The SCN2A gene encodes the alpha subunit of a voltage-gated sodium channel which is necessary for creating and propagating action potentials in neurons. Impairment of the Nav1.2 function is associated with neurodevelopmental disorders such as Developmental and Epileptic Encephalopathy, Self-limited Neonatal/Infantile Seizures, and Autism Spectrum Disorder. In this study, we used orthologous sequence comparisons, as well as disease associated variants to analyze their location in the structure of Nav1.2, with the aim of understanding the impact of genetic variants in the structure of this protein at an evolutionary and clinical level. Our analyses reveal different spatial distribution of interspecific variation where different residues locate preferentially in the first cytoplasmic linker, while disease-associated variants tend to cluster in the voltage-sensing segments of the protein domains. Altogether, these discoveries point to structurally important segments in the Nav1.2 structure that have been conserved through evolution due to their role in maintaining the function of the channel.

Pathogenic variants of KCNQ2 lead to a spectrum of disorders including self-limited familial neonatal-infantile epilepsy (SeL(F)NIE), developmental and epileptic encephalopathies (DEEs), and neurodevelopmental disorders (NDDs) with intellectual disability (ID). This study aimed to delineate the clinical progression and underlying pathogenesis of these disorders. Particularly, we unraveled the role of gain-of-function (GoF) variants in neurodevelopmental impairment. We conducted a longitudinal study of a 90-patient Chinese cohort with KCNQ2-related disorders, classified into SeL(F)NIE, DEEs, and NDDs subgroups. Clinical phenotyping was integrated with functional analyses (electrophysiology, biochemistry) of five missense variants in homomeric and heteromeric (with Kv7.3/Kv7.5) channel assemblies. Despite comparable seizure control to SeL(F)NIE (96% vs 100%), the NDDs group exhibited significant cognitive impairment. All deceased patients (8/90) were in the DEEs group. Functional profiling revealed a spectrum from loss-of-function (LoF) to GoF. LoF variants (e.g., S247L in DEEs) were linked to severe epilepsy. Crucially, we identified strong GoF variants (P335A/L in NDDs) in the S6-HelixA domain that confer insensitivity to phosphatidylinositol 4,5-bisphosphate (PIP2) regulation and are associated with a primary neurodevelopmental phenotype, distinct from the severe epileptic phenotype of established voltage-sensing domain (VSD) GoF variants. Our integrated clinical and functional analysis showed that the clinical outcome relies on the functional consequence of a KCNQ2 variant (LoF vs GoF) and its behavior in heteromeric complexes, rather than its mere location. We defined a novel class of strong GoF KCNQ2 variants that are mechanistically and phenotypically distinct, highlighting aberrantly enhanced channel function as a key driver of cognitive dysfunction and presenting new targets for precision medicine.

The aim of this study was to evaluate the long-term follow-up data of Chinese children with self-limited focal epilepsy with neonatal/infantile onset (SeLFE) and to investigate the clinical features, genetic background and treatment outcomes of this type of epileptic syndrome. We conducted a retrospective cohort study of twenty-six children with SeLFE admitted to or followed by the Department of Pediatrics, Second Affiliated Hospital of Xi'an Jiaotong University from October 2011 to October 2021. Treatment decisions were based on the children's seizure semiology, frequency, economy, medication accessibility, allergies and other factors, and initial medications including levetiracetam, phenobarbital and oxcarbazepine. All children were followed up regularly in the outpatient clinic. The 26 children, 13 male and 13 female, were followed for a mean of 54.0 (49.0, 58.5) months. Trio whole-exome sequencing (WES) revealed no pathogenic genetic abnormalities in 16 children, and known pathological genes including PRRT2, SCN2A and KCNQ2 were detected in 10 children. Thirteen children (50.0%) achieved complete seizure control after first-line monotherapy. Among the 12 patients who failed to respond to the first monotherapy, 9 patients achieved a seizure free status with oxcarbazepine, which was used as the second-line monotherapy or as add-on therapy. One patient recovered spontaneously without treatment. Although SeLFE is often self-limited, this study showed that complete seizure control is not always achieved with initial medication therapy. Oxcarbazepine may be an effective option for the treatment of SeLFE.