Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the ALDH5A1 gene), an enzyme essential for metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in broad spectrum encephalopathy including developmental delay, ataxia, seizures, and a heightened risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable intervention for SSADHD. However, before testing enzyme replacement therapy or gene therapy in patients, we must consider its safety and feasibility in the context of early brain development and unique SSADHD pathophysiology. Specifically, a profound use-dependent downregulation of GABA_A receptors in SSADHD indicates a risk that any sudden SSADH restoration might diminish GABAergic tone and provoke seizures. In addition, the tight developmental regulation of GABA circuit plasticity might limit the age window when SSADH restoration is accomplished safely. Moreover, given SSADH expressions are cell type–specific, targeted instead of global restoration might be necessary. We therefore describe 3 key parameters for the clinical readiness of SSADH restoration: (1) rate, (2) timing, and (3) cell type specificity. Our work focuses on the construction of a novel SSADHD mouse model that allows “on-demand” SSADH restoration for the systematic investigation of these key parameters. We aim to understand the impacts of specific SSADH restoration protocols on brain physiology, accelerating bench-to-bedside development of enzyme replacement therapy or gene therapy for SSADHD patients.

琥珀酸半醛脱氢酶缺乏症 (SSADHD) 是一种罕见的先天性代谢疾病，由 SSADH 功能障碍引起（由ALDH5A1编码）基因），一种对抑制性神经递质γ-氨基丁酸（GABA）代谢必不可少的酶。在 SSADHD 中，GABA 及其代谢物 γ-羟基丁酸 (GHB) 的病理积累导致广谱脑病，包括发育迟缓、共济失调、癫痫发作和癫痫猝死 (SUDEP) 的风险增加。通过酶替代疗法进行概念验证系统性 SSADH 恢复增加了 SSADH 敲除小鼠的存活率，这表明 SSADH 恢复可能是 SSADHD 的可行干预措施。然而，在对患者进行酶替代疗法或基因疗法测试之前，我们必须考虑其在早期大脑发育和独特的 SSADHD 病理生理学背景下的安全性和可行性。_{具体来说，GABA A}的深度使用依赖性下调SSADHD 中的受体表明任何突然的 SSADH 恢复都可能降低 GABA 能张力并引发癫痫发作的风险。此外，GABA 电路可塑性的严格发育调节可能会限制安全完成 SSADH 恢复的年龄窗口。此外，鉴于 SSADH 表达式是特定于细胞类型的，因此可能需要有针对性而不是全局恢复​​。因此，我们描述了 SSADH 恢复临床准备的 3 个关键参数：（1）速率，（2）时间，和（3）细胞类型特异性。我们的工作重点是构建一种新颖的 SSADHD 小鼠模型，该模型允许“按需”SSADH 恢复，以系统地研究这些关键参数。我们旨在了解特定 SSADH 恢复方案对大脑生理学的影响，