Familial hyperinsulinism

Familial hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin, which is a hormone that helps control blood sugar levels. People with this condition have frequent episodes of low blood sugar (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, and/or difficulty feeding. Repeated episodes of low blood sugar increase the risk for serious complications such as seizures, intellectual disability, breathing difficulties, and coma.

The severity of familial hyperinsulinism varies widely among affected individuals, even among members of the same family. Most people with this condition develop signs or symptoms of hypoglycemia soon after birth, although some do not experience frequent hypoglycemia episodes until late infancy or early childhood. Unlike typical episodes of hypoglycemia, which occur after periods without food (fasting), episodes of hypoglycemia in people with familial hyperinsulinism can also occur after eating or exercising.

Familial hyperinsulinism has an estimated incidence of 1 in 50,000 live births. This condition is more common in countries where there are high rates of marriages between relatives. In these populations the condition is thought to affect 1 in 2,500 live births.

Familial hyperinsulinism is caused by mutations in genes that regulate the release (secretion) of insulin, which is produced by beta cells in the pancreas. Insulin controls how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy.

Gene mutations that cause familial hyperinsulinism lead to over-secretion of insulin from beta cells. Normally, insulin is secreted in response to the amount of glucose in the bloodstream, but in people with familial hyperinsulinism, insulin is secreted from beta cells despite the amount of glucose present. This excessive secretion of insulin results in glucose being rapidly removed from the bloodstream and taken up by tissues such as muscle, liver, and fat. A lack of glucose in the blood results in frequent states of hypoglycemia in people with familial hyperinsulinism. Insufficient blood glucose also deprives the brain of its primary source of fuel.

In most affected individuals, all beta cells secrete too much insulin. These people have the diffuse form of the disease. In others, only some beta cells have impaired insulin secretion. These people have the focal form of the disease.

Mutations in at least seven genes have been found to cause familial hyperinsulinism. Mutations in the ABCC8 gene are the most common cause of the disorder. They are responsible for this condition in approximately 40 percent of affected individuals. Less frequently, mutations in the KCNJ11 gene have been found in people with familial hyperinsulinism. Mutations in each of the other genes associated with familial hyperinsulinism account for only a small percentage of cases.

In approximately 50 percent of cases, the cause of familial hyperinsulinism is unknown.

Read more about the ABCC8 and KCNJ11 genes.

See a list of genes associated with familial hyperinsulinism.

Familial hyperinsulinism has different inheritance patterns.

Most often, the diffuse form of the condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Less frequently, the diffuse form is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

The inheritance of the focal form of familial hyperinsulinism is more complex. Most people with this condition inherit one copy of an altered gene from their unaffected father. During embryonic development, a mutation occurs in the other copy of the gene. This second mutation is only found within some cells in the pancreas. As a result, some pancreatic beta cells have impaired insulin secretion, while other beta cells function normally.