ESPE Abstracts (2016) 86 P-P1-212

Permanent Neonatal Diabetes Mellitus due to a Novel Homozygous GCK Mutation in a Premature Baby with IUGR and Its Management

Nirit Brahaa, Elisa De Francob, Adam Dawesc, Kate Sharplesc, Abdul Moodambaild, Claire Hughesc, Sian Ellardb & Evelien Geversc


aNeonatal Intensive Care Unit, Royal London Hospital, Barts Health NHS Trust, London, UK; bInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; cDepartment of Paediatric Endocrinology and Diabetes, Royal London Hospital, Barts Health NHS Trust, London, UK; dDepartment of Paediatrics, Newham Hospital, Barts Health NHS Trust, London, UK


Background: Glucokinase (GCK) acts as the glucose sensor of β-islet cells, regulating insulin secretion in response to changing glucose concentrations. Homozygous GCK mutations are a rare cause of permanent neonatal diabetes. Heterozygous mutations lead to GCK MODY, causing mild hyperglycaemia, not usually requiring treatment.

Case: The index case was born to consanguineous parents at 36+2 weeks gestation, weighing 1610 g (0.4th centile). Hyperglycaemia (16–20 mmol/l) developed on day 1. Investigations showed insulin <1 mU/l, C-peptide 75 pmol/l and normal pancreas on USS. Both grandmothers and the father were diagnosed with Type 2 DM at 40–50 years (Metformin treated). Mother had gestational DM and continues on Metformin. Two sisters were diagnosed with anti-GAD negative Type 1 DM at 12–13 years (HbA1c 11%, insulin requirement 1–1.5 U/kg).

Genetic analysis: Sanger sequencing excluded mutations in ABCC8, KCNJ11, INS and EIF2AK3. Methylation analysis showed normal 6q24 methylation. Targeted next-generation sequencing revealed a homozygous missense mutation (c.661G>A, p.Gly221Lys) in a highly conserved region of GCK, coding for the hexokinase domain. In the heterozygous state, p.Gly221Lys causes GCK MODY. Homozygous mutations have not been described. SIFT, PolyPhen2 and AGVG analysis predict a deleterious effect.

Treatment: Intravenous insulin (0.6–0.8 U/kg) was started. A referral was made to our unit for CSII via Medtronic pump (G640). Pump adjustments were needed, including dilution of insulin x 10 in 0.9% saline, adapted cannula insertion and low glucose suspend, manual corrections for hyperglycaemia and manual bolusing for feeds. At 6 months, insulin requirement is 0.5 U/kg (35% basal) and HbA1c 6.3%.

Discussion: This is the first description of a homozygous p.Gly221Lys mutation in neonatal diabetes. Grandmothers and parents likely have GCK MODY and may not require treatment. Sisters have unusually high HbA1c for a heterozygous GCK mutation. Family genetic test results will provide further insight. Specialist CSII therapy with neonatal adaptations achieves good control of neonatal diabetes.

Article tools

My recent searches

No recent searches.