Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia

Abstract

Background: Hyperinsulinaemic hypoglycaemia (HH) is a group of clinically and genetically heterogeneous disorders characterized by unregulated insulin secretion. Abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, UCP2 and HNF1A) have been reported in HH, the most common being ABCC8 and KCNJ11. We describe the genetic aetiology and phenotype of Iranian patients with HH. Methods: Retrospective clinical, biochemical and genetic information was collected on 23 patients with biochemically confirmed HH. Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, GCK, HADH and HNF4A. Results: 78 % of the patients were identified to have a genetic cause for HH. 48 % of patients had mutation in HADH, whilst ABCC8/KCNJ11 mutations were identified in 30 % of patients. Among the diazoxide-responsive patients (18/23), mutations were identified in 72 %. These include two novel homozygous ABCC8 mutations. Of the five patients with diazoxide-unresponsive HH, three had homozygous ABCC8 mutation, one had heterozygous ABCC8 mutation inherited from an unaffected father and one had homozygous KCNJ11 mutation. 52 % of children in our cohort were born to consanguineous parents. Patients with ABCC8/KCNJ11 mutations were noted to be significantly heavier than those with HADH mutation (p = 0.002). Our results revealed neurodevelopmental deficits in 30 % and epilepsy in 52 % of all patients. Conclusions: To the best of our knowledge, this is the first study of its kind in Iran. We found disease-causing mutations in 78 % of HH patients. The predominance of HADH mutation might be due to a high incidence of consanguineous marriage in this population. Further research involving a larger cohort of HH patients is required in Iranian population.