Understanding Inborn Errors of Metabolism

Most common human diseases involve perturbed metabolism at the level of the organism and/or the individual cell.  However, it can be very difficult to know exactly how these perturbations relate to the disease, because some are adaptive responses to the underlying pathological process while others are disease drivers per se. Cancer is a prime example of a disease process where carcinogenic and metabolic changes are intertwined to promote cell survival and growth.  One approach to unravel this complex relationship is to focus on rare, monogenic disorders caused by mutations in genes encoding metabolic enzymes or regulators. There are hundreds of these diseases, most of which manifest in childhood and which are collectively termed “inborn errors of metabolism” (IEMs). Several IEMs are associated with tissue overgrowth and/or an inborn elevated cancer risk, while many others involve genes that are abnormally expressed in common, sporadically-acquired cancer. Hence, IEMs provide a unique opportunity to understand the chain of events emanating from a single metabolic perturbation and resulting in malignancy.  Importantly, for therapeutic applications, IEMs also demonstrate the consequences of chronic, systemic loss of a particular metabolic activity.