Abstract：
Organic acidurias, such as glutaric aciduria type 1 (GA1), methylmalonic (MMA), and propionic aciduria (PA) are a prominent group of inherited metabolic diseases involving accumulation of eponymous metabolites causing endogenous intoxication. For all three conditions, guidelines for diagnosis and management have been developed and revised over the last years, resulting in three revisions for GA1 and one revision for MMA/PA. The process of clinical guideline development in rare metabolic disorders is challenged by the scarcity and limited quality of evidence available. The body of literature is often fragmentary and where information is present, it is usually derived from small sample sizes. Therefore, the development of guidelines for GA1 and MMA/PA was initially confronted with a poor evidence foundation that hindered formulation of concrete recommendations in certain contexts, triggering specific research projects and initiation of longitudinal, prospective observational studies using patient registries. Reversely, these observational studies contributed to evaluate the value of newborn screening, phenotypic diversities, and treatment effects, thus significantly improving the quality of evidence and directly influencing formulation and evidence levels of guideline recommendations. Here, we present insights into interactions between guideline development and (pre)clinical research for GA1 and MMA/PA, and demonstrate how guidelines gradually improved from revision to revision. We describe how clinical studies help to unravel the relative impact of therapeutic interventions on outcome and conclude that despite new and better quality of research data over the last decades, significant shortcomings of evidence regarding prognosis and treatment remain. It appears that development of clinical guidelines can directly help to guide research, and vice versa.
摘要：
有机酸透，如戊二酸尿症1型，甲基丙二酸，和丙酸尿症（GA1，MMA，PA）是一组突出的遗传性代谢疾病，涉及导致内源性中毒的同名代谢物的积累。在过去的几年中，已经制定和修订了所有三种疾病的诊断和管理指南，导致GA1的三个修订和MMA/PA的一个修订。罕见代谢性疾病的临床指南制定过程受到缺乏和可用证据质量有限的挑战。文学的主体往往是零碎的，信息存在的地方，它通常来自小样本量。因此,GA1和MMA/PA指南的制定最初面临的证据基础不足，阻碍了在某些情况下制定具体建议，触发具体的研究项目和纵向的启动，使用患者登记的前瞻性观察性研究。相反,这些观察性研究有助于评估新生儿筛查的价值，表型多样性，和治疗效果，从而显著提高证据质量，直接影响指南建议的制定和证据水平。这里,我们提出了对指南制定和GA1和MMA/PA（临床前）研究之间相互作用的见解，并演示指南如何从修订到修订逐步改进。我们描述了临床研究如何帮助揭示治疗干预对结果的相对影响，并得出结论，尽管在过去的几十年中，研究数据的质量更高，关于预后和治疗的证据仍然存在重大缺陷。看来，临床指南的制定可以直接帮助指导研究，反之亦然。本文受版权保护。保留所有权利。
