Metabolite flux: A dynamic concept for inherited metabolic disorders as complex traits

In 2000 and 2001, we described factors that lead to the phenotypes of individuals with "simple," "single" gene disorders, like inherited metabolic disorders, being complex, multi-genic traits. These factors include functional thresholds, genetic and environmental modifiers, and systems dynamics, encompassing metabolic control analysis and scale-free, hub-and-spoke networks. This mini-review will consider topics influencing complexity developed in the ensuing nearly two decades, such as "synergistic heterozygosity" and "moonlighting proteins." There will be a focus on the value of the measurement of flux in evaluating the metabolome to ascertain phenotypic variability and the potential role of the gut microbiome in metabolomic flux. A point-of-care metabolomics tool, under development to improve the real time, inter-operative ascertainment of tumor margins and similar devices, will provide opportunities to improve acute care and ongoing management of individuals with inherited metabolic disorders.