The use of patient-derived induced pluripotent stem cells (iPSCs) and iPSC-derived cerebral organoids to explore pathomechanisms of succinc semialdehyde dehydrogenase deficiency


Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an autosomal-recessive disorder caused by variants of the ALDH5A1 gene. Symptoms include developmental delay, behavioral problems, impaired motor skills and seizures. High concentrations of the neurotransmitter gamma-amino butyric acid (GABA) and its degradation byproduct gamma-hydroxybutyrate (GHB) are pathognomonic, yet, it is unclear how this abundance contributes to the pathology of SSADHD. In addition, little is known about the extra-synaptic role of these metabolites in early brain development. Using patient-derived induced pluripotent stem cells (iPSCs) we generated a three-dimensional cerebral organoid model to study SSADH disease mechanisms. Immunohistochemical analyses of organoids at early stages revealed premature neuronal differentiation with simultaneous reduction of neuronal progenitor cells in SSADHD organoids. Mitotic activity analysis of organoid-resident progenitors showed a strong reduction of M-Phase cells in SSADHD organoids, which may point to an overall decreased stem cell pool and premature cell cycle exit of symmetrically dividing stem cells. Despite this fact, mature and electrophysiological active neurons and neuronal networks evolve. We propose an unprecedented role of GABA and GHB as extra-synaptic, non-neurotransmitter related trophic factors, contributing to the pathophysiology of SSADHD.

In Monatsschrift Kinderheilkunde 167:365, 2019
Heiko Brennenstuhl
Board-certified Pediatrician, Human Geneticist, Junior Research Group Leader

I am interested in genomic data generation and analysis for screening purposes.