Janicki Piotr K, Bezinover Dmitri, Postula Marek, Thompson Robert S, Acharya Jayant, Acharya Vinita, McNew Cathy, Bowman J Daniel, Kurkowska-Jastrzebska Iwona, Mirowska-Guzel Dagmara
Laboratory 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.
ISRN Neurol. 2013 Aug 7;2013:261497. doi: 10.1155/2013/261497. eCollection 2013.
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 μ mol/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.
医学文献中先前已报道了许多与使用丙戊酸（VPA）治疗癫痫发作相关的严重且危及生命的高氨血症（HA）病例。这项前瞻性多中心研究的目的是，在142例接受VPA治疗至少1年且肝功能正常的成年白种癫痫患者队列中，验证T1405多态性与VPA诱导的HA发生之间的假定关联。通过实时TaqMan PCR基因分型进行非同义T1405N多态性基因分型。除血浆氨水平外，还采用标准实验室方法测定血浆中肝酶和总VPA的浓度。接受VPA治疗的患者中共有11例（7.7%）出现HA（定义为血浆氨水平>65 μmol/L），所研究多态性的携带者状态与HA的发生显著相关（P = 0.009，优势比5.4，95%置信区间为1.58 - 18.43）。本研究结果支持这样一种观点，即在接受VPA治疗的白种癫痫患者中，即使在血浆VPA水平正常的患者中，T1405N（4217C>A，rs1047891）非同义变异也是HA发生的一个重要危险因素。
