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 11 (CITN). The purpose of the longitudinal study project is to perform a long-term follow-up study of up to 1,100 patients with UCD. We will assess biochemical status, nutrition and cognitive function over time. We will evaluate morbidity and mortality of the most commonly used forms of treatment for UCD. We will also seek to identify biochemical parameters (biomarkers) that may predict future metabolic imbalances so that they can be corrected before clinical symptoms develop. The overall goal of this stiJdy is to improve treatment and outcome of this devastating group of disorders.
Our specific aims are to;1 Define the relationship between specific biomarkers and hyperammonemic crises;2) Determine the long-term morbidities associated with specific UCD, especially neurocognitive deficits and hepatic and renal disease;3) Define the outcomes of specific UCDs, including physical and neurodevelopmental deficits and their effect on quality of life;and 4) Evaluate the long-term safety and efficacy of currently used therapy for UCD (nitrogen scavengers and liver transplantation) and new and emerging treatments (N-carbamylglutamate, inorganic nitrites).
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 of the pathogenesis and treatment of UCD is likely to advance our understanding of more common disorders of liver dysfunction.
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