Liang Ziqi, Wu Junjie, Liu Qiang, Qin Dezhe, Wang Min, Zhong Xiaofen, Guo Weixiang
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100093, China.
J Neurosci. 2025 Jun 4;45(23):e0370252025. doi: 10.1523/JNEUROSCI.0370-25.2025.
Pyridoxine-dependent epilepsy (PDE), a rare autosomal recessively inherited metabolic disease, results from mutations in ALDH7A1, a gene crucial for lysine metabolism. Although early high-dose pyridoxine treatment can control seizures, ∼75% of PDE patients still have intellectual disabilities. In this study, we test the hypothesis of substrate reduction therapy for PDE by genetically perturbing lysine α-ketoglutarate reductase (LKR), an enzyme upstream of the defective ALDH7A1, in male and female laboratory mice. A homozygous mutation in LKR completely abolishes the accumulation of toxic lysine catabolism intermediates (α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate), ends the epileptic state, and restores the defective brain development and cognitive impairments in ALDH7A1-deficient mice. Therefore, these genetic data prove the concept of the effectiveness of substrate reduction therapy for PDE via LKR inhibition.
吡哆醇依赖性癫痫（PDE）是一种罕见的常染色体隐性遗传代谢疾病，由赖氨酸代谢关键基因ALDH7A1发生突变所致。尽管早期大剂量吡哆醇治疗可控制癫痫发作，但约75%的PDE患者仍存在智力障碍。在本研究中，我们通过在雄性和雌性实验小鼠中对有缺陷的ALDH7A1上游的一种酶——赖氨酸α-酮戊二酸还原酶（LKR）进行基因干扰，来验证PDE的底物减少疗法的假设。LKR中的纯合突变完全消除了有毒的赖氨酸分解代谢中间体（α-氨基己二酸-δ-半醛及其环状形式，δ-1-哌啶-6-羧酸）的积累，终止了癫痫状态，并恢复了ALDH7A1缺陷小鼠中存在缺陷的大脑发育和认知障碍。因此，这些遗传学数据证明了通过抑制LKR进行底物减少疗法治疗PDE有效性的概念。
