Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of the lysine catabolism pathway. PDE is characterized by recurrent seizures that are resistant to conventional anticonvulsant treatment but are well-controlled by pyridoxine (PN). Most PDE patients also suffer from neurodevelopmental deficits despite adequate seizure control with PN. To investigate potential pathophysiological mechanisms associated with ALDH7A1 deficiency, we generated a transgenic mouse strain with constitutive genetic ablation of Aldh7a1. We undertook extensive biochemical characterization of Aldh7a1-KO mice consuming a low lysine/high PN diet. Results showed that KO mice accumulated high concentrations of upstream lysine metabolites including ∆¹-piperideine-6-carboxylic acid (P6C), α-aminoadipic semialdehyde (α-AASA), and pipecolic acid (PIP) both in brain and liver tissues, similar to the biochemical picture in ALDH7A1-deficient patients. We also observed preliminary evidence of a widely deranged amino acid profile and increased levels of methionine sulfoxide, an oxidative stress biomarker, in the brains of KO mice, suggesting that increased oxidative stress may be a novel pathobiochemical mechanism in ALDH7A1 deficiency. KO mice lacked epileptic seizures when fed a low lysine/high PN diet. Switching mice to a high lysine/low PN diet led to vigorous seizures and a quick death in KO mice. Treatment with PN controlled seizures and improved survival of high-lysine/low PN fed KO mice. This study expands the spectrum of biochemical abnormalities that may be associated with ALDH7A1 deficiency and provides a proof-of-concept for the utility of the model to study PDE pathophysiology and to test new therapeutics.

中文翻译：

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由于古蛋白缺乏症导致的吡哆醇依赖性癫痫的新型小鼠模型。

吡哆醇依赖性癫痫 (PDE) 是一种罕见的常染色体隐性疾病，由ALDH7A1基因突变导致赖氨酸分解代谢途径受阻。PDE 的特点是反复发作，对常规抗惊厥治疗有抵抗力，但能被吡哆醇 (PN) 很好地控制。尽管 PN 能充分控制癫痫发作，但大多数 PDE 患者也患有神经发育缺陷。为了研究与ALDH7A1缺乏相关的潜在病理生理机制，我们生成了具有Aldh7a1组成型遗传消融的转基因小鼠品系。我们对Aldh7a1进行了广泛的生化表征-KO 小鼠消耗低赖氨酸/高 PN 饮食。结果表明，KO小鼠积累高浓度的上游赖氨酸代谢物包括Δ ¹ -piperideine -6-羧酸（P6C），α氨基己二酸半醛（α-AASA），和哌啶酸（PIP）无论是在脑和肝组织中，类似ALDH7A1缺陷患者的生化图片。我们还观察到 KO 小鼠大脑中广泛紊乱的氨基酸谱和甲硫氨酸亚砜（一种氧化应激生物标志物）水平升高的初步证据，表明氧化应激的增加可能是ALDH7A1 的一种新的病理生化机制不足。当喂食低赖氨酸/高 PN 饮食时，KO 小鼠没有癫痫发作。将小鼠改用高赖氨酸/低 PN 饮食导致 KO 小鼠剧烈癫痫发作和快速死亡。PN 治疗控制癫痫发作并提高高赖氨酸/低 PN 喂养的 KO 小鼠的存活率。这项研究扩展了可能与ALDH7A1缺乏相关的生化异常的范围，并为该模型用于研究 PDE 病理生理学和测试新疗法的效用提供了概念验证。