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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 69, Number 13, September 25, 2007 All Versions of this Article: 01.wnl.0000268488.51776.53v1 69/13/1342    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shimomura, K. Articles by Ebinger, F. Search for Related Content PubMed PubMed Citation Articles by Shimomura, K. Articles by Ebinger, F.

A novel mutation causing DEND syndrome

A treatable channelopathy of pancreas and brain

From University Laboratory of Physiology (K.S., H.d.W., F.A.), Oxford, UK; Department for General Pediatrics (F.H.) and Department for Child Neurology (N.I.W., F.E.), University Pediatric Hospital, Ruprecht-Karls-University of Heidelberg, Germany; and Institute of Biomedical and Clinical Science (S.E.F., S.E., A.T.H.), Peninsula Medical School, Exeter, UK.

Address correspondence and reprint requests to Dr. Frances Ashcroft, University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK frances.ashcroft{at}physiol.ox.ac.uk

Objectives: 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.

Editorial, see page 1310

e-Pub ahead of print on July 25, 2007, at www.neurology.org.

*Both authors contributed equally to this publication.

Supported by the Wellcome Trust, the Royal Society, the European Union (Integrated Project EuroDia LSHM-CT-2006-518153 in the Framework Programme 6 [FP6] of the European-Community), and the Research & Development Directorate at the Royal Devon & Exeter NHS Foundation Trust. F.M.A. is a Royal Society Research Professor.

Disclosure: The authors report no conflicts of interest.

Received February 21, 2007. Accepted in final form April 17, 2007.

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