ESPE Abstracts (2015) 84 P-1-30

A Novel Mutation in the abcc8 Gene Causing a Variable Phenotype of Impaired Glucose Metabolism in the Same Family

Evelina Mainesa, Khalid Hussainb, Sarah E Flanaganb, Sian Ellardb, Claudia Pionaa, Grazia Grazia Morandia, Sarah Dal Bena, Paolo Cavarzerea, Franco Franco Antoniazzia & Rossella Gaudinoa

aDepartment of Life and Reproduction Science, Hospital of the University of Verona, Verona, Italy; bMolecular Genetics University of Exeter Medical School The Wellcome Wolfson Medical Research Centre, Exeter, UK

Background: Dominantly acting loss-of-function mutations in the ABCC8 gene, encoding the sulfonylurea receptor 1 (SUR1) subunit of the β-cell potassium channel (KATP), are usually responsible for mild diazoxide-responsive congenital hyperinsulinism (CHI). In rare cases dominant ABCC8 mutations can cause diffuse diazoxide-unresponsive CHI. Recent reports suggest that medically responsive CHI due to a dominant ABCC8 mutation may confer an increased risk of diabetes mellitus (DM) in adulthood. The mechanism is not clear at present; possible explanations include a progressive failure in β-cell function due to ‘exhaustion’, increased β-cell beta cell apoptosis as a result of raised intracellular calcium concentration and the influence of other genetic or environment factors.

Method: The index patient was born at term to non consanguineous parents with a birth weight of 3900 g. Pregnancy was complicated by gestational diabetes. Biochemical diagnosis of CHI was performed during the first week of life. The patient started diazoxide when he was 3 months old because the drug was not available in his country. He showed a good response to the drug. Molecular genetic analysis revealed a novel heterozygous ABCC8 missense mutation (p.A478T). F-DOPA PET/CT scanning was not conclusive. The patient’s mother had gestational diabetes and after delivery she fulfilled the criteria for DM. She did not present hypoglycemia during childhood. The patient’s grandfather developed DM at 45 years of age and he also had no past history of hypoglycaemia. Patient’s mother and grandfather were heterozygous for the p.A478T mutation.

Conclusion: Our experience confirms that dominantly acting ABCC8 mutations can cause CHI during childhood and/or gestational diabetes and DM later in life. The novel mutation identified in our patient was not previously reported in diazoxide-responsive forms of CHI; nevertheless a different mutation at the same residue has been reported in a family with CHI. The p.A478T ABCC8 mutation seems to be associated to an incomplete penetrance of hypoglycaemia in infancy.