A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.
OBJECTIVE
Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome.


METHODS
We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes.


RESULTS
We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities.


CONCLUSIONS
We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.
Shimomura
K
K
University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK.
Hörster
F
F
de Wet
H
H
Flanagan
S E
SE
Ellard
S
S
Hattersley
A T
AT
Wolf
N I
NI
Ashcroft
F
F
Ebinger
F
F
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005905:Glyburide / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009865:Oocytes; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014982:Xenopus laevis; D000099161:Kcnj11 Channel
D000927:Anticonvulsants; D005819:Genetic Markers; D005905:Glyburide; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel