Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Congenital hyperinsulinism (Congenital hyperinsulinism) - Genes ABCC8 and KCNJ11.

Congenital hyperinsulinemia is a disorder that causes individuals present abnormally high levels of insulin. People with this disease have frequent episodes of hypoglycaemia. In infants and young children, these episodes are characterized by lethargy, irritability and difficulty feeding. Repeated episodes of hypoglycemia increase the risk of serious complications such as respiratory distress, seizures, mental retardation, vision loss, brain damage and coma.

The severity of the disease varies widely among affected individuals, even among members of the same family. About 60% of newborns with this disorder have a hypoglycemic episode during the first month of life. Other affected children develop hypoglycemia in early childhood. Unlike typical episodes of hypoglycemia, which occur more frequently after fasting or after exercise, episodes of hypoglycemia in people with the disease can also occur after eating.

Congenital hyperinsulinemia is due to mutations in genes that regulate insulin secretion. Mutations in ABCC8, located on the short arm of chromosome 11 (11p15.1), are the most common known cause of disease and represents approximately 40% of cases. Less frequently, the disease is due to mutations in KCNJ11 gene, located on the short arm of chromosome 11 (11p15.1), which represent only a small percentage of all cases. In about half of people with congenital hyperinsulinism, the cause is unknown.

KCNJ11 and ABCC8, encoding genes channel subunits ATP - sensitive potassium (K ATP), found through cell membranes in the beta cells of the pancreas. Beta cells secrete insulin, which controls the amount of glucose that goes from the bloodstream into cells to be used as energy. The K-ATP channel controlling insulin secretion from the beta cells into the bloodstream. These channels open and close in response to the amount of glucose in the bloodstream, which helps regulate insulin secretion and control blood glucose concentrations. The closure of the channels leads to a process that triggers insulin secretion by the beta cells.

There are more than 300 mutations in ABCC8 and more than 30 mutations in the KCNJ11 gene, causing congenital hyperinsulinism. Most of these mutations change the amino acids in protein. Some mutations prevent the protein reaches the cell membrane, interfering with proper formation of the K-ATP channel. Other mutations interfere with the function of K-ATP channel or responses to external molecules. K-ATP channels cause defective constant insulin release from the beta cells, leading to glucose is rapidly cleared from the bloodstream. Lack of blood glucose results in frequent statements of hypoglycemia. If left untreated, hypoglycemia caused by congenital hyperinsulinism can lead to serious complications such as mental retardation and seizures.

This disease has different inheritance patterns that vary, usually depending on the form of the disease. They have identified at least two forms of the disease. The most common form is the diffuse form, which occurs when all beta cells in the pancreas secrete too much insulin. The focal form of the disease occurs when only some of the beta cells secrete insulin excess. Very often, the diffuse form of congenital hyperinsulinism is inherited as an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Less frequently, the diffusely inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause disease. Inheriting the focal form of congenital hyperinsulinism is more complex. For most genes, both copies are active in all cells, but for a small subset of genes, one of the two copies is inactivated. Most people with focally inherit one copy of the mutation, the inactive gene from his father unaffected. During embryonic development, a mutation occurs in the other copy, active gene. This second mutation found only in a few cells in the pancreas. As a result, some pancreatic beta cells have abnormal insulin secretion, while other beta cells function normally.

Tests in IVAMI: in IVAMI perform detection of mutations associated with congenital hyperinsulinism, by complete PCR amplification of exons of ABCC8 and KCNJ11, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).