A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain
K Shimomura1, F Hörster, H de Wet
1University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK.
Insights
A novel KCNJ11 mutation caused DEND syndrome, characterized by neonatal diabetes, developmental delay, and epilepsy. Sulfonylurea treatment improved symptoms, offering therapeutic benefits for affected patients.
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Neurology
Background:
- Activating mutations in the KCNJ11 gene cause neonatal diabetes mellitus.
- Some KCNJ11 mutations lead to DEND syndrome, a triad of developmental delay, epilepsy, and neonatal diabetes.
- This study investigated a novel KCNJ11 mutation associated with DEND syndrome.
Observation:
- A novel Kir6.2 mutation (I167L) was identified in a patient with DEND syndrome.
- Electrophysiologic analysis revealed that the mutation resulted in less inhibited ATP-sensitive potassium (K(ATP)) channels.
- This led to increased intrinsic open probability and enhanced whole-cell K(ATP) currents.
Findings:
- The novel I167L mutation in KCNJ11 causes DEND syndrome.
- Mutant K(ATP) channels showed reduced inhibition by MgATP, increasing channel activity.
- The patient showed significant clinical improvement, including cessation of insulin therapy and amelioration of epilepsy and psychomotor deficits, after treatment with glibenclamide.
Implications:
- Early identification of DEND syndrome is crucial for timely intervention.
- Sulfonylurea therapy can effectively manage DEND syndrome, improving neurological and metabolic outcomes.
- This finding highlights the therapeutic potential of targeting K(ATP) channels in specific genetic disorders.
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.
Related Concept Videos
01:26Type I Diabetes II: Pathophysiology
01:30Cardiomyopathy II: Dilated Cardiomyopathy
02:23Abnormal Proliferation
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
01:21Chronic Pancreatitis II: Pathophysiology
01:22Cerebral Edema ll: Pathophysiology