Authors :
Presenting Author: ASLI AYKANAT, MD – Boston Children's Hospital , Harvard Medical School
Isabel Haviland, MD – Boston Children's Hospital, Harvard Medical School
Soleha Patel, BS – Boston Children's Hospital, Harvard Medical School
Theodore Cummins, PhD – School of Science, Indiana University, Purdue University
Chellamani Harini, MD – Boston Children's Hospital, Harvard Medical School
Heather Olson, MD, MS – Boston Children's Hospital, Harvard Medical School
Rationale:
This study describes two patients with nearby pathogenic variants in the SCN2A gene in a region with recurrent variants. Both patients had early infantile DEE (EIDEE) but later achieved seizure control, either off anti-seizure medications (ASM) or on monotherapy. Through the characterization of these patients, we aimed to assess if there are features of the variants that might be associated with resolution of epilepsy in contrast to ongoing epilepsy in many others with EIDEE. Methods:
We performed detailed phenotyping through a retrospective review of clinical records and genetic testing results. Functional properties of the SCN2A variants were assessed via manual patch-clamp recordings following expression in HEK293 cells and biophysical gating properties were compared to wildtype channels.Results:
Patient 1 had a pathogenic variant in SCN2A (c.1289A >C, p.E430A). He had neonatal onset seizure which were initially refractory to treatment but became seizure-free by age 2. He was successfully weaned off ASMs and was seizure free off medications until age 10 when he presented with a breakthrough seizure but remained well controlled on lacosamide up until his last visit at age 12. Patient 2 had a pathogenic variant in SCN2A (c.1301C >A, p.A434D) with neonatal seizure onset and was diagnosed with EIDEE. He achieved seizure freedom at 4 months and was weaned off ASMs and ketogenic diet. He remained off ASMs at his last follow up at age 7 with one breakthrough seizure at age 2. The functional properties of the p.E430A and p.A434D variants were studied in recombinant human Nav1.2 channels expressed in HEK293 cells. Both variants shifted the voltage-dependence of activation by approximately 10 mV in the negative direction but had minimal impacts on other properties including no significant increase in persistent currents. Conclusions:
We present two patients with nearby pathogenic missense variants in the I-II linker of the Nav1.2 channel with similar clinical trajectories in their epilepsies. Both patients had explosive onset medically refractory epilepsy which progressed to seizure freedom. Furthermore, literature shows two p.E430A cases with explosive onset refractory seizures followed by resolution1,2. Structural modeling suggests these variants may interact differently with the DI-S5-S5 linker or affect accessory subunits. They also differ from some gain-of-function variants by not impacting the persistent current. This study is significant for reporting two patients with pathogenic SCN2A missense variants who experienced explosive-onset, refractory neonatal seizures followed by remission, contrasting with the typical EIDEE course linked to SCN2A gain-of-function mutations and offering new insights into genotype-phenotype correlations.
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Funding: None