How guideline development has informed clinical research for organic acidurias (et vice versa)

Abstract

AbstractOrganic 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.