2. Academic Validation
  3. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy

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

  • Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5516-E5525. doi: 10.1073/pnas.1800077115.
Géza Berecki 1,  Katherine B Howell 2 3 4,  Yadeesha H Deerasooriya 5,  Maria Roberta Cilio 6 7,  Megan K Oliva 8,  David Kaplan 8,  Ingrid E Scheffer 8 2 3 9,  Samuel F Berkovic 9,  Steven Petrou 1 10 11 12
Affiliations

Affiliations

  • 1 Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; geza.berecki@florey.edu.au steve.petrou@unimelb.edu.au.
  • 2 Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
  • 3 Department of Pediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
  • 4 Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
  • 5 Department of Mechanical Engineering, University of Melbourne, Parkville, VIC 3052, Australia.
  • 6 Department of Neurology, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA 94158.
  • 7 Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, University of California, San Francisco, CA 94158.
  • 8 Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.
  • 9 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • 10 Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC 3050, Australia.
  • 11 Australian Research Council (ARC) Centre of Excellence for Integrated Brain Function, University of Melbourne, Parkville, VIC 3052, Australia.
  • 12 RogCon, Inc., Cambridge, MA 02142.
PMID: 29844171 DOI: 10.1073/pnas.1800077115
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 variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, SCN2A genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.

Keywords

de novo SCN2A mutation; dynamic action potential clamp; epilepsy; modeling; voltage clamp.

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