EP013: Novel biomarkers of succinic semialdehyde dehydrogenase deficiency highlight opportunities for screening and detection of GABA catabolism pathway abnormalities

Abstract

GABA (gamma-aminobutyric acid) is catabolized in the mitochondrial matrix via the GABA shunt, a 2-step enzymatic pathway which encompasses the transamination of GABA to succinic semialdehyde by GABA-transaminase (GABA-T), followed by oxidation to succinate by succinic semialdehyde dehydrogenase (SSADH). Deficiency of SSADH results in accumulation of GABA and reduction of succinic semialdehyde to gamma-hydroxybutyrate (GHB), the principal neurotoxin in SSADH deficiency (SSADHD). SSADHD is an autosomal recessive disorder associated with biallelic pathogenic variants in ALDH5A1, typically characterized by developmental delay, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances.