Enzyme Diagnostics in a Changing World of Exome Sequencing and Newborn Screening as Exemplified for Peroxisomal, Mitochondrial, and Lysosomal Disorders

Abstract

Enzymes are the ultimate catalysts of chemical reactions and thus form the essence of metabolic pathways to ensure metabolic homeostasis. This occurs in close conjunction with the multiple transmembrane metabolite transporters which allow enzymes localized in different compartments within each individual cell to interact with one another. Until recently, enzymology was the obligatory, second step in the diagnostic algorithm aimed to identify the underlying defect in any patient suspected to suffer from an inborn error of metabolism (IEM) as a logical follow-up of metabolic investigations. This classical approach has led to the discovery of numerous inborn errors of metabolism. The introduction of sophisticated, highly accurate, and fast DNA sequencing technologies has revolutionized the field of inborn errors of metabolism and DNA sequencing may soon be the first line of investigation, especially in patients with an undefined set of signs and symptoms. Although these new developments will definitely change the sequence of events in the diagnosis of patients suspected to suffer from an inborn error of metabolism, enzymological studies will remain of crucial importance since it is the only way to resolve the functional consequences of the DNA variants found upon whole exome or whole genome sequencing in close conjunction with metabolite studies in such patients. We will describe the importance of enzymology for the diagnosis of patients affected by a peroxisomal disorder, a disorder of mitochondrial beta-oxidation, a defect in oxidative phosphorylation (OXPHOS), or a lysosomal disorder.