Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an autosomal-recessive neurometabolic disorder caused by bi-allelic mutations in the ALDH5A1 gene. SSADH deficiency is the most prevalent inherited disorder of GABA (4-aminobutyrate) metabolism and is characterized by accumulation of two neuromodulators, GABA and GHB (gamma-hydroxybutyric acid), in the central nervous system. The clinical phenotype of SSADH deficiency includes a static or slowly progressive encephalopathy with early developmental delay and intellectual disability. Hypotonia, motor delay, and impaired speech development are common in children with SSADH deficiency. About two-thirds of patients will develop epilepsy with different types of seizures, and many will develop movement disorders such as ataxia and behavioral symptoms such as attention-deficit hyperactivity disorder, autism-spectrum disorder, anxiety and sleep disorders. A symmetric increase in T2-weighted signal of the globus pallidus on MR imaging is present in many cases and can help establish a diagnosis. The biochemical hallmark, elevation of the GABA metabolite GHB, is universally present in plasma, urine or CSF. Identified in about 450 individuals to date, SSADH deficiency is likely vastly underdiagnosed given its relatively non-specific presentation and the need for advanced biochemical and genetic testing to confirm a diagnosis. Treatment is generally symptomatic and available therapies improve quality of life but are grossly inefficient in slowing the disease progression. Therefore, in this project we are using induced pluripotent stem cells (iPSC)-derived neurons to study SSADH-related phenotypes with the goal of developing a high content screen for well-annotated bioactive small molecular collections and FDA approved molecules. ​