LONGITUDINAL STUDY OF UREA CYCLE DISORDERS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 尿素循环障碍(UCD)是一组罕见的先天性代谢错误，通常出现在儿童时期，伴有呕吐、嗜睡和昏迷。症状是氨积累的结果，氨是蛋白质降解的有毒产物，由于出生时就存在酶缺乏症，氨在受影响的人的肝脏中没有充分代谢。构成尿素循环的8种酶和转运体中的每一种都被发现在患者中存在缺陷，除了最常见的疾病鸟氨酸转氨酶缺乏症外，所有这些都是以隐性特征遗传的，鸟氨酸转氨酶缺乏症是作为X连锁性状遗传的。这些疾病导致死亡或严重残疾的风险接近50%，目前的治疗被认为是不够的。本研究的目的是对一大群患有各种尿素循环障碍的患者进行长期随访。我们将减少生化状态、生长和各种尿素循环障碍。我们将评估两种最常用的治疗形式--替代途径治疗和肝移植--的存活率和认知结果。我们还将寻求识别可能预示未来代谢失衡的生化变化(生物标记物)，以便在临床症状出现之前纠正这些变化。这项研究的总体目标是改善这一破坏性疾病的治疗和结果。 美国国立卫生研究院(NIH)罕见疾病办公室(ORD)与国家研究资源中心(NCRR)/综合临床研究联盟(GCRC)计划建立了罕见疾病临床研究网络(RDCRN)，并与其他NIH研究所合作，资助了10个罕见疾病临床研究联盟和一个数据和技术协调中心。作为RDCRN的一部分，尿素循环紊乱联盟(UCDC)是为了研究尿素循环紊乱而成立的。UCDC由八个学术机构组成：儿童国家医学中心、费城儿童医院、范德比尔特大学、贝勒医学院、加州大学洛杉矶分校、耶鲁大学医学院、西奈山医学院和凯斯西储大学。所有八个UCDC中心都参与了尿素循环障碍的纵向研究。 假设 对尿素循环障碍患者的自然病史、发病率和死亡率进行纵向多学科调查将改善这一破坏性疾病的治疗和结果。 具体目标 该方案的目的是对UCD患者的自然病史、发病率和死亡率进行纵向多学科调查。 研究问题包括： A.在纵向队列中，疾病严重程度的特定病态指标，包括高氨血症、发育障碍、各种长期的肾脏和肝脏影响，以及与各种形式的UCD相关的病死率是什么？ B.各种生物标志物与疾病严重程度和进展的相关性是什么？ 目前使用的和新的UCD疗法的安全性和有效性是什么？

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?