Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.

Henry H C Lee,Phillip L Pearl,Alexander Rotenberg,Gabrielle E McGinty

doi:10.3390/ijms23052606

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.

Highlights

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic metabolic disorder caused by loss-of-function mutations of the ALDH5A1 gene
We previously described the concept of developing a novel SSADHD mouse model axons [97]
Pilot results indicated that aldh5a1STOP/STOP mice do not express SSADH in cortex, and they exhibit obligatory premature lethality before three weeks of postnatal age (Figure 5). These results suggest that our lox-STOP insertion leads to compulsory premature aldh5a1 termination in aldh5a1STOP/STOP mice

Summary

Introduction

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic metabolic disorder caused by loss-of-function mutations of the ALDH5A1 gene. SSADH which is essential for the mitochondrial breakdown of succinic semialdehyde (SSA), a γ-aminobutyric acid (GABA) downstream metabolite, into succinate. In the absence of SSADH, SSA conversion to succinate is prohibited, leading to SSA conversion to γ-hydroxybutyrate (GHB). Both GABA and GHB are accumulated in the brain and body fluids (cerebrospinal fluid, blood) up to pathologic levels, resulting in numerous downstream neurological and metabolic abnormalities. A fundamentally different approach is targeted SSADH restoration, which may be accomplished via gene therapy or enzyme replacement therapy (ERT). We describe our ongoing work aimed to develop SSADH-targeted

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