ESPE Yearbook of Paediatric Endocrinology

World J Diabetes 2024 August 15;15(8): 1811-1819. doi: 10.4239/wjd.v15.i8.1811

Brief Summary: This paper presents 2 cases of transient neonatal diabetes mellitus (TNDM)¹ due to a novel gain-of-function heterozygous missense variant in ABCC8 (c.3880C>T); these are added to the 10 previously described cases where sulfonylurea therapy has been used, also summarised here. This defect, along with other rare variants in KCNJ11, are the second most common cause of TNDM.

Their patients, born AGA with no dysmorphisms, presented at ages 2m and 7m with post-infectious DKA and were negative for multiple diabetes-specific antibodies. Both infants were successfully treated with oral glyburide, following a short course of insulin. No major side effects were noted, and they were able to stop after 1 month in the first case, and after 1 year in the second case.

There are >700 pathogenic or likely pathogenic variants in ABCC8, which encodes the sulfonylurea receptor 1 of the ATP-sensitive potassium channel in pancreatic beta cells. Previous series have shown that most cases present by age 6 m, although 5-8% can occur after age 1y. These authors conclude from their cases, and the others with ABCC8 gain-of-function variants who were transitioned to oral sulfonylureas, that we are far from being able to predict responses to this therapy. The rationale for its use is clear: the mutated multimeric K-ATP channel is unable to release insulin, but sulfonylureas act by targeting the SUR1 subunits, promoting channel closure and thus insulin release. Our ability to predict not only response to sulfonylurea therapy but also whether diabetes will be transient, relapse if initially transient, or be permanent will await additional strides in personalised medicine, when genotype-phenotype associations and the contribution of other loci beyond the NDM loci identified to date become clearer.

Reference: 1. Greeley SAW et al, Pediatr Diabetes. 2022 Dec;23(8):1188-1211. doi: 10.1111/pedi.13426. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents