Water intake disorder in a DEND syndrome afflicted patient with R50P mutation

Abstract

The ATP-sensiTive K + (K ATP ) channel is a key factor that couples cell metabolisms with the changes in cell excitability in various tissues including pancreatic b-cells and the brain [1,2]. It is a hetero-octameric complex composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits. In pancreatic β-cells, K ATP channels play a major role in regulating insulin secretion. A rise in plasma glucose stimulates glucose uptake and metabolism, causing an increase in intracellular ATP in β-cells. These changes in adenine nucleotide concentration result in the closure of the K ATP channel. The decrease in the membrane's K + permeability by closureWater intake disorder in a DEND syndrome afflicted patient with R50P mutation Abstract. In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K + (K ATP ) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 mL aliquot of 340 mM K ATP channel opener diazoxide or 100 mM K ATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the K ATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered K ATP channel activity. ] i , and this increase triggers the release of insulin [3].Mutations in KCNJ11, the gene encoding the Kir6.2 subunit, are known to cause neonatal diabetes. Some mutations are known to give rise to a severe form of disease, the DEND syndrome [3,4]. Aside from hyperglycaemia, DEND syndrome is characterized by severe neurological features such as developmental delay, epilepsy, and muscle weakness [5].The case we present in this paper was diagnosed with DEND syndrome at the age of 7 months due to the presence in his genome of a mutation of arginine to proline in residue 50 of Kir6.2 (R50P). Previously, we reported that the R50P mutation of Kir6.2 causes DEND syndrome [6]. A functional electrophysiological study on the K ATP channel with the R50P mutation

Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2

“…However, patients with DEND may also fail to respond to SU [5]. Importantly, neonatal diabetes with diabetic ketoacidosis (DKA) at onset and/or cerebral edema may impact CNS function, making it difficult to distinguish direct effects of overactive neuronal K ATP channels from additional metabolic insults to the brain [6, 7]. Functional assessment of the specific mutation in vitro can provide critical clues about the responsiveness of the mutated channel to SU and shed light on its effect on the CNS [5, 6, 8].…”