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.

暂无摘要。

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100\'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.

In January 2011, Children\'s National Medical Center in Washington, D.C. hosted a consensus conference to discuss and develop recommendations for the diagnosis and management of propionic acidemia. Several resulting manuscripts from this conference are included in this issue. Topics covered include recommendations for acute management of metabolic decompensations, recommendations for chronic management and health monitoring, natural history of disease in patients with propionic acidemia, and neurologic complications in propionic acidemia.