Persistent hyperinsulinemic hypoglycemia of infancy (Persistent hyperinsulinemia hypoglycemia of infancy) - Genes ABCC8, KCNJ11, GCK, GLUD1 HADH, HNF1A, HNF4A, SLC16A1 and UCP2

Persistent hyperinsulinemic hypoglycemia of infancy or neonate (HHPI), also known as congenital hyperinsulinemia and nesidioblastosis, is a heterogeneous genetic disease characterized by insulin secretion unregulated by the ? cells relative to concentration of blood glucose. It is the most common cause of persistent hypoglycemia during childhood and carries risks of irreversible brain damage and neurological disability, so prior to the appearance of brain damage diagnosis is essential.

Initial symptoms include tremors, lethargy, seizures, irritability and intolerance orally. Repeated episodes of hypoglycemia increase the risk of serious complications such as respiratory distress, 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 affected children 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 most often after periods of fasting or after exercise, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after food intake.

This may be due to mutations in at least nine genes: ABCC8, KCNJ11, GCK, GLUD1 HADH, HNF1A, HNF4A, SLC16A1 and UCP2. Mutations in ABCC8, located on the short arm of chromosome 11 (11p15.1) are the most common known cause of the disease, representing approximately 40% of cases. Less frequently, the process is due to mutations in KCNJ11 gene, located on the short arm of chromosome 11 (11p15.1). Mutations in each of the other associated genes are responsible for only a small percentage of cases. In about half of those affected, the cause is unknown process.

KCNJ11 and ABCC8, encoding Kir6.2 genes and SUR1 subunits, respectively, of pancreatic ATP - sensitive channels potassium (K ATP) involved in the regulation of insulin secretion. K ATP channels located in the membrane of pancreatic ? cell, are complexes formed by four subunits Kir6.2, constituting the channel pore and SUR1 four subunits, which form the outside of the channel and act as a regulator of this . Under normal conditions, when the ? cell is at rest, the channels are open, allowing the entry of potassium. With the entry of glucose into the cell and its subsequent phosphorylation to enter the Krebs cycle, the intracellular ATP levels increase and potassium channels are closed, causing the membrane depolarization and subsequent opening of calcium channels . Calcium entry into the cell allows the exocytosis of insulin. Thus, the inactivating mutations in ABCC8 and KCNJ11 genes are responsible for boxes hypoglycaemia neonatal hyperinsulinism, since when the cell is at rest, the K ATP channel is closed, and remains in spite of decreased glucose and thus blood amount of ATP. Thus, the membrane remains depolarized and thus, calcium channels are constantly open, so that those affected by these anomalies are continuously secreting insulin. There are more than 300 mutations in ABCC8 and more than 30 mutations in the KCNJ11 gene responsible for this process.

They have also been found in other genes alterations result in the hyperinsulinemic hypoglycemia in other ways, such as mutations that increase metabolism and affect the concentration of ADP / ATP. For example, they are taking place in the glucokinase gene (GCK), located on the short arm of chromosome 7 (7p15.3-p15.1) and the gene encoding glutamate dehydrogenase (GLUD1), located in the long arm of chromosome 10 (10q23.3).

Glucokinase (GCK) acts as cell sensor glucose concentrations and that determines the limiting rate of metabolism of glucose. Activation promotes the entry of glucose into the mitochondria, generating more ATP. This will cause the closure of the K ATP channel, depolarizing the membrane and opening the calcium channel, so that more insulin will segregate. Mutations reported in the GCK gene lead to increased affinity Glucokinase glucose, thereby increasing insulin secretion unnecessarily.

Meanwhile, mutations that occur in the gene encoding glutamate dehydrogenase (GDH), called GLUD1 involved in the development of hyperinsulinemic hypoglycemia, causes increased activation of this enzyme in ? cells since makes insensitive inhibition by GTP (GDH is leucine allosterically activated and inhibited by GTP). In any case, this increased activation of GDH increases glutamate oxidation, the resulting increase in ATP and therefore insulin. This increase in degradation glutamate generates an increase in ammonium concentration, so that individuals with HHPI generated by genetic alterations in gene present GLUD1 associated sometimes hyperammonemia.

Persistent hyperinsulinemic hypoglycemia of infancy or neonate (HHPI) may have different patterns of inheritance, usually depending on the form of the disease. They have identified at least two forms of the disease. The most common form is diffuse, which occurs when all secreting pancreatic beta cells too much insulin. The focal form occurs when only some of the beta cells secrete insulin excess. Often the diffusely inherited with 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 diffuse form is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Inheriting the focal form is more complex. For most genes, two copies are active in all cells, but to a small subset of genes, one of the two copies is inactivated. Most people with the focal form of the disease inherit one copy of the mutated gene, inactivates his father unaffected. During embryonic development, a mutation occurs in the other active gene copy. This second mutation is found in only 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 the detection of mutations associated with persistent hyperinsulinemic hypoglycemia of infancy or neonate (HHPI), by complete PCR amplification of the exons of ABCC8, KCNJ11, GCK, GLUD1 HADH genes, HNF1A , HNF4A, SLC16A1 and UCP2, respectively, and subsequent sequencing. We recommend starting the study by the ABCC8 where most changes are localized, with possible reduction of time and cost involved in most cases. If not found the mutation in this gene, it offers the possibility of completing the study by those genes with greater frequency of mutations.

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).