Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a rare, autosomal dominant disorder caused by a frameshift three prime exonuclease 1 (TREX1) gene mutation.  RVCL mimics other inflammatory CNS diseases making proper diagnosis difficult.

A 52-year-old man presented with imbalance, headaches, and episodic confusion and language impairment lasting several hours. His past medical history included prior retinal vein occlusion, retinitis, and he was status post orthoptic liver transplant for primary sclerosing cholangitis.  His father died at age 62 with a seven year history of a brain disease causing progressive impairment of cognition and gait with autopsy revealing multiple foci of vascular white matter disease without definitive diagnosis. Neurological examination demonstrated normal Kokmen mental status exam (37/38) and left central scotoma, with normal motor power, reflexes and coordination.

Brain MRI showed multiple T2 hyperintense and gadolinium-enhancing lesions in the basal ganglia, cerebellar hemispheres, and cerebral white matter. Moderate parenchymal volume loss of the cerebral cortex and cerebellum was present. A left cerebral cortex lesions displayed mild diffusion restriction. Susceptibility weighted imaging did not display calcification of lesions. CSF examination revealed 1 white blood cell, mildly elevated CSF protein (58 mg/dL), no CSF oligoclonal bands, normal IgG index, and no malignant cells. Cerebral angiography, cervical and thoracic spinal cord MRI, and FDG-PET/CT were normal. Extensive autoimmune, infectious, and paraneoplastic work-up was negative.  With no definitive diagnosis, a brain biopsy was planned, but a genetic test for TREX1 revealed a p. Val235Glyfs*6 (V235fs) mutation diagnostic for RVCL.

 Retinal vasculopathy, brain dysfunction, multifocal gadolinium enhancing white matter lesions, and a family history of similar disease with a middle-age onset should raise suspicion for RVCL. Identification of a TREX1 mutation can confirm this diagnosis and avoid invasive diagnostic procedures like brain biopsy.