Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene.
OBJECTIVE
Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K(ATP) channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K(ATP) channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K(ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment.


METHODS
We report the response to sulfonylurea treatment in a boy with neonatal diabetes and marked developmental delay resulting from the KCNJ11 mutation V59M.


RESULTS
Glibenclamide (glyburide) treatment was started at 23 months and resulted in insulin being discontinued, lower overall glycaemia, reduced glucose fluctuations and reduced hypoglycaemia. Good control (HbA(1c) 6.5%) was maintained 2 years after discontinuing insulin, despite a reduction in the glibenclamide dose (from 0.41 to 0.11 mg.kg(-1).day(-1)). Within 1 month of starting glibenclamide there was marked improvement in motor function, resulting in the patient progressing from being unable to stand unaided to walking independently, but there was no improvement in mental function.


CONCLUSIONS
This 2-year follow-up of a patient highlights that sulfonylurea treatment can result in prolonged, excellent glycaemic control and may improve motor features, but not mental features, associated with KCNJ11 mutations. This suggests that the neurological actions of sulfonylurea are initially principally on peripheral (nerve or muscle) rather than on central (brain) K(ATP) channels. Early molecular diagnosis is important in patients with neonatal diabetes and neurological features.
Slingerland
A S
AS
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK.
Nuboer
R
R
Hadders-Algra
M
M
Hattersley
A T
AT
Bruining
G J
GJ
D019943:Amino Acid Substitution; D001786:Blood Glucose / Q000378:metabolism*; D002658:Developmental Disabilities / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005500:Follow-Up Studies; D005905:Glyburide / Q000627:therapeutic use*; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007231:Infant, Newborn; D008297:Male; D009043:Motor Activity; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000099161:Kcnj11 Channel
D001786:Blood Glucose; D005905:Glyburide; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel