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Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.

ABSTRACT: 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.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 (K(ATP)) channel genes (ABCC8 and KCNJ11), GLUD1, GCK, HADH and HNF4A.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.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.

SUBMITTER: Senniappan S

PROVIDER: S-EPMC4535259 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.

Senniappan Senthil S Sadeghizadeh Atefeh A Flanagan Sarah E SE Ellard Sian S Hashemipour Mahin M Hosseinzadeh Majid M Salehi Mansour M Hussain Khalid K

BMC research notes 20150813

<h4>Background</h4>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.<h4>Methods</h4>Retrospective clinical, biochemical and genetic information was colle ...[more]

PMID: 26268944

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Project description:BACKGROUND:Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS:We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS:HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.

Dataset Information

Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.

Publications

Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.

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