Neonatal diabetes caused by mutations in KCNJ11 or ABCC8

Neonatal diabetes is a clinically and genetically heterogeneous disease. To date there are over 20 different genetic causes of neonatal diabetes which identify different clinical subtypes of the disease).

The most common cause of neonatal diabetes are mutations in the ABCC8 and KCNJ11 genes encoding respectively the SUR1 and Kir6.2 subunits of the voltage-dependant potassium channel. Correct function of the potassium channel is necessary for secretion of insulin in response to glucose levels. Approximately 40% of patients with neonatal diabetes have a potassium channel gene mutation. Patients with mutations in these two genes are sensitive to sulphonylurea treatment and their glycaemic control can be greatly improved switching from insulin to sulphonylurea therapy. This has led to international guidelines suggesting immediate referral for genetic testing after a clinical diagnosis of neonatal diabetes.

Mutations in KCNJ11 and ABCC8 can cause transient neonatal diabetes, permanent neonatal diabetes, or DEND (Developmental delay, Epilepsy and Neonatal Diabetes) syndrome. Whilst the mutations in KCNJ11 identified so far have all been dominantly acting, mutations in ABCC8 can act as either dominant or recessive and are often inherited.