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Multiple acyl-CoA dehydrogenase deficiency (MADD; also known as glutaric aciduria type II) is an ultra-rare inborn error of metabolism (IEM). The disorder is not included in the Dutch newborn blood spot (NBS) screening program due to a lack of evidence for sufficient health gain upon early detection. Complicating factors concern the limited knowledge on the natural history, disease severity prediction and monitoring of the spectrum of MADD patients, and the absence of systematic evidence of an effective treatment for severely affected patients. MADD is also an exemplary IEM that can escape identification due to nonspecific symptoms and unexpected childhood death. In this thesis, we combined reviews of the literature, with experimental research and studies on clinical outcome in patients. In part I, we present the IEMs that are associated with unexpected death in early childhood, and how their detection through acylcarnitine profile analysis can be improved. We recommend that every child participates in a population NBS program, even after death. In part II, we describe that functional studies in patient fibroblasts can predict the MADD phenotype, we propose a clinical monitoring system, and we describe the efficacy and safety of D,L-3-hydroxybutyrate treatment in severe MADD. The results of this thesis can guide clinicians in their care of MADD patients and their families, and can also support decision-makers in their aims to improve NBS programs and facilitate access to novel treatments for (ultra-)rare diseases.