ESPE Abstracts (2014) 82 P-D-2-3-354

An Infant with a Novel Kir6.2 Mutation Causing Neonatal Diabetes and Unexplained Lack of Response to Sulphonylurea

Susan M O’Connella, Aoife Mc Donalda, Norma O’Toolea, Anne Bradfielda, Maura Bradleya, Andrew Hattersleyb, Sian Ellardb, Peter Proksc, Katia K Mattisc, Frances Ashcroftc & Stephen M P O’Riordana


aDepartment of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland; bRoyal Devon and Exeter Foundation Trust, Exeter, UK; cDepartment of Physiology Anatomy and Genetics Parks Road, Oxford, UK


Background: Neonatal diabetes (NDM) is defined as diabetes developing before 6 months of age, affecting one in 100 000 live births. Permanent NDM is diagnosed in the first 6 months of life with no remission. The majority have a mutation in the ATP-sensitive potassium (KATP) channel (KCNJ11 in 31%, ABCC8 in 13%). Autosomal dominant and recessive forms are described. The majority of patients with NDM caused by KATP mutations respond to sulphonylureas.

Objective and hypotheses: To describe response to sulphonylurea in an infant with NDM, heterozygous for a novel Kir6.2 subunit KCNJ11 missense de novo mutation (W68G).

Method: A female born at 37 weeks by Caesarean section for intrauterine growth retardation (birth weight 1.95 kg <0.4th centile) was hyperglycaemic from day one of life. Initial encouraging C-peptide response was seen (post feed glucose 21.5 mmol/l with C-peptide 223 pmol/l). Initially stabilised with intravenous insulin she was treated with subcutaneous basal insulin with erratic glucose control. Glibenclamide was commenced slowly (0.05 mg/kg per day) from day 20 of life up to a maximum dose of 1 mg/kg per day over 2 months according to the Exeter transfer protocol. At age 2 months insulin pump therapy was commenced resulting in tighter glycaemic control and weight gain.

Results: Transfer off insulin was unsuccessful. Subsequent C-peptide levels have been low (<94 pmol/l). In vitro testing of the mutant channels indicates she should respond to glibenclamide. Further investigations are continuing. She doing well on insulin pump (total daily dose 0.7 units/kg per day) – HbA1c 55 mmol/mol (20–42).

Conclusion: This infant with a novel Kir6.2 mutation failed to respond to glibenclamide despite a sustained period on a recognised effective dose and clear in vitro response. Investigations are progressing to explain the unexpected failed response. If an unusually rapid rate of sulphonylurea metabolism can be demonstrated by ongoing pharmacokinetic studies, a higher dose of glibenclamide will be warranted in this patient.