NEW research has identified rare genetic variants that may predispose some children to severe neurological complications following varicella zoster virus (VZV) infection, pointing to opportunities for targeted prevention and treatment.
The study followed 38 children who developed central nervous system infections during or shortly after varicella zoster virus infection, including six with meningoencephalitis, ten with encephalitis, nine with cerebellitis, and thirteen with stroke. None of the children had been vaccinated against VZV. Researchers collected detailed clinical information, cerebrospinal fluid results, neuroimaging scans, and electroencephalography data to understand the spectrum of disease. Whole exome sequencing was used to search for rare genetic variants that might underlie these unusually severe outcomes.
The analysis identified 46 rare variants across 40 genes in 26 patients. While a few genes appeared in multiple children (PRKRA in four, CSMD2 in three, and POLR3A in two) most variants were unique, though many converged on similar immune pathways.
Some variants affected the body’s ability to detect viral infections, including POLR3A, which helps cells sense viral DNA, and PRKRA, a regulator of antiviral inflammatory responses. Laboratory testing showed that immune cells from children with PRKRA variants could still control viral replication, but they produced unusually high levels of inflammatory signals, suggesting hyperactive immune responses may contribute to brain damage. Around a quarter of the variants affected NF-κB signalling, a key driver of inflammation. Another group of variants disrupted autophagy, the cell’s process for clearing damaged components and intracellular pathogens, highlighting how defects in basic cellular defences may leave some children vulnerable to severe disease.
These findings provide a genetic map of susceptibility in children who experience serious neurological complications from chickenpox. They suggest that both antiviral sensing and cellular defence pathways are critical for controlling VZV in the brain. Recognising these genetic risks could inform targeted vaccination, immunomodulatory therapy, or novel gene-based interventions for children most at risk.
Reference
Winzig F et al. Genetic landscape of a cohort of children with varicella-zoster virus encephalitis, cerebellitis and stroke. J Infect Dis. 2025; DOI:10.1093/infdis/jiaf448.
