Abstract
Background and objectives
SCN2A disease spans a broad clinical spectrum from self-limited (familial) neonatal-infantile epilepsy to severe developmental and epileptic encephalopathies. Systematic characterization of the spectrum of neuroradiologic abnormalities in SCN2A disease has not been performed. This study aimed to delineate MRI findings across SCN2A phenotypes, their frequency and evolution, and their relevance for prognosis and clinical trials.Methods
This retrospective multicenter cohort study recruited individuals with (likely) pathogenic SCN2A variants and available MRI data from the SCN2A Natural History Study (Bonn/Melbourne) and an international research network ("novel cohort"). Two blinded pediatric neuroradiologists evaluated all brain MRIs. In addition, we performed a systematic literature review (PubMed, search term "SCN2A," last updated January 31, 2026) including patients with available data on SCN2A variants, MRI findings, and phenotype. MRI findings were categorized by predefined criteria, and patients were assigned to phenotypic subgroups based on seizure onset and developmental outcomes.Results
A total of 354 individuals with SCN2A disease were included (novel cohort n = 46; literature cohort n = 308). In the novel cohort, the median age was 6 years, and 54% were female. MRI abnormalities were present in 41% (19/46) of the novel cohort and 45% (139/308) of published cases. The most frequent overall findings were supratentorial atrophy (15%), white matter changes (17%), and corpus callosum thinning (10%). Findings differed significantly between phenotypic subgroups. Atrophy occurred mainly in early-onset severe and later-onset infantile phenotypic subgroups, on MRIs performed ≥4 weeks after seizure onset. White matter changes were often transient and nonspecific. Cortical malformations, especially polymicrogyria, were found in 5% (19/354) of patients. Hippocampal alterations were more frequent in the novel cohort (7/46, 15%) than in published cases (5/308, 2%). In episodic ataxia, isolated cerebellar atrophy was occasionally observed (4/23, 17%).Discussion
This comprehensive characterization of brain MRI abnormalities in SCN2A disease revealed distinct imaging patterns across phenotypic subgroups. Atrophy was typically absent at seizure onset, highlighting progressive disease impact over time. These findings highlight the importance of early seizure control, guide counselling of patients and families, and inform MRI interpretation and biomarker research for future clinical trials. The retrospective design and heterogeneous imaging data represent important limitations.