J P H Shield
Neonatal diabetes or monogenic diabetes of infancy can manifest as a transient or permanent condition. TNDM is most commonly caused by imprinting disorders on chromosome 6q24 (TNDM1.Uniparental Isodisomy Chromosome 6, Paternal Duplication of 6q24, loss of maternal methylation). Recently it has been identified that over half of those with maternal hypomethylation at 6q24 have relaxed maternal methylation at other imprinted loci and that the majority of these patients have mutations in transcription factor ZFP57. Transient neonatal diabetes has also been described with mutations in the genes encoding the ATP-sensitive potassium channel ABCC8 (TNDM2) and KCNJ11 (TNDM3). TNDM1 is characterised by third trimester IUGR, low birth weight and very early onset diabetes. Treatment is usually with insulin but remission occurs within 3 months with a liability to relapse in adolescence or early adulthood. PNDM is a more diverse condition with an unknown genetic cause in about 40% of cases. Diabetes may be caused by defects in pancreatic development (IPF-1, GLIS3, PTFA1, and most recently NEUROD1 the latter two having severe cerebellar hypoplasia), defects in Beta cell function (KCNJ11, ABCC8, homozygous GCK inactivating mutations) or increased islet cell destruction (INS and EIF2AK3 by apoptosis and FOXP3 by the only autoimmune condition causing neonatal diabetes). Whilst the effectiveness and diversity of treatment is very dependent on associated organ damage accrued from the diverse mutations, KCNJ11 and ABCC8 mutations are remarkable as one of the first successful examples of pharmacogenetics: identification of patients with these mutations causing neonatal diabetes led to many being successfully transferred from a previous lifetime of insulin therapy with relatively poor glycaemic control to excellent control on oral sulphonylureas. With the rapid advances in molecular biology techniques more causes of permanent neonantal diabetes are likely to be identified soon.