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

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.

Keywords: ALDH5A1; GABA receptors; enzyme replacement therapy; epilepsy; gene therapy; inhibition; mouse model; plasticity; succinic semialdehyde dehydrogenase deficiency (SSADHD); γ-aminobutyric acid (GABA); γ-hydroxybutyrate (GHB).

Publication types

  • Review

MeSH terms

  • Amino Acid Metabolism, Inborn Errors* / metabolism
  • Animals
  • Child
  • Developmental Disabilities / genetics
  • Humans
  • Mice
  • Succinate-Semialdehyde Dehydrogenase* / deficiency
  • Succinate-Semialdehyde Dehydrogenase* / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • gamma-Aminobutyric Acid
  • Succinate-Semialdehyde Dehydrogenase

Supplementary concepts

  • succinic semialdehyde dehydrogenase deficiency