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 (NAGS);Carbamyl phosphate synthase I (CPSI) deficiency;Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase (AS) deficiency (Citrullinemia);Argininosuccinate lyase (AL) deficiency (Argininosuccinic aciduria);Arginase (ARG) deficiency (Argininemia);Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome;and Citrullinemia type II. The purpose of the longitudinal project is to perform a long-term follow-up study of a large group of patients with UCD. We will assess biochemical status, nutrition and cognitive function over time. We will evaluate morbidity and mortality of the two most commonly used forms of treatment for UCD, alternate pathway therapy and liver transplantation. 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 study is to improve treatment and outcome of this devastating group of disorders.
The specific aims are to address the following questions: a. In the longitudinal cohort, what is the prevalence of specific morbid indicators of disease severity, including hyperammonemia, developmental disabilities, and various long-term renal and hepatic abnormalities? b.What is the relationship between various biomarkers and disease severity and progression? c.What is the safety and efficacy of currently used and new UCD therapies?
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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