Abstracts

Rationale: DEND syndrome, first described in 2004, is characterized by heterozygous activating mutation in KCNJ11 gene encoding the Kir6.2 subunit of the ATP-dependent potassium(KATP) channel. KATP channels are octameric complex with 2 kind of subunits: 4 sulfonylurea receptor 1 or 2 (SUR1 or 2) embracing 4 inwardly rectifying potassium channel (Kir). Kir6.2/SUR1 distributes to pancreatic beta cells, and plays a key role in glucose-stimulated insulin secretion. Kir6.2/SUR2 functions in brain, involving with seizure susceptibility and neurodevelopment. Thus, KCNJ11/Kir6.2 mutation is a channelopathy involving with multiple organ systems ranging from diabetes, epilepsy, and to developmental delay. Methods: Sulfonylurea, a widely-used type-2 diabetes medicine, binds to KATP channel and improves its function, and enhances insulin secretion. Neonatal diabetes due to KATP mutation has been successfully transferred from insulin to oral sulfonylurea. Non-selective sulfonylurea (i.e. glibenclamide) refers to a subclass of sulfonylurea which binds to all type of KATP channels. It is speculated that in DEND syndrome patients, oral sulfonylureas not only controls diabetes, but may also treat neurological problems, especially when sulfonylureas are started early in life. In reality, however, all 4 cases of previously reported DEND syndrome failed to switch to sulfonylurea.Results: A four-month-old, in-vitro-fertilized boy presented with developmental delay and spasms in cluster. Interictal electroencephalogram (EEG) showed hypsarrhythmia compatible with West syndrome. Cranial magnetic resonance imaging (MRI) revealed no structural abnormalities. His blood glucose level was 280mg/dl, glycated hemoglobin level(HbA1c) was 9.8%. Subsequently he was diagnosed with permanent neonatal diabetes mellitus. Genetic studies of the patient and his parents revealed de novo mutation (R50P) on the patient’s KCNJ11 gene. Vitamin B6, clonazepam and valproate were ineffective for spasms. Synthetic adrenocorticotropic hormone(ACTH) was started under close monitoring of blood glucose levels. After 10-day course of 0.013mg/kg intramuscular ACTH, cessation of spasms and resolution of hypsarrhythmia were obtained. He remains to be seizure-free. Following genetic diagnosis, his diabetic regimen was successfully switched from intensive insulin therapy to high-dose oral sulfonylurea (glibenclamide, 0.87mg/kg/day), resulting in good glycemic control to date. At 15 months, his functional age is 6-7 months for mental and motor aspects. He also has poor eye contact, requiring watchful observation for the emergence of pervasive developmental disorder.Conclusions: We describe the first case of DEND syndrome who was successfully transferred from multiple-daily insulin injections to oral sulfonylurea. This disease entity shows how the molecular understanding of some monogenic/channelopathic form of epilepsy may lead to an unexpected change of the treatment.