? Extensive basic research in the last 15 years has significantly extended our understanding of the pathophysiology and potential treatment strategies for succinic semialdehyde dehydrogenase deficiency (SSADHD), a rare heritable disorder of GABA metabolism. Yet, significant knowledge gaps remain as barriers to early detection and prognosis of the disease, and to the assessment of the efficacy of novel therapeutics. These gaps include a comprehensive description of the natural disease course, an understanding of the prognostic value of neurophysiological and biochemical markers of the disease and a validated GABA assay suitable for high-throughput NBS platforms. Thus, we propose a natural history study of SSADHD with the following 3 aims: 1) to determine the natural course of the clinical presentation of SSADHD with comprehensive yearly assessments. We hypothesize that disease presentation will worsen with age and propose to use a novel semi-quantitative clinical severity score to quantify the most prominent clinical features of the disease; 2) to determine the natural evolution of neurophysiological and biochemical indices known to be abnormal in SSADHD, including: cerebral volume, brain GABA concentration (MRS), brain myelination (DTI), indices of cortical GABAergic function measured with EEG and transcranial magnetic stimulation (TMS), and blood and urine levels of GABA and GABA-related metabolic derivatives such as GHB and others. Embedded in this aim is the validation of a dried bloodspot assay for GABA suitable for NBS; 3) to identify neurophysiological and biochemical predictors of clinical severity, framed by the hypothesis that higher plasma and brain GABA concentrations at first visit predict more severe clinical outcomes in later years. The study will follow 30 patients with yearly assessments: 20 patients enrolled at Boston Children's Hospital, and 10 patients enrolled at foreign academic sites participating in the International Working Group of Neurotransmitter Related Diseases (iNTD). In addition, we will collected standard-of-care data from approximately 25 patients followed by an international network of rare disease specialists also related to iNTD. Cumulatively, we will obtain longitudinal data from up to 55 patients over the course of 5 years (~25% of reported cases). Biospecimens will be analyzed by the WSU laboratory and banked for future testing (biorepository). Brain imaging scans, EEG and TMS recordings will be analyzed by the BCH Imaging Core. Data will be managed by the RDCRN Data Management & Coordinating Center at University of South Florida. The DMCC will also provide biostatistics support. On-line data entry forms will be developed to facilitate standardized world-wide entry of relevant disease information, thus creating a truly international SSADHD registry that will outlive the funding years of the study. The project is enthusiastically supported by several patient advocacy groups representing over 125 patients worldwide. The proposed research will provide the information needed to better predict the natural course of SSADHD, better monitor the success of future therapeutics, and will lay the foundation for addition of SSADHD screening to existing NBS panels.
? Significant knowledge gaps remain in our understanding of succinic semialdehyde dehydrogenase deficiency (SSADHD, a defect of GABA metabolism), including an understanding of the natural disease course, an objective measure of clinical severity to monitor disease progression, knowledge of the prognostic value of neurophysiological and biochemical disease markers, and a dried blood spot (DBS) GABA assay applicable to high throughput NBS analytical platforms. Our project will develop a clinical severity score that monitors the natural clinical course of SSADHD, evaluate the evolution of neurophysiological and biochemical markers known to be abnormal, comprehensively examine biomarkers of clinical severity, and complete the validation of a DBS assay for GABA. The significance of our proposal is reflected in the creation a comprehensive international SSADHD registry and database that will ensure collection of data well beyond the funding years, while simultaneously providing the clinical and biochemical information needed to better predict the natural disease course, better monitor future therapeutic strategies, and to lay a rational foundation for the addition of SSADHD to existing newborn screening panels.
