Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options

Abstract

Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.

Fig. 1

HLA distribution in infants diagnosed with diabetes mellitus under 1 year of age. Modified from Edghill et al. [25].

Fig. 2

Prevalence of the three more common genetic subtypes of monogenic diabetes during the first year of life. Redrawn from Rubio-Cabezas et al. [22].

Fig. 3

Influence of parental consanguinity on the genetic aetiology in the Exeter cohort of PNDM. Updated from Rubio-Cabezas et al. [72].