New mutation in mitochondrial antioxidant gene offers new insights in the pathogenesis of a rare fo

Familial gluocorticoid deficiency (FGD) is a rare, hereditary form of adrenal insufficiency characterised by resistance of the adrenal glands to stimulation by their trophic hormone, ACTH (adrenocoticotropic hormone). FGD patients typically present in infancy or early childhood with failure to thrive or seizures and prompt glucocorticoid replacement is essential to prevent or successfully manage a life-threatening adrenal crisis. Interestingly, no other organ dysfunction has been reported in these individuals. Until recently, this enigmatic condition had exclusively been attributed to mutations on the ACTH recepotor (MC2R) and its accessory protein (MRAP).

A recent study published in the Journal of Clinical Endocrinology and Metabolism reveals a new genetic link between FGD and inactivating mutations of a gene encoding a mitochondrial antioxidant protein, thioredoxin reductase 2 (TXNRD2). The study was based on whole exome sequencing of three affected individuals from a consanguineous family. Two years ago, the same group discovered a causal link between FGD and another mitochondrial antioxidant, Nicotinamide Nucleotide Transhydrogenase (NNT). Both TXNRD2 and NNT are crucial parts of the mitochondrial system which detoxifies reactive oxygen species (ROS), the harmful byproducts of aerobic metabolism. These findings underline the, hitherto unsuspected, importance of oxidative balance in adrenal physiology. Further research is required to delineate the complex interplay between ROS and steroidogenesis and explain the selective susceptibility of the adrenal glands to oxidative stress.

#familialglucocorticoiddeficiency #adrenal #acth #nnt