Familial hyperinsulinism (FH) is a genetic disorder that occurs when an individual has abnormally high concentrations of circulating insulin. This condition is associated with mutations in genes that encode proteins involved in the regulation of insulin secretion. FH is typically inherited in an autosomal recessive manner, meaning that both alleles of a particular gene must harbor a mutation for it to manifest in an individual. The mutations generally lead to altered insulin release from pancreatic beta cells due to decreased responsiveness to glucose and other physiological stimuli, or increased release of insulin due to decreased regulation. This can result in abnormally high levels of insulin, leading to a range of medical complications such as hypoglycemia and organ damage.
FH is a relatively rare disorder, with an estimated prevalence of 0.015-1.1 per 100,000 individuals in the United States. The disease manifests differently in different individuals, depending on the genetic cause and the type of mutation present. The effects of these mutations can manifest as congenital onset FH, in which the hyperinsulinemia manifests early in life and can lead to recurrent hypoglycemia, or neonatal onset FH, which is characterized by severe hypoglycemia that presents very soon after birth.
FH is typically diagnosed through a combination of clinical observations and laboratory tests, including a fasting glucose test, an oral glucose tolerance test, and/or a measurement of insulin levels during a hypoglycemic episode. Genetic testing is also available to diagnose the specific type of FH present in an individual. Treatment for FH typically includes lifestyle modifications and medications to control blood glucose levels, as well as a number of other therapies depending on the individual’s specific type of FH and associated medical complications.
FH is caused by mutations in a number of different genes that are involved in the regulation of insulin release and metabolism. These genes are typically associated with either the secretion (hormone) form of the condition, which involves mutations in the genes encoding the beta cell K ATP channel or the transcriptional-modulating form of the condition, which involves mutations in a number of genetic regulators of insulin synthesis and storage. Mutations in some of these genes are seen in all forms of the FH, while others, such as the beta cell K ATP channel and transcriptional regulators, are associated only with particular forms of the disease.
In addition to these gene mutations, a number of environmental factors can also contribute to the development of FH, including a number of medications, maternal environmental exposures, and inborn errors of metabolism. With the increasing prevalence of obesity and other metabolic disorders, the likelihood of FH occurring due to environmental factors is increasing.
The diagnosis of FH has been greatly aided by advances in genetic testing. In particular, sequencing of the genes related to insulin-releasing pathways has greatly improved our understanding of the genetic cause of the condition, allowing for more targeted treatments and more accurate diagnoses. As genetic testing continues to advance, the hope is that more accurate diagnoses and more effective treatments can be developed to help manage the condition.
