2.1. Familial glucocorticoid deficiency

At least 25 mutations in the NNT gene have been found to cause familial glucocorticoid deficiency. This condition is characterized by potentially life-threatening low blood sugar (hypoglycemia), recurrent infections, and skin coloring darker than that of other family members (hyperpigmentation). The features of familial glucocorticoid deficiency are caused by an inability of the adrenal glands to produce a group of hormones called glucocorticoids, which play a role in many functions in the body. NNT gene mutations account for approximately 10 percent of cases of this condition.

Most of the mutations that cause familial glucocorticoid deficiency change single protein building blocks (amino acids) in the nicotinamide nucleotide transhydrogenase enzyme. These mutations impair the enzyme's ability to produce NADPH, leading to an increase in reactive oxygen species in the adrenal glands. Over time, these toxic molecules can impair the function of adrenal gland cells and lead to the death of those cells (apoptosis), diminishing the production of glucocorticoids. A shortage of these hormones impairs blood sugar regulation, immune system function, and other cellular functions, leading to the signs and symptoms of familial glucocorticoid deficiency.

It is unclear why NNT gene mutations seem to only affect adrenal gland function. Researchers suggest that individuals with familial glucocorticoid deficiency caused by NNT gene mutations could develop problems in other tissues over time as reactive oxygen species exert their harmful effects.