Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins
ME Carter-Timofte, AF Hansen, M Mardahl… - Neurology …, 2018 - neurology.org
Neurology: Neuroimmunology & Neuroinflammation, 2018•neurology.org
Objective Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently
described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs.
Here, we describe a pair of monozygotic female twins, who both experienced severe
recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings
included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with
pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic …
described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs.
Here, we describe a pair of monozygotic female twins, who both experienced severe
recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings
included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with
pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic …
Objective
Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs. Here, we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions.
Methods
We performed whole-exome sequencing and identified a rare mutation in the POL III subunit POLR3F. Subsequently, antiviral responses in patient peripheral blood mononuclear cells (PBMCs) were examined and compared with healthy controls.
Results
The identified R50W POLR3F mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls.
Conclusions
Altogether, these cases add genetic and immunologic evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.
American Academy of Neurology