Impact of Timing of Initiation of Sulphonylurea Therapy on Neurodevelopmental Outcomes in Individuals With Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome Due to the V59M Mutation in the KCNJ11 Gene

Background:

The role of the KATP channel in the pancreas The KATP channel is made up of 4 pore-forming Kir6.2 subunits (encoded by the KCNJ11 gene) and 4 regulatory SUR1 subunits (encoded by the ABCC8 gene). In the pancreas, the KATP channel plays a central role in glucose-stimulated insulin secretion.

KATP channel mutations cause neonatal diabetes that can be treated with oral sulphonylureas Neonatal diabetes is defined as diabetes occurring in the first 6 months of life; it has an incidence of approximately 1 in 200,000 live births. Neonatal diabetes is due to a monogenic defect, and mutations in the KCNJ11 and ABCC8 genes are the commonest cause. These are important to diagnose as over 90% of patients can switch from insulin treatment to an oral sulphonylurea with a resulting improvement in glycaemic control which is maintained long-term.

Central Nervous System features occur in patients with neonatal diabetes due to KATP mutations.

Around 20% of patients with mutations in the KCNJ11 gene have an overt severe neurological phenotype. This is consistent with the expression of the KATP channel in the brain. There is a phenotype/genotype relationship e.g. most patients with the V59M mutation have the intermediate DEND syndrome (iDEND - Developmental delay, Epilepsy and Neonatal Diabetes), with moderate developmental delay and substantial intellectual disability. DEND syndrome is characterised by severe developmental delay and epilepsy diagnosed within the first 12 months of life. People with iDEND syndrome also show hyperactivity, impulsivity, inattention and impaired visuomotor performance. Autism (comprising impaired language and social interaction and restricted/repetitive behaviours), ADHD and anxiety disorders have been reported in individuals with the V59M mutation. Mouse models with V59M mutations have replicated the hyperactive phenotype seen in humans. These finding suggests a possible role for the KATP channel in neurodevelopment.