ctor 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 in consanguineous families. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from the diagnosis had an isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common.
We present the fist case reported from Ukraine of a child diagnosed with permanent NDM resulting from a EIF2AK3 gene missense mutation of exon 15 (Wolcott-Rallison Syndrome).Confirmation of the gene mutation EIF2AK3 presence in our patient was done by the laboratoryof Exeter University, UK.
A diabetic boy was admitted for usual check up to the Endocrinology Department of Ternopil Regional Childrens’ Hospital.
From anamnesis: he is full-term child from second physiological pregnancy and delivery, birth weight 2,500 g. Neonatal period was usual. Family history is unremarkable. In the age of 6 weeks he was hospitalized due to moderate dehydration and intoxication syndromes without vomiting or diarrhea. Capillary blood glucose was 22 mmol/l (N=3,3-5,5) [396 mg/dl], Hb1Ac = 9.662 %.(N = 4,8-5,9),C-peptide = 0,27 ng/ml, (N = 0,9-7,10) and manifestation of NDM had been diagnosed. General condition of the child quickly improved due tothe combined insulin therapy. By genetic DNA analysis of parents and child blood novel EIF2AK3 gene missense mutation of exon 15 was revealed by Sanger sequencing which confirmed the clinical diagnosis of Wolcott-Rallison syndrome. The analysis of all other known neonatal diabetes genes did not identify a pathogenic mutation.
The child grew and developed properly on a regular basis-bolus insulin therapy in adaily dose of 0.36 U/kg body weight. The course of diabetes was stable, glycosylated hemoglobin per year observation was 8.2–8.5%.
In the age of 1 year the boy was hospitalized in the intensive care unit due to a grave general condition: fever, intoxication, lethargy, anorexia, jaundice, generalized edema, hepatomegaly, oliguria, acholic stool. A blood test revealed: mild hypoch