Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Department of Neurology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Neurol Neurochir Pol. 2024;58(5):519-530. doi: 10.5603/pjnns.99826. Epub 2024 Aug 21.
The use of valproic acid (VPA) in the treatment of some psychiatric and neurological disorders such as bipolar disorder, migraines, and epilepsy is associated with hyperammonemia. However, the mechanism of this negative effect of VPA is unclear. In this study, we investigate gene glutamate-ammonia ligase (GLUL) polymorphisms for the glutamine synthetase (GS) enzyme, a key enzyme that catalyzes the removal of ammonia by incorporating it with glutamate to form glutamine, and we investigate whether it has a relationship with the emergence of hyperammonemia during VPA-based therapy.
We enrolled 180 Egyptian epilepsy patients in this study. Patient history, general and neurological examination and blood samples from arm veins were taken. Real time TaqMan PCR polymorphism for three polymorphism SNPs (rs2296521, rs10911021 and rs12136955) of GLUL was done. We assessed the relationship between the patient features, including three GLUL polymorphisms, and the development of hyperammonemia during VPA-based therapy.
We found that the ammonia levels showed a positive correlation with VPA treatment duration (p = 0.015) and a negative correlation with carbamazepine total dose per day (p = 0.027) and with WBCs count (p = 0.026). Also, female patients having rs2296521 SNPs with the A allele and patients having rs10911021 SNPs with the C allele were at high risk for elevated plasma ammonia levels. Moreover, patients having rs12136955 SNPs with the A allele or associated hypertension as a co-morbidity were at high risk for elevated plasma ammonia levels.
Female patients who have rs2296521 with the A allele, rs10911021 with the C allele, or rs12136955 with the A allele, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy. Moreover, carbamazepine combined therapy may protect against the development of hyperammonemia in VPA-treated patients.
丙戊酸（VPA）在治疗某些精神和神经疾病（如双相情感障碍、偏头痛和癫痫）中的应用与高氨血症有关。然而，VPA 产生这种负面影响的机制尚不清楚。在这项研究中，我们研究了谷氨酸-氨连接酶（GLUL）基因多态性，即谷氨酰胺合成酶（GS）的关键酶，它通过将氨与谷氨酸结合形成谷氨酰胺来催化氨的去除，并研究其是否与 VPA 治疗期间高氨血症的发生有关。
我们招募了 180 名埃及癫痫患者参与这项研究。采集患者病史、一般和神经系统检查以及手臂静脉血样。使用实时 TaqMan PCR 对 GLUL 的三个多态性 SNP（rs2296521、rs10911021 和 rs12136955）进行多态性分析。我们评估了患者特征（包括三个 GLUL 多态性）与 VPA 治疗期间高氨血症的发生之间的关系。
我们发现，氨水平与 VPA 治疗时间呈正相关（p=0.015），与卡马西平日总剂量呈负相关（p=0.027），与白细胞计数呈负相关（p=0.026）。此外，携带 rs2296521 SNP 的 A 等位基因的女性患者和携带 rs10911021 SNP 的 C 等位基因的患者血浆氨水平升高的风险较高。此外，携带 rs12136955 SNP 的 A 等位基因或合并高血压作为合并症的患者血浆氨水平升高的风险较高。
携带 rs2296521 的 A 等位基因、rs10911021 的 C 等位基因或 rs12136955 的 A 等位基因的女性患者是 VPA 治疗期间血浆氨水平升高的独立危险因素。此外，卡马西平联合治疗可能会预防 VPA 治疗患者高氨血症的发生。
