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 (1620 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 4050 years (Metformin treated). Mother had gestational DM and continues on Metformin. Two sisters were diagnosed with anti-GAD negative Type 1 DM at 1213 years (HbA1c 11%, insulin requirement 11.5 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 (0.60.8 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.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology