Permanent neonatal diabetes mellitus in a young Ukrainian child
Wolcott-Rallison Syndrome, neonatal diabetes
Diabetes mellitus is a chronic metabolic disease with the manifestation possible in any period of life. The incidence of diabetes is rising around the world, and studies show that children are at an increasing risk of developing the disease. Type 1 diabetes accounts for over 90% of childhood and adolescent diabetes, although less than 10% of children suffer from type 2 diabetes. Over the last few decades, inherited monogenic forms of DM were discovered and studied. An extremely rare form of diabetes (less than 1-2% of all diabetes in young people), with neonatal diabetes as a subset, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. We present the first case reported in Ukraine of a child diagnosed with permanent neonatal diabetes resulting from a EIF2AK3 gene missense mutation of exon 15 (WolcottRallison Syndrome). Despite low incidence of the permanent neonatal diabetes, this diagnosis should be considered in infants with persistent hyperglycaemia requiring insulin therapy.
Article published in polish language
Diabetes mellitus is a chronic metabolic disease with manifestations possible in any period of life. The incidence of diabetes is rising around the world, and studies show that children are at an increasing risk of developing the disease. Type 1 diabetes accounts for over 90% of childhood and adolescent diabetes, although less than 10% of children suffer from type 2 diabetes. Over the last few decades, inherited monogenic forms of DM were discovered and studied. It is anextremely rare form of diabetes (less than 1–2% of all diabetes in young people), with neonatal diabetes as a subset, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. About one in half a million children all over the world are diagnosed with neonatal diabetes at birth or a few weeks after .
Neonatal diabetes mellitus (NDM)was first described by doctor Kitselle in1852, when his child presented with severe hyperglycemia at birth. From different studies scientists have concluded that thise form of diabetes results from mutations that occur on the surface of pancreatic beta cells. These can be KCNJ11, ABCC8, FOXP3 IBEX, GCK EIF2AK3 etc. .
Clinically two subgroups of NDM are recognised: transient and permanent. Transient NDM resolves at a median of 12 weeks but as many as 50%of cases will ultimately relapse. The majority ofpatients with transient NDM have an abnormality of imprintingof the ZAC and HYMAI genes on chromosome 6q.Permanent NDM requiresan ongoing insulin treatment when diagnosed. The commonest, but not the only one known cause of permanent NDMare mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the β-cell KATP channel .
Due to the octamer structure of the pancreatic beta cell, the K ATP channels, which regulate insulin release, are affected by mutations in either the SUR1(ABCC8) or KCNJ11 (kir6.2) that will result in insufficient insulin release and anincreased calcium influx. In case of Wolcott-Rallison Syndrome the affected protein will be the eukaryotic translation initiation factor alpha kinase 3 (EIF2KA3),also known as PKR endoplasmic reticulum kinase. It is an autosomal recessive mutation which usually shows its first signs at the age of 3 months.
Between January 2000 and August 2013 in the Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK genetic testing was conducted in 1020 patients (571 boys, 449 girls). This large, international, cohort studyincluded patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries . Mutations by comprehensive genetic testing, including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes we identified.Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently