Induced pluripotent stem cells (iPSCs) and iPSC-derived cerebral organoids as a model of Succinic Semialdehyde Dehydrogenase Deficiency

Abstract

Succinic semialdehyde dehydrogenase defi-ciency (SSADHD) represents a rare monogenetic diseasecausing disturbed degradation of γ-aminobutyric acid (GABA) due to variants in ALDH5A1. Succinic-semialdehyde cannot be oxidized to succinate and is consecutively reduced to γ-hydroxybutyrate (GHB). The phenotype is comprised of developmental delay, motor difficulties, behavioral problems, and epilepsy. It is unclear how altered concentrations of GABA and GHB contribute to the pathophysiology of SSADHD. We used patient-derived inducedpluripotent stem cells (iPSCs) to generate a three-dimensional cell culture model to study early neuronaldevelopment in SSADHD. Immunohistochemistry and whole-cell patch clamp were used to determine morphological and electrophysiological properties.