While SCN2A variants are known to cause a spectrum of neurodevelopmental disorders, it looks like the full extent of SCN2A-related conditions remains to be fully clarified.

A recent study has uncovered a significant association between rare SCN2A variants and malformation of cortical development (MCD) in patients with developmental and epileptic encephalopathy (DEE).

The researchers identified seven de novo heterozygous SCN2A variants in eight individuals with DEE and prominent MCD.

Electrophysiological characterization using manual and automated patch-clamp (the SyncroPatch 768PE) revealed that the neonatal isoforms of these SCN2A variants exhibit a marked depolarizing shift in steady-state inactivation, leading to enhanced window currents.

Computational modeling demonstrated that expression of one variant (NaV1.2-p.Met1770Leu-N) in developing neocortical pyramidal neurons results in hyperexcitability.

Overall, these findings expand the clinical spectrum of SCN2A-related disorders and suggest previously undescribed roles for SCN2A in fetal brain development. The study provides valuable insights into the potential mechanisms by which sodium channel dysfunction might contribute to cortical malformations, offering a new perspective on the role of SCN2A in neurodevelopment and epileptogenesis.

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Find the full article here: Rare dysfunctional SCN2A variants are associated with malformation of cortical development

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