Rare biochemical & genetic conditions: clues for broader mechanistic insights.

Abstract

Rare disorders often represent a molecular deviation from hi-fidelity genomic integrity networks and are often perceived as too difficult or unimportant for further mechanistic studies. Here, we synthesize evidence demonstrating how valuable knowledge of biochemical pathways related to rare disorders can be for biomedicine. To this end, we describe several rare congenital lipid, protein, organic acid, and glycan metabolism disorders and discuss how rare phenotypes (such as "extreme responders") and case reports (such as the lenalidomide cases) have provided clues for drug discovery or repurposing. We also discuss how rare disorders such as Gaucher disease and ultra-rare genetic syndromes can provide insights into cancer and mTOR-driven metabolism, respectively. Our discussion highlights the continued value of biochemical pathways and studies in understanding human pathophysiology and drug discovery even in the genomics era.