In recent years, there has been significant progress in defining the genetic aetiology of neonatal diabetes (NDM). It is likely that all cases result from single gene disorders since markers of autoimmunity associated with polygenic type 1 diabetes are rare in patients diagnosed before 6 months.
Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the β-cell ATP sensitive potassium (KATP) channel are the most common cause of neonatal diabetes, accounting for around 40% of case. The majority (~90%) of patients can achieve improved glycaemic control on high dose sulphonylureas.
The mutation severity defines the phenotype which ranges from isolated transient neonatal diabetes to DEND syndrome (severe developmental delay, epilepsy and permanent neonatal diabetes). Around 20% of patients with activating KATP channel mutations have mild to moderate developmental delay and case reports have described improved neurological function in some of these patients following transfer to sulphonylureas.
Some patients with transient neonatal diabetes caused by a KATP channel mutation have inherited the mutation from a parent who did not present with diabetes in the neonatal period, but developed permanent diabetes in later life. Analysis of a cohort of patients referred for HNF1A/4A MODY testing identified activating ABCC8 mutations in 6/86 cases (7%). The identification of specific subtypes of monogenic diabetes not only provides accurate information regarding inheritance and prognosis, but can inform treatment decisions and improve clinical outcome.