Clinical-Res-Project1

摘要-临床研究项目1 尿素循环障碍(UCD)是一组罕见但具有破坏性的先天性代谢错误 从新生儿到成年期的高死亡率和高发病率。UCD包括以下任何方面的缺陷 参与尿素生物合成的六种酶和两种膜转运体：N-乙酰谷氨酸合成酶 缺乏症(NAGSD)；氨基甲酰磷酸合成酶I缺乏症(CPSID)；鸟氨酸转氨甲基酶 精氨酸琥珀酸合成酶缺乏症(瓜氨酸血症)；精氨酸琥珀酸裂解酶 精氨酸缺乏症(ASLD)(精氨酸琥珀酸尿症)；精氨酸酶缺乏症(ARGD)(精氨酸血症)； 高氨血症，高瓜氨酸尿症(HHH)综合征；瓜氨酸血症II型(CITN)。纵向研究 (LS)对RDCRC尿素循环障碍联合会(UCDC)的总体目标至关重要，是基础 其研究任务是解决病理生理学、发病率/死亡率以及其他结果的问题 包括：(A)生长发育，(B)代谢状况，(C)营养状况，(D)认知功能， (E)治疗效果；(F)受影响母亲及其子女的妊娠结局； (H)生活质量/心理健康状况。LS不仅提供了可供探索的临床数据 这些问题也使识别预测结果和反应的关键生物标志物成为可能 治疗，作为临床试验准备和实验疗法的基础。对晋升至关重要 在这组罕见疾病中，在当前和之前的赠款期间，美国疾病控制与预防中心已经成功登记， 对一个大的(800)患者队列进行分类和表征，并使用这些数据来扩展对自然疾病的知识 UCD的历史。 LS的具体目标是：1)检查UCD对受影响个人结局的影响 在整个生命周期中。需要解决的问题包括：UCD及其相关治疗是否会影响 受影响儿童的生长发育以及这些是否会改变受影响儿童的成人生活功能结果 个人？高氨血症发作的频率和严重程度对并发 结果呢？基因分型会影响结果吗？受影响的婴儿进入 青春期和青壮年？患有UCD的妇女是否能够成功和安全地怀孕？ 在整个生命周期中，反复出现的代谢危机是如何演变的？这些问题的定义 应该允许未来针对改善结果的治疗和在未来临床试验中的直接优先事项。 2)建立罕见UCD亚型和疾病的自然病史，并特别关注其特征 CPS1D、ARGD、CITR、HHH和NAGSD以及区分不常见的More亚型的影响 常见的UCD。3)促进包括肝病和癫痫在内的并存疾病的研究。照亮了 这些重要但认识不多的疾病的作用将是本申请中项目2和3的重点 并将在一定程度上依赖于LS收集的数据元素。

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.