Atypical Absences, developmental delay, and neonatal diabetes-think of DEND-Syndrome. A Channelopathy involving pancreas, muscle, and brain with possible improvement by sulfonylurea treatment

Mutations in the gene KCNJ11 encoding for the ATP-sensitive potassium channel subunit Kir6.2 have been shown to be a common cause of neonatal diabetes. Sulfonylurea, which bind to the sulfonylurea receptor 1 (SUR1) subunit of the K (ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. Kir6.2 is expressed not only in the pancreatic β-cell, but also in muscle and central nervous system. This explains why due to KCNJ11 mutations, approximately 25% of the patients have neurologic findings including developmental delay (D) and epilepsy (E) besides neonatal (N) diabetes (D), known as DEND syndrome. There have been rare cases of juvenile patients with DEND syndrome reporting variable improvement in neurological function following transition from insulin to sulfonylurea treatment. We report on a 23-year-old woman with neonatal diabetes since the age of 2 months. She developed severe psychomotor retardation. At the age of 7 years, she presented with atypical absence epilepsy, refractory to treatment with valproate and lamotrigine. At the age of 18 years, KCNJ11 mutation V59 M/N could be detected in our patient to be the cause of the neonatal diabetes. Transition from subcutaneous insulin to oral sulfonylurea therapy was performed and resulted in considerably reduced need of insulin by improvement of HbA_1c, although complete replacement was not possible. Following transition to sulfonylurea therapy, neurologic findings improved in both, epilepsy as well as mental development. Frequency of absences clearly diminished and finally she was seizure free. Also marked increase in cognition was recognized through the family, although this was not yet verified by developmental testing. With this case report, we want to emphasize the importance of early genetic diagnosis of patients with epilepsy, developmental delay, and neonatal diabetes (DEND-syndrome). There is potential improvement of psychomotor development and epilepsy besides better glycemic control due to sulfonylurea therapy.