Progress in Understanding and Treating SCN2A-Mediated Disorders

Abstract

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

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

“…The PTVs in SCN2A/3A/8A do not lead to a clinically defined epilepsy syndrome but to heterogeneous NDDs, including autism with or without later onset seizures. 15,17,22,26,40 Moreover, in the SCN CNV cohort, we observed that patients with duplications presented with significantly earlier seizure onset and responded better to SCBs compared to patients with deletions. This early seizure onset is likely caused by duplication of the SCN2A/SCN3A genes, which are the earliest SCNs expressed during development, resulting in GoF effects due to SCN2A/SCN3A protein overexpression.…”

“…By contrast, the majority of SCN2A/3A/8A ‐associated early onset epilepsies including benign epilepsies and epileptic encephalopathies are caused by GoF missense variants and full gene duplications. The PTVs in SCN2A/3A/8A do not lead to a clinically defined epilepsy syndrome but to heterogeneous NDDs, including autism with or without later onset seizures . Moreover, in the SCN CNV cohort, we observed that patients with duplications presented with significantly earlier seizure onset and responded better to SCBs compared to patients with deletions.…”

“…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 .…”

“…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. [15][16][17][18]40 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. 28 Recent case series of patients with SCN8A variants clearly demonstrate how variants associated with NDDs showed LoF effects, whereas those associated with epilepsy showed GoF effects with good response to SCBs.…”

Autism and developmental disability caused by KCNQ3 gain‐of‐function variants

“…34 This similarity may not be coincidental, as both channels are localized at the axon initial segment and seizures in early epilepsy caused by KCNQ3 LoF variants, like those caused by SCN2A GoF variants, are responsive to sodium channel blockers, such as carbamazepine. In particular, it is unclear why the LoF condition presents in the neonatal period, whereas the GoF condition results in cognitive and behavioral disturbances that only become apparent later.…”