LONGITUDINAL STUDY OF UREA CYCLE DISORDERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Urea cycle disorders (UCD) are a group of rare inborn errors of metabolism that commonly present in childhood with episodes of vomiting lethargy and coma. Symptoms are the result of an accumulation of ammonia, a toxic product of protein degradation, which is not adequately metabolized in the liver of affected individuals due to an enzyme deficiency present from birth. Deficiencies in each of the 8 enzymes and transporters that comprise the urea cycle have been identified in patients and all are inherited as recessive traits except for the most common disorder, ornithine transcarbamylase deficiency, which is inherited as an X-linked trait. The risk of death or severe disability from these disorders approaches 50%, and current therapy is considered inadequate. The purpose of this study is to perform a long-term follow-up of a large group of patients with the various urea cycle disorders. We will asess biochemical status, growth and various urea cycle disorders. We will evaluate survival and cognitive outcome of the two most commonly used forms of treatment, alternate pathway therapy and liver transplantation. We will also seek to identify biochemical changes (biomarkers) that may predice 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 Office of Rare Diseases (ORD) of the National Institutes of Health (NIH) established a Rare Diseases Clinical Research Network (RDCRN) together with the National Center for Research Resources (NCRR)/General Clinical Research Consortium (GCRC) Program and in collaboration with other NIH Institutes funded ten rare diseases clinical research consortia and one Data and Technology Coordinating Center. As part of the RDCRN, the Urea Cycle Disorders Consortium (UCDC) was created to study urea cycle disorders. The UCDC consists of a consortium of eight academic insitutions: Children's National Medical Center, Children's Hospital of Philadelphia, Vanderbilt University, Baylor College of Medicine, University of California Los Angeles, Yale University School of Medicine, Mount Sinai School of Medicine and Case Western Reserve University. All eight UCDC Centers are participating in the Longitudinal Study of Urea Cycle Disorders. HYPOTHESIS A longitudinal multidisciplinary investigation of the natural history, morbidity, and mortality in people with urea cycle disorders will improve treatment and outcome of this devastating group of disorders. SPECIFIC AIMS The objective of this protocol is to conduct a longitudinal multidisciplinary investigation of the natural history, morbidity, and mortality in people with UCD. The research questions are: a. In the longitudinal cohort, what is the prevalance of specific morbid indicators of disease severity, including hyperammonemia, developmental disabilities, and various long-term renal and hepatic effects, as well as case-fatality associated with the various forms of UCD? b. What are the correlations between various biomarkers and disease severity and progression? c. What is the safety and efficacy of currently used and new UCD therapies?