Effect of <i>CPS1</i>4217C&gt;A genotype on valproic‐acid‐induced hyperammonemia

Yagi, Minoru; Nakamura, Tsutomu; Okizuka, Yo; Oyazato, Yoshinobu; Kawasaki, Yoko; Tsuneishi, Shuichi; Sakaeda, Toshiyuki; Matsuo, Masafumi; Okumura, Katsuhiko; Okamura, Noboru

doi:10.1111/j.1442-200x.2010.03157.x

Cited by 28 publications

(20 citation statements)

References 15 publications

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“…CPS1 4217C>A heterozygous and homozygous mutation carriers (CA and AA) had a greater risk of hyperammonaemia compared with wild‐type (CC) carriers. These results were consistent with those reported by previous studies . However, a recent study by Inoue et al .…”

Section: Discussionsupporting

confidence: 94%

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Risk Factors for Valproic Acid‐induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy

Zhu

Zhang

et al. 2018

Basic Clin Pharma Tox

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This study was aimed at identifying genetic and non-genetic risk factors for valproic acid (VPA)-induced hyperammonaemia in Chinese paediatric patients with epilepsy. A total of 210 epileptic patients, treated with VPA as monotherapy, were enrolled and classified into hyperammonaemia and control groups according to their blood ammonia level (cut-off value 50 μmol/L). Serum concentrations of VPA and its major metabolites were simultaneously determined by ultrahigh-performance liquid chromatography-tandem mass spectrometry. Six single nucleotide polymorphisms in the candidate genes, CYP2C9, CYP2A6, CYP2B6 and CPS1, were analysed by a matrix-assisted laser desorption ionization-time of flight mass spectrometry method or nested PCR. Significant differences in age, aspartate transaminase level and the incidence of liver injury were observed between patients of hyperammonaemia and control groups. Genotype distributions of CYP2C9*3, CYP2A6*4 and CPS1 4217C>A allelic variants were also significantly different between the two groups. According to multiple regression analysis, a significant negative correlation was detected between age and the blood ammonia level, while liver injury, the concentration-dose ratio (CDR) of VPA and 2-propyl-4-pentenoic acid (4-ene VPA), and the presence of CYP2A6*4 or CPS1 4217C>A showed positive correlations with the blood ammonia level. In addition, the risk factors for hyperammonaemia identified by logistic regression analysis were as follows: a younger age (odds ratio [OR] = 0.85; 95% confidence interval [CI] = 0.76-0.96; p = 0.007), occurrence of liver injury (OR = 4.60; 95% CI = 1.27-16.74; p = 0.021), higher CDR of 4-ene VPA (OR = 1.08; 95% CI = 1.03-1.14; p = 0.001), and carrying mutant alleles of CYP2C9*3 (OR = 3.42; 95% CI = 1.15-10.19; p = 0.028), CYP2A6*4 (OR = 3.23; 95% CI = 1.40-7.48; p = 0.006) and CPS1 4217C>A (OR = 3.25; 95% CI = 1.52-6.94; p = 0.002). Our findings indicated that multiple genetic and non-genetic risk factors that were identified can be used to predict the development of VPA-induced hyperammonaemia in Chinese paediatric patients with epilepsy.

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Section: Discussionsupporting

confidence: 94%

“…This finding was consistent with that reported by Yagi et al . . However, recent research has indicated that γ‐GT rather than alanine aminotransferase levels were significantly higher in patients with hyperammonaemia .…”

Section: Discussionmentioning

confidence: 95%

Risk Factors for Valproic Acid‐induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy

Zhu

Zhang

et al. 2018

Basic Clin Pharma Tox

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“…Both heterozygous and homozygous carrier states of the T1405N polymorphism and concomitant administration of two or more anticonvulsants with VPA were shown previously to be independent risk factors for developing HA in the relatively small cohort of patients ( N = 79) from Japan and single case report from our laboratory [4, 5]. 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, although genetic polymorphism was not analyzed in this study [6].…”

Section: Discussionmentioning

confidence: 99%

“…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 polymorphism (SNP) in the carbamoyl phosphate synthetase 1 gene might be more likely to experience HA [4]. The main goal of this project was to investigate, for the first time in Caucasian cohort, if carbamoyl phosphate synthetase 1 (CPS1) gene T1405N missense variant can be associated with increased occurrence of HA in subjects treated with VP.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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“…Alternatively, CPS1 may be impacted by general mitochondrial dysfunction caused by toxic VPA metabolites. In a small study ( n = 79), the rs1047891A (4217C > A) polymorphism of CPS1 was associated with an increased risk of hyperammonemia when receiving combined treatment of VPA with two or more other antiepileptics [33]. This SNP is also associated with lower CPS1 activity [34].…”

Section: Introductionmentioning

confidence: 99%

Valproic acid pathway

Ghodke‐Puranik¹,

Thorn²,

Lamba³

et al. 2013

Pharmacogenetics and Genomics

308

103

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

Abstract: These findings suggested that in epileptic patients undergoing VPA therapy, CPS14217A polymorphism and the number of coadministered anticonvulsants would be considered as risk factors for hyperammonemia, even if the serum VPA concentrations were controlled.

Cited by 28 publications

References 15 publications

Risk Factors for Valproic Acid‐induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy

Risk Factors for Valproic Acid‐induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy

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

Valproic acid pathway

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