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

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.

The presence and severity of epilepsy coincide with reduced γ‐aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency

“…46 Therefore, these findings are relevant to the timing of genetically targeted intervention. 7 Additionally, this study's findings, providing a comprehensive mapping of clinical, biochemical, and neurophysiological correlative features of seizures in SSADHD, set the stage for future mechanistic investigations determining the elements that regulate the maturational trajectory of GABA and related metabolites, leading to seizures. Moreover, utilizing the biomarkers we have identified, future studies could be replicated in SSADHD and in other disease states of GABA metabolism, ranging from GABA transaminase deficiency to the numerous disorders of GABA receptors and transporters, to pharmacological hyper-GABAergic states, such as those induced by vigabatrin, an irreversible inhibitor of GABA transaminase.…”

“…In the presence of downregulated GABA A receptors, fast SSADH restoration may inadvertently result in a hypo‐GABAergic state, which may intensify seizures and neurodevelopmental deficits 46 . Therefore, these findings are relevant to the timing of genetically targeted intervention 7 . Additionally, this study's findings, providing a comprehensive mapping of clinical, biochemical, and neurophysiological correlative features of seizures in SSADHD, set the stage for future mechanistic investigations determining the elements that regulate the maturational trajectory of GABA and related metabolites, leading to seizures.…”

“…Previous studies in the ALDH5A1 −/− null mouse 3 and in patients with SSADHD 4 have suggested that seizures in a hyper‐GABAergic environment occur because of heightened compensatory activity, likely associated with downregulation of GABA A and GABA B receptors leading to impaired GABA signaling 5–7 . Additionally, the elevation of GABA and GHB (in blood and hair) observed in newborn dried blood spots or in young patients decreases over the first decade 8 .…”

“…2 Previous studies in the ALDH5A1 −/− null mouse 3 and in patients with SSADHD 4 have suggested that seizures in a hyper-GABAergic environment occur because of heightened compensatory activity, likely associated with downregulation of GABA A and GABA B receptors leading to impaired GABA signaling. [5][6][7] Additionally, the elevation of GABA and GHB (in blood and hair) observed in newborn dried blood spots or in young patients decreases over the first decade. 8 We employed TMS, magnetic resonance spectroscopy (MRS) imaging with GABA editing, and GABArelated metabolite quantification to test the hypothesis that seizure onset or exacerbation in SSADHD occurs with reduced cortical inhibition or GABA-related metabolite levels.…”

Human iPSC-derived neural stem cells with ALDH5A1 mutation as a model of succinic semialdehyde dehydrogenase deficiency

“…Furthermore, dermal fibroblasts of SSADH-D patients have a short life span and low expression levels of SSADH, limiting their application for study. Several animal models of SSADH-D have been reported [4][5][6][7], however, making a mouse model is much more expensive and time consuming than obtaining a cell model. Induced pluripotent stem cells (iPSCs) provide a well-defined source of tissue-specific cells and are invaluable disease modeling tools.…”