Clinical-Res-Project1

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ABSTRACT - CLINICAL RESEARCH PROJECT 1 Urea cycle disorders (UCD) are a group of 8 rare 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 (CPSID); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD) (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II (CITN). The Longitudinal Study (LS) is essential to the overall goals of the RDCRC Urea Cycle Disorders Consortium (UCDC) and is the basis of its research mission to address questions of pathophysiology, morbidity/mortality, as well as other outcomes of UCD including: (a) growth and development, (b) metabolic status, (c) nutritional status, (d) cognitive function, (e) treatment effects, (f) pregnancy outcomes of affected mothers and their children, (g) late effects and co- morbidities, and (h) quality of life/mental health status. The LS not only furnishes the clinical data to explore these issues but also enables the identification of critical biomarkers that predict outcome and response to treatment, serving as a basis for clinical trial readiness and experimental therapeutics. Critical to advancement in this group of rare diseases, during the current and previous grant periods the UCDC has successfully enrolled, classified, and characterized a large (> 800) patient cohort and used this data to expand knowledge of the natural history of UCD. The specific aims for the LS are to: 1) Examine the impact of UCD on outcomes of affected individuals throughout the lifespan. Questions to be addressed include: Do UCD and their associated treatments affect the growth and development of affected children and do these alter adult life functional outcomes of affected individuals? What is the contribution of the frequency and severity of hyperammonemic episodes in complicating outcomes? Does genotype impact outcome? What are the longer-term outcomes for affected infants into adolescence and young adulthood? Are women with UCD able to successfully and safely undergo pregnancy? How does the profile of recurring metabolic crisis evolve throughout the lifespan? Definition of these issues should allow future targeting of therapies towards improved outcomes and direct priorities in future clinical trials. 2) Establish the natural history of rare UCD subtypes and disorders with a particular focus on characterizing CPS1D, ARGD, CITR, HHH, and NAGSD and on differentiating the impact of uncommon subtypes of more common UCD. 3) Facilitate the study of co-morbidities including hepatic disease and seizures. Illuminating the role of these important but poorly recognized morbidities will be the focus of Projects 2 and 3 in this application and will rely, in part, on elements of data collected in the LS.