Journal article

Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy

Geza Berecki, Katherine B Howell, Yadeesha H Deerasooriya, Maria Roberta Cilio, Megan K Oliva, David Kaplan, Ingrid E Scheffer, Samuel F Berkovic, Steven Petrou

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2018

Abstract

De novo variants in SCN2A developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent SCN2A variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy v..

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Grants

Awarded by Australian Research Council Centre of Excellence for Integrative Brain Function Grant


Awarded by National Health and Medical Research Council (NHMRC) programme


Awarded by NHMRC Fellowship


Funding Acknowledgements

We thank the patients and their families for participating in our research; and Ian C. Forster for helpful comments on an earlier version of this manuscript. This study was supported by Australian Research Council Centre of Excellence for Integrative Brain Function Grant CE14010007; National Health and Medical Research Council (NHMRC) programme Grant 10915693 and NHMRC Fellowship GNT1005050 (to S. P.); and a Practitioner fellowship (to I. E. S.). K. B. H. was supported by a clinician-scientist fellowship from the Murdoch Childrens Research Institute. G. B. was funded by RogCon, Inc. The Florey Institute of Neuroscience and Mental Health is supported by Victorian State Government infrastructure funds.