SUMMARY – Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disease caused by impaired γ-aminobutyric acid (GABA) neurotransmission. Since SSADHD was first identified in 1983, research has focused on identifying the spectrum of pathogenic ALDH5A1 mutations, understanding the molecular and biochemical bases of disease presentation, and testing promising therapeutics. To date, however, there remain significant knowledge gaps that are barriers to early detection and prognosis of the disease, and to the assessment of the efficacy of novel promising therapeutics. These gaps include a comprehensive description of the natural course of the clinical severity of the disease, an in-depth assessment of the neurophysiology of the disease, and the prognostic value of biochemical markers. We began to address these knowledge gaps four years ago with our currently funded natural history study (NHS) of SSADHD and have already demonstrated significant correlations between age of the patients, severity of the disease, blood biomarkers, and neurophysiological parameters. However, the 4-5 year span of the current study and varying age and clinical severity of the study participants has mostly afforded a cross-sectional perspective on disease progression and the prognostic value of biomarkers. In order to gain the longitudinal insight needed to assess the predictive power of disease markers at study intake on prognosis, a longer follow-up of the participants is needed. The purpose of this application is to extend this natural history study for five years. We propose the following aims: 1) to determine patient-specific changes over time in the clinical severity of SSADHD, 2) to determine patient-specific changes over time in neurophysiological markers known to be dependent on GABA homeostasis, and 3) to determine patient-specific changes over time in biochemical markers known to be abnormal in SSADHD. To accomplish these aims, the study will follow ~70 patients representing ~30% of all known cases worldwide. The project will be led by research teams at three academic institutions and is supported by patient advocacy groups and families from all over the world. The research will provide the clinical and biochemical information needed to predict the natural course of the disease, monitor the success of future therapeutic trials, and provide a strong rationale for adding SSADHD screening to existing NBS panels.