ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Diabetes Care. 2020 Mar;43(3):526–533. doi: 10.2337/dc19-1013. Epub 2020 Jan 13. PMID:31932458

Neonatal diabetes mellitus (NDM) is defined as diabetes that develops in the first 6 months of age. In Western countries, the most common causes of NDM are activating mutations in the KCNJ11/ABCC8 genes. Neurological dysfunction is also common (up to 30%) in patients with NDM and includes: developmental delay, muscle hypotonia, attention deficit hyperactivity disorder and in some cases epilepsy (DEND syndrome, developmental delay and epilepsy). Some mutations in these genes (in particular p.V59M genotype in KCNJ11 )are linked to abnormal neurological development including the DEND syndrome. It is currently unclear if early treatment for NDM with oral sulphonylureas can delay, improve or prevent the onset of abnormal neurological development in patients with NDM.

This study found a strong genotype-phenotype correlation; the p.V59M genotype in KCNJ11 showed the strongest association with substantial intellectual disability. Interestingly, there was no significant correlation with age at initiation of sulfonylurea therapy. Consistent with previous studies, other genotypes were associated with minor cognitive impairment. In all patients (except one) the brain MRI scan showed normal anatomy, suggesting that the KCNJ11 mutation does not affect brain development.

Thus, early treatment with oral sulphonylurea does not improve neurocognition in patients with p.V59M genotype in KCNJ11. The reasons for this are unclear but could be due to the fact that sulphonylureas no not cross the blood brain barrier and may even be actively transported out of the brain (1). Another possibility is that overactivity of K_ATP channels at an early developmental stage results in permanent neurological changes

Reference:

1. Lahmann C, Kramer HB, Ashcroft FM. Systemic administration of glibenclamide fails to achieve therapeutic levels in the brain and cerebrospinal fluid of rodents. PLoS One 2015; 10:e0134476.