Frontiers in Congenital Disorders of Glycosylation

总体--项目摘要/摘要 20世纪90年代的遗传学定义，先天性糖基化异常(CDG)由130种不同的先天疾病组成 代谢错误，总发病率为1：100,000。三十年后：没有疾病的自然历史数据， 没有全面的患者登记，也没有对许多CDG类型进行可靠的筛查。此外，几乎没有任何治疗方法 是可用的。我们确实有一个强大的患者协会，忠诚的临床医生，以及一个不断壮大的科学家小组，形成了一个 虚拟联盟，密切合作以改善患者结果。我们需要未来的自然历史 关于健康问题的数据，以影响生活质量，验证疾病生物标志物，并开发可靠的诊断方法 提高临床试验准备情况。 我们的初步发现包括追溯自然历史数据，以及新型生化生物标记物的数据。 和含有糖组分的技术，这些技术是在筛选和验证的试点试验中建立和验证的 CDG中的诊断。针对特定CDG类型的第一次临床试验是从饮食干预开始的，因为大多数 CDG治疗的常用方法。我们的合作小组是这些试验的先驱，最重要的是D- 半乳糖治疗PGM1-CDG。我们还同时启动了第一个(有限的)PMM2-CDG自然历史研究 与美国国立卫生研究院单中心CDG自然历史研究。我们覆盖全国的区域中心网络将进一步 在慢性萎缩性胃炎的诊断、随访、治疗和临床研究方面合作。 我们超乎寻常的目标是a)建立早期可靠的诊断b)提高诊断成功率和敏感性，c) 提高我们对自然历史的认识，d)寻找新的生物标志物，e)开发先天性心脏病的治疗方法 糖基化紊乱。我们将包括所有类型的CDG，重点关注三个主要的生化障碍组 在多方面的CDG中：a)最常见的CDG形式；PMM2-CDG，b)潜在的可治疗组 影响蛋白质半乳糖化的疾病，以及c)新的糖基化障碍组的缺陷( 去糖基化)--NGLY1缺乏症。 为了实现这些里程碑，我们将应用跨学科、基于团队的临床研究来1)定义自然 病史，验证患者报告的结果，并分享先天性糖基化障碍的知识；2) 为临床试验开发和验证新的生化诊断技术和治疗生物标志物；以及 恢复适当的糖基化，以改善糖基化紊乱的临床症状和生活质量。 我们财团中的合作伙伴十多年来一直在合作寻找复杂问题的解决方案 CDG生物学、共享知识、个体化治疗、组织患者会议和支持 护理CDG患者的医生。我们已经改善了这种罕见疾病的患者护理，但这还不够。 利用全国范围的网络，这项提案的目的是开始缓解数十年来悬而未决的问题， 解决知识匮乏的问题，开发治疗方法，满足目前未得到满足的患者需求。

OVERALL-PROJECT SUMMARY/ABSTRACT Genetically defined in the 1990s, congenital disorders of glycosylation (CDG) consist of 130+ different inborn metabolism errors with overall incidence of ~>1:100,000. Thirty years later: there is no disease natural history data, no comprehensive patient registry, and no reliable screening for many CDG types. Furthermore, almost no therapy is available. We do have a strong patient association, committed clinicians, and a growing scientist group forming a virtual consortium, which closely collaborates to improve patient outcomes. We need prospective natural history data on health concerns to impact quality of life, validate disease biomarkers, and develop reliable diagnostics to increase clinical trial readiness. Our preliminary findings include retrospective natural history data, as well as data on novel biochemical biomarkers and techniques containing glycomics, which were established and validated in pilot trials for screening and diagnostics in CDG. The first clinical trials in specific CDG types started with dietary intervention, as is the most common approach in CDG therapy. Our collaborating group pioneered in these trials, most importantly in D- galactose therapy in PGM1-CDG. We also initiated the first (limited) PMM2-CDG natural history study, in parallel with the NIH single center CDG natural history study. Our nation-wide network of regional centers will further collaborate on diagnosis, follow up, treatment and clinical research in CDG. Our overreaching aims are a) establishing early reliable diagnosis b) increase diagnostic success and sensitivity, c) improve our knowledge on the natural history, d) find new biomarkers and e) develop therapies in congenital disorders of glycosylation. We will include all types of CDGs, focusing on three major biochemical disorder groups within multifaceted CDG: a) the most common form of CDG; PMM2-CDG, b) the group of potentially treatable disorders affecting protein galactosylation, and c) a defect from the new glycosylation disorder group (disorders of de-glycosylation)--NGLY1 deficiency. To achieve these milestones, we will apply cross-disciplinary, team-based clinical research to 1) define natural history, validate patient reported outcome and share knowledge on congenital disorders of glycosylation; 2) develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for clinical trials; and 3) restore appropriate glycosylation to improve clinical symptoms and quality of life in disorders of glycosylation. Partners in our consortium have collaborated for more than a decade in finding solutions to complex problems in CDG biology, sharing knowledge, individualizing therapy, organizing patient conferences, and supporting physicians caring for CDG patients. We have improved patient care in this rare disease, but it is not enough. Leveraging on a nation-wide network, this proposal's aims begin to relieve decades of unresolved questions, address lack of knowledge, develop treatment and meet currently unmet patient need.