When a disease strikes two members of the same family in the same rare pattern after the same viral exposure, it raises a question that extends far beyond the individual cases: what genetic architecture are we missing? Acute necrotizing encephalopathy following COVID-19 is already vanishingly rare, but its occurrence in two siblings points toward an uncharacterized susceptibility landscape that could reshape how clinicians evaluate rapid neurological collapse in post-infection settings.
The two patients — an 18-year-old woman and her 24-year-old brother — both developed ANE within days of confirmed SARS-CoV-2 infection in late 2022. The sister presented with seizures and deteriorating consciousness; her brother followed with altered mental status and rapid clinical decline. Brain MRI in both cases revealed bilateral symmetrical lesions, though with differing regional emphases: the sister showed involvement across the thalami, basal ganglia, corpus callosum, cerebellum, and white matter, while her brother's lesions centered on the lenticular and caudate nuclei. Critically, targeted genetic analysis found no pathogenic variants in RANBP2 — the gene canonically associated with familial ANE susceptibility — suggesting that additional, as-yet-unidentified genetic loci may govern vulnerability to this catastrophic neuroimmune response.
The broader research context here is significant. ANE has historically been linked to influenza A and other respiratory viruses, with SARS-CoV-2 emerging as a new trigger category since 2020. The RANBP2-negative result in this sibling pair is scientifically meaningful: it implies the familial clustering is not artifactual, yet cannot be explained by the only well-established genetic risk factor currently known. This widens the diagnostic challenge considerably, as clinicians may need to consider whole-exome or genome sequencing in familial cases. The case series is limited by its small size and retrospective design, but its contribution lies less in statistical power than in narrowing — and simultaneously complicating — the mechanistic map of post-COVID neurological injury.