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
  • 1. Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; [email protected] [email protected].
  • 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.