabolites and elevated ammonia levels [2, 3]. The prior limited data from exclusively Japanese cohort suggested that patients treated with VPA and who carry the T1405N (4217C > A, rs1047891) missense single nucleotide

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