Abstract
BACKGROUND AND PURPOSE: Acute necrotizing encephalopathy (ANE) is a rare and severe type of parainfectious encephalopathy. The pathogenesis and genetic features of ANE remain underinvestigated. In this study we aimed to characterize the genetic profiles of ANE, including novel variants and pathways. METHODS: We conducted a retrospective cohort study of 16 ANE patients and 7 controls, collecting clinical data, cerebrospinal fluid (CSF) findings, neuroimaging findings, and treatment information. Whole-exome sequencing (WES) was performed to investigate potential function-impacting genetic mutations in RANBP2, CPT II, and RNH1. Enrichment analyses were conducted to explore the associated pathways. RESULTS: The median age of the ANE patients was 21 years, and viral infections such as SARS-CoV-2 and influenza were common triggers. The CSF interleukin-6 level was elevated in four patients (median=598 pg/mL, interquartile range=101-4,000 pg/mL). WES identified 278 low-frequency variants. Four pathogenic/likely pathogenic mutations (p.T585M and p.I656V) and one novel mutation of uncertain significance (p.P2733S) were identified in RANBP2, while the susceptibility alleles of p.F352C and p.V368I in CPT II were detected in three patients. Functional enrichment analyses revealed that, relative to the control group, pathways including nucleocytoplasmic transport, defense response to virus, positive regulation of tumor necrosis factor production, and JAK-STAT signaling pathways were significantly enriched in ANE patients. CONCLUSIONS: This study integrated genetic profiles with the clinical characteristics of ANE patients, and revealed the role of RANBP2 as well as the potential involvement of cytokine pathways in ANE pathogenesis.