A Novel KCNJ11 Mutation Associated with Transient Neonatal Diabetes

Abstract

Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes that presents in the first 6 months of life. Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the ATP-sensitive potassium (KATP ) channel can lead to transient NDM (TNDM) or to permanent NDM (PNDM). A female infant presented on the 22nd day of life with severe hyperglycemia and ketoacidosis (glucose: 907mg/dL, blood gas pH: 6.84, HCO3: 6 mmol/L). She was initially managed with intravenous (IV) fluids and IV insulin. Ketoacidosis resolved within 48 hours and she was started on subcutaneous insulin injections with intermediate acting insulin NPH twice daily requiring initially 0.75-1.35 IU/kg/d. Pre-prandial C-peptide levels were 0.51 ng/mL (normal: 1.77-4.68). Insulin requirements were gradually reduced and insulin administration was discontinued at the age of 10 months with subsequent normal glucose and HbA1c levels. C-peptide levels normalized (pre-prandial: 1.6 ng/mL, postprandial: 2 ng/mL). Genetic analysis identified a novel missense mutation (p.Pro254Gln) in the KCNJ11 gene. We report a novel KCNJ11 mutation in a patient who presented in the first month of life with a phenotype of NDM that subsided at the age of 10 months. It is likely that the novel p.P254Q mutation results in mild impairment of the KATP channel function leading to TNDM.

Case report: Better late than never, but sooner is better: switch from CSII to sulfonylureas in two patients with neonatal diabetes due to KCNJ11 variants

“…In our case series, the first patient has PNDM, while the second one is still too young to predict the disease’s clinical course. Their diabetes onset was similar to that seen in other children with KCNJ11 mutations ( 6 , 8 , 10 , 17 ). In particular, the second child showed low birth weight, a sign of intrauterine growth retardation consistent with low insulin production in utero , and the diabetic onset was characterized by marked hyperglycemia and ketoacidosis.…”

“…More than 30 activating KCNJ11 variants have been related to NDM to date ( 19 ), with a spectrum of clinical manifestations of the disease, ranging from TNDM to PNDM with neurological complications (developmental delay, epilepsy, and neonatal diabetes syndrome) or maturity-onset diabetes in the young ( 1 , 6 ). This variability could be explained by a mild beta cell defect caused by some mutations that may be compensated transiently but could be insufficient during puberty when is observed an increased insulin requirement ( 10 ). In our case series, the first patient has PNDM, while the second one is still too young to predict the disease’s clinical course.…”

“…Managing infants with NDM is very difficult, given the very small insulin doses required, the lack of subcutaneous fat, and the necessity to coordinate the insulin therapy with the frequent and uncontrolled feeding schedule of the newborn, exposing the child to a high risk of hypoglycemia. Based on all these reasons, CSII is considered the best treatment option in the initial management of infants with NDM ( 3 , 5 , 10 , 13 , 20 ). However, while the first case started CSII at 9 months of age after a period of MDI therapy, the second one was switched to pump therapy directly at the onset after intravenous insulin infusion.…”

“…More than 30 genes have been associated with NDM so far ( 10 , 11 ). The underlying mechanisms involved in the development of NDM are pancreas malformation or abnormal function of the β cells responsible for insulin synthesis or secretion ( 3 , 12 ).…”

“…About 80% of children with NDM have genetic mutations affecting the pancreatic β cells, mainly abnormalities of chromosome region 6q24 and pathogenic variants of the ABCC8 or KCNJ11 genes coding for the ATP-dependent potassium (KATP) channel. The KATP channel can regulate insulin secretion by linking glucose metabolism and ATP production: higher glucose level within the β cell increases the intracellular ATP concentration, with the subsequent closing of the KATP channel leading to cell membrane depolarization that triggers insulin secretion ( 10 , 13 ). Activating mutations in ABCC8 or KCNJ11 prevent the channel closure, the insulin cannot be released within the bloodstream, and the blood glucose level keeps increasing till the development of NDM symptoms ( 14 – 16 ).…”