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P.016 A novel de novo GABRA1 mutation linked to epileptic encephalopathy: pathophysiology and potential therapeutic options

Published online by Cambridge University Press:  27 June 2018

M Chiu
Affiliation:
(Vancouver)
Y Bai
Affiliation:
(Vancouver)
EH Chan
Affiliation:
(Vancouver)
L Huh
Affiliation:
(Vancouver)
I Guella
Affiliation:
(Vancouver)
MJ Farrer
Affiliation:
(Vancouver)
M Connolly
Affiliation:
(Vancouver)
L Liu
Affiliation:
(Vancouver)
M Demos
Affiliation:
(Vancouver)
Y Wang
Affiliation:
(Vancouver)
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Abstract

Background: Epileptic encephalopathy (EE) is a severe neurological disorder characterized by treatment-resistant seizures and poor neurodevelopmental outcomes. EE is associated with mutant genes, including those that encode for γ-aminobutyric acid type A (GABAA) receptor subunits. We identified a novel de novo GABRA1 mutation in a patient with EE, characterized its impact on GABAA receptor function, and sought potential therapeutic options. Methods: We described the clinical and electrophysiological features of a patient with a novel de novo GABRA1 (R214C) mutation; performed functional studies; and determined the effect of diazepam and insulin on wild type and mutant GABAA receptors. Results: The patient is a 10-year-old girl with EE, treatment-resistant seizures, intellectual disability and autism. Her GABRA1 (R214C) mutation dramatically decreased whole-cell GABA-evoked currents by reducing GABAA surface receptors, decreasing single channel open time, and altering channel kinetic properties. The combination of diazepam and insulin partially repaired these effects by enhancing channel activity and increasing the number of surface receptors, respectively. Conclusions: Diazepam and insulin partially mitigated a de novo GABRA1 (R214C) mutation’s effects on GABAA receptor number and function. Given the risks of insulin use, pharmacological agents with similar mechanisms of action but fewer side effects, such as IGF-1, should be studied and considered for clinical application.

Type
POSTER PRESENTATIONS
Copyright
© The Canadian Journal of Neurological Sciences Inc. 2018 

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