%0 Journal Article
%T Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy.
%A Berecki G
%A Howell KB
%A Deerasooriya YH
%A Cilio MR
%A Oliva MK
%A Kaplan D
%A Scheffer IE
%A Berkovic SF
%A Petrou S
%J Proc Natl Acad Sci U S A
%V 115
%N 24
%D 06 2018 12
%M 29844171
%F 12.779
%R 10.1073/pnas.1800077115
%X 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.