Too much and too little: inborn errors of manganese homeostasis

Manganese is an indispensable cofactor for a wide range of enzymes in human metabolism, yet in excess it becomes toxic. Its homeostasis is therefore tightly controlled, and members of the solute carrier (SLC) family of transport proteins are central to this regulation. Over the past decade, inherited disorders of several manganese transporters have emerged as a distinct class of inborn errors of metabolism. Strikingly, pathogenic variants within this small group of transporters can disturb manganese balance in opposite directions: loss-of-function variants in SLC30A10 and SLC39A14 cause manganese overload, typically presenting with dystonia and parkinsonism, whereas variants in SLC39A8 cause manganese deficiency and a congenital disorder of glycosylation. Importantly, and in contrast to most inborn errors of metabolism, several treatment approaches for these conditions already exist and are under active evaluation. This review summarizes the current understanding of the pathophysiology, clinical phenotypes, and therapeutic options for the inborn errors of manganese homeostasis.