F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA.
Int J Mol Sci. 2022 Feb 26;23(5):2606. doi: 10.3390/ijms23052606.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables 'on-demand' SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.
琥珀酸半醛脱氢酶缺乏症（SSADHD）是一种罕见的遗传疾病，由主要抑制性神经递质γ-氨基丁酸（GABA）的代谢分解效率低下引起。病理性脑内 GABA 和 γ-羟基丁酸（GHB）的积累，GHB 是 GABA 分解代谢的神经活性副产物，导致多种分子异常，这些异常从生命早期开始，最终导致多方面的临床表现，包括精神运动发育迟缓、智力障碍、肌张力低下和共济失调。矛盾的是，超过一半的 SSADHD 患者也会发展为癫痫，并面临癫痫猝死（SUDEP）的重大风险。在这里，我们回顾了一些相关的分子机制，这些机制可能导致突触抑制受损、星形胶质细胞功能障碍和髓鞘缺陷，从而导致 SSADHD 复杂的表型。我们还讨论了需要解决的知识空白，以便实施成功的 SSADHD 基因和酶替代治疗。最后，我们描述了一种新型的 SSADHD 小鼠模型，该模型能够实现“按需”SSADH 恢复，从而可以进行概念验证研究，以调整 SSADH 恢复，为最终的人体试验做准备。
