{Reference Type}: Journal Article
{Title}: Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy.
{Author}: Berecki G;Howell KB;Deerasooriya YH;Cilio MR;Oliva MK;Kaplan D;Scheffer IE;Berkovic SF;Petrou S;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 115
{Issue}: 24
{Year}: 06 2018 12
{Factor}: 12.779
{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.