A Next Generation Multiscale View of Inborn Errors of Metabolism

Abstract

Inborn errors of metabolism (IEM) are not unlike common diseases. They often present as a spectrum of disease phenotypes that correlates poorly with the severity of the disease-causing mutations. This greatly impacts patient care and reveals fundamental gaps in our knowledge of disease modifying biology. Systems biology approaches that integrate multi-omics data into molecular networks have significantly improved our understanding of complex diseases. Similar approaches to study IEM are rare despite their complex nature. We highlight that existing common disease-derived datasets and networks can be repurposed to generate novel mechanistic insight in IEM and potentially identify candidate modifiers. While understanding disease pathophysiology will advance the IEM field, the ultimate goal should be to understand per individual how their phenotype emerges given their primary mutation on the background of their whole genome, not unlike personalized medicine. We foresee that panomics and network strategies combined with recent experimental innovations will facilitate this.

Systematic analysis of complex genetic interactions

“…Thus, our findings show that negative trigenic interactions often highlight the potential for a third mutation to amplify the phenotype of a digenic interaction. Analogously, in human genetics, the variation in an individual’s genetic background can have profound influence on the penetrance of the phenotype associated with a disease gene (35). …”

How mice are indispensable for understanding obesity and diabetes genetics

“…This integrated view complements reductionist approaches (1,2). These reductionist approaches identify the nature and function of elements that compose the foundation of complex biology, whereas systems studies define the context and consequence of the collective and integrated action of these elements focusing on such essential systems properties as robustness, resilience, homeostasis, hysteresis, and criticality (79).…”

“…Many diseases and most phenotypes are not properties of single cell types in vitro. Insteadm most metabolic conditions, even those resulting from single-gene Mendelian conditions, involve multiple cell types across multiple organs, and thus are problems in systems biology (1,2). We therefore propose that an interdependency between humans and model organisms will emerge as the centerpiece of biomedical research.…”

“…Various metabolic organs, such as brain, stomach, liver, adipose, muscle, interact in complex, poorly understood ways to integrate and coordinate activities throughout life and across environments. The ongoing challenge is to identify the genetic variants that control function of individual elements and their complex interactions (1,2). …”

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

“…For any patient with an IEM, the metabolic landscape that is determined by the combination of (a) the primary genetic defect in a certain IEM gene and (b) the genetic and environmental background of any patient, is the ultimate driver of disease . This recognition in itself brings metabolomics to the center stage in the diagnostic process and has led to the concept that—at least in our minds—this can best be achieved using a multidisciplinary strategy that we have termed the Translational Metabolism approach.…”