PDF(Pubmed)
Abstract：
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.
摘要：
琥珀酸半醛脱氢酶缺乏症（SSADHD）是由主要抑制性神经递质的低效率代谢分解引起的一种罕见的遗传性疾病，γ-氨基丁酸(GABA)。GABA和γ-羟基丁酸（GHB）的病理性脑积累，GABA分解代谢的神经活性副产物，导致许多从生命早期开始的分子异常，最终导致多方面的临床表现，包括精神运动发育延迟，智力残疾,低张力,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.这里,我们回顾了一些相关的分子机制，通过这些机制受损的突触抑制，星形细胞功能障碍和髓鞘缺陷可能导致复杂的SSADHD表型。我们还讨论了实施成功的基因和酶替代SSADHD疗法需要解决的知识差距。最后，我们描述了一种新颖的SSADHD小鼠模型，该模型可以实现“按需”SSADH恢复，允许概念验证研究微调SSADH恢复，为最终的人体试验做准备。
