Pathogenic Variants in SCN2A Are Associated with Severe Developmental and Epileptic Encephalopathy with Bilateral Polymicrogyria and Incomplete Opercularization

Background/Purpose: Pathogenic variants in SCN2A are one of the most common causes of developmental and epileptic encephalopathies beginning in the first months of life. Brain MRIs have been described as unspecific, with brain atrophy, T2 hyperintensities or delayed myelination.

Methods: We report two unrelated patients with different SCN2A variants (likely pathogenic, ACMG 3) with developmental and epileptic encephalopathy. Brain MRI in both patients revealed a characteristic malformation of cortical development.

Results: Patient 1: 2 years, microcephaly, global developmental delay, ataxia, downbeat-nystagmus, pharmaco-refractory epilepsy from 1st week of life; myoclonic, and focal motor seizures. EEG with frequent multifocal epileptiform activity.

MRI (2 years): bilateral fronto-parietal and temporo-lateral polymicrogyria, incomplete opercularization, bilateral hippocampal atrophy, global brain atrophy, delayed myelination.

Patient 2: 14 months, GA 35 + 4, microcephaly, muscular hypotonia, global developmental delay, pharmacorefractory epilepsy from 2nd day of life with focal tonic seizures and epileptic spasms. EEG: multifocal epileptiform activity.

MRI (GA37 + 1 GW): bilateral fronto-parietal and temporo-lateral polymicrogyria, incomplete opercularization, brain atrophy.

Conclusion: Polymicrogyria can be associated with pathogenic variants in SCN3A, a gene with 87% sequence homology to SCN2A. We report a characteristic malformation of cortical development with bilateral polymicrogyria and incomplete opercularization in two patients with likely pathogenic variants in SCN2A. A third reported patient (Vlachou et al 2019) shows a similar malformation associated with a variant in SCN2A coding for the same region of the canal pore as one of our patients. Malformations of cortical development are supposed to be part of the phenotypic spectrum in SCN2A-associated neurodevelopmental diseases.

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Publikationsverlauf

Artikel online veröffentlicht:
28. Oktober 2021