Urea cycle disorders (UCD) are a group of 8 rare (overall incidence 1:30,000) but devastating inborn errors of metabolism that carry a high mortality and morbidity from the newborn period through adulthood. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis: N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthase I deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase deficiency (ASSD); Argininosuccinatelyase deficiency (ASLD); Arginase (ARGID) deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II . A decade ago we created the Urea Cycle Disorders Consortium (UCDC) as one of the first members of the Rare Diseases Clinical Research Network (RDCRN) and have subsequently conducted 11 research protocols aimed at understanding the natural history of UCD, developing biomarkers of morbidity and testing novel therapies. Currently the UCDC consists of 14 sites in the U.S., Canada and Europe with an interdisciplinary team of over 60 investigators and staff. The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for UCD and has collaborations with industry to develop innovative therapies for these disorders. We propose in this application 3 full clinical research projects and 3 pilot projects. In the clinical projects we will: 1) Expand our longitudina study that investigates the natural history, morbidity, mortality and biomarkers in children and adults with UCD; 2) Perform a Phase II trial of inorganic nitrites to assess efficacy in correcting nitric oxide deficiency and its consequences in ASLD; and 3) Assess neural and cognitive mechanisms of injury in OTCD, ASLD and ASSD using neuropsychological testing combined with structural MRI, functional MRI, and magnetic resonance spectroscopy. In the proposed pilot projects we will investigate NexGen sequencing for newborn screening of NAGSD, CPS1D and OTCD; perform a trial of urease inhibitors to decrease N accumulation; and use the DMCC maintained contact registry to study compliance with clinical guidelines. In addition to the research studies, we will expand and enhance our website for educational and research resources and continue to provide training and career development opportunities through our educational programs.
We anticipate that the results of our studies will be a marked improvement in the outcome of patients with UCD through the development of new therapies and improved clinical management through evidenced based medicine. Furthermore, an improved understanding ofthe pathogenesis and treatment of UCD is likely to advance our understanding of more common disorders of liver dysfunction.
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