Diabetes mellitus permanent neonatal (Permanent Neonatal Diabetes Mellitus -PNDM-) - Genes ABCC8, KCNJ11 and INS.
Permanent neonatal diabetes mellitus is a type of diabetes that occurs within the first 6 months of life and persists for the rest of life. This form of diabetes is characterized by hyperglycemia due to insufficient insulin. Those affected by this type of diabetes show a delayed intrauterine development, and have an excessive loss of fluids (dehydration) and not gain weight or have the growth rate expected for their age. In some cases, those affected by this type of diabetes have some neurological problems, including developmental delay and recurrent seizures (epilepsy). The association between developmental delay, epilepsy, and neonatal diabetes is known of DEND syndrome (Developmental Delay, Epilepsy, Neonatal Diabetes). Intermediate DEND syndrome, is a similar combination, but with moderate delay in the development without epilepsy. A small number of individuals with diabetes mellitus permanent neonatal have an underdeveloped pancreas, and for this reason, in addition to diabetes mellitus, these individuals suffer from digestive problems, with fatty stools, and inability to absorb fat-soluble vitamins.
This type of permanent neonatal diabetes mellitus is caused by mutations in several genes. About 30% of patients have mutations in the KCNJ11 gene, another 20% have mutations in ABCC8, and 20% mutations in the INS gene. The remaining cases are due to mutations in other genes still unknown.
The ABCC8 (ATP-binding cassette, subfamily C, member 8), located on the short arm of chromosome 11 (11p15.1), and KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11), located in the short arm of chromosome 11 (11p15.1), encoding eight channel subunits sensitive potassium ATP (ATP-sensitive potassium [K-ATP] channel), four of these subunits encoded by the gene ABCC8 and four encoded by the KCNJ11. K-ATP channels are through the cell membrane of the insulin - secreting pancreatic beta cells. These channels open or close in response to blood glucose levels. Closing the channels in response to increased blood glucose by insulin makes free pancreatic beta cells to control blood glucose levels.
Mutations in ABCC8 or KCNJ11 genes causing diabetes mellitus neonatal permanent, because the components of the K-ATP channels are not closed in response to elevated blood sugar, and thus the insulin needed are not secreted by of pancreatic beta cells, losing control of glycemia. They have been described at least 14 mutations in ABCC8, and at least 30 mutations in the KCNJ11 gene, causing changes in amino acids isolated, missing functionality potassium channels.
The gene INS (Insulin), located on the short arm of chromosome 11 (11p15.5), encoding the proinsulin, which is subsequently cleaved to form the A and B chains, which bind disulfide to yield insulin. Have been described at least 10 mutations in the INS gene in affected individuals of diabetes mellitus neonatal permanent, causing isolated amino acid changes in the sequence of proinsulin. Mutations in the gene INS alter the cleavage of the proinsulin or the junction between the A and B chains to form insulin, and consequently the glycemic control is lost.
Other genes involved still unknown must exist.
This form of diabetes mellitus permanent neonatal can have various patterns of inheritance. Cases due to mutations in KCNJ11 or INS genes are inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the alteration is manifested. In 90% of cases, the alteration must be a new mutation in the gene, and occurs in people with no family history of the disorder. In other cases , an affected person inherits the mutation from an affected parent.
When the permanent neonatal diabetes mellitus is caused by mutations in ABCC8, it can be inherited as an autosomal dominant, autosomal recessive , or as a pattern. In the autosomal recessive both gene copies in each cell without the mutation. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the mutated gene, but do not show signs or symptoms of the disorder.
Mutations in other genes may exist that also inherited in an autosomal recessive pattern.
Tests performed in IVAMI: IVAMI performed in detecting mutations involved in neonatal diabetes mellitus permanent, by PCR amplification of all exons of KCNJ11, ABCC8 and INS genes, respectively, followed by sequencing.
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).