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

Abstract

De novo variants in developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent 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, 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.

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

“…Contributing to the different ages at onset and clinical symptoms may be the two different developmental expression patterns of Na V 1.2 channels in myelinated and unmyelinated nerve fibers . Recent work showed that early infantile epilepsy patients carrying SCN2A GoF missense variants responded well to SCBs, compared to late onset patients carrying LoF variants . Thus, taken together, the association between SCN2A and early seizure onset can be mostly explained by the early developmental expression of SCN2A and elevated channel function due to GoF variants and duplications.…”

“…Among SCN2A variant carriers, the responsiveness to medication appears to be more complex and directly linked to variant function. Those with early onset seizures (<3 months) due to GoF effects appear to respond well to SCBs, whereas those with later onset epilepsy and NDDs due to LoF variants often remain treatment resistant . There are only limited reports on pathogenic SCN3A variants; however, most of these present within the first days of life due to GoF effects and there is evidence to show that mutant channels may respond to SCBs .…”

“…15,49,50 Recent work showed that early infantile epilepsy patients carrying SCN2A GoF missense variants responded well to SCBs, compared to late onset patients carrying LoF variants. 15,18 Thus, taken together, the association between SCN2A and early seizure onset can be mostly explained by the early developmental expression of SCN2A and elevated channel function due to GoF variants and duplications.…”

“…Variants in SCN2A have been identified in different forms of infantile epilepsy, including benign infantile seizures, developmental and epileptic encephalopathies (DEEs), Ohtahara syndrome, and West syndrome . Recent studies propose that GoF missense variants in SCN2A are associated with neonatal or early infantile seizures presenting at <3 months of age, whereas LoF missense and PTVs are associated with later onset epilepsy and autism spectrum disorder (ASD)/NDDs . SCN8A encephalopathy presents in infancy with multiple seizure types including focal, tonic, clonic, myoclonic absence seizures, and epileptic spasms .…”

“…[11][12][13] Recent studies propose that GoF missense variants in SCN2A are associated with neonatal or early infantile seizures presenting at <3 months of age, whereas LoF missense and PTVs are associated with later onset epilepsy and autism spectrum disorder (ASD)/NDDs. [14][15][16][17][18] SCN8A encephalopathy presents in infancy with multiple seizure types including focal, tonic, clonic, myoclonic absence seizures, and epileptic spasms. [19][20][21][22] The developmental outcome is poor, and many patients have motor manifestations, including hypotonia and movement disorders.…”