Succinate-semialdehyde dehydrogenase (ALDH5A1) (ALDH5A1)

Succinate-semialdehyde dehydrogenase (ALDH5A1) is a mitochondrial enzyme that plays a critical role in the catabolism of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (UniProt P51649). It catalyzes the final step of the GABA shunt by converting succinate semialdehyde into succinate, which then enters the tricarboxylic acid (TCA) cycle (NCBI Gene 7915). Mutations in the ALDH5A1 gene lead to Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a rare autosomal recessive neurometabolic disorder characterized by the accumulation of GABA and 4-hydroxybutyric acid (GHB) (Pearl et al., 2015, PMID: 25575612). This metabolic imbalance results in clinical manifestations such as developmental delay, hypotonia, ataxia, and seizures. AAV-mediated gene augmentation, such as the investigational candidate TSHA-111, aims to deliver a functional ALDH5A1 gene to restore enzyme activity, normalize metabolite levels, and potentially halt or reverse the progression of neurological symptoms (Taysha Gene Therapies, 2021).

Other names

SSADHAldehyde dehydrogenase 5 family member A1NAD(+)-dependent succinate-semialdehyde dehydrogenaseSSADH deficiency proteinMitochondrial succinate-semialdehyde dehydrogenase

Gene augmentation therapy designed to deliver a functional copy of the ALDH5A1 gene to target cells, thereby restoring the production of the succinate-semialdehyde dehydrogenase enzyme and facilitating the conversion of succinate semialdehyde to succinate to reduce toxic metabolite accumulation.