Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations

David Goldemund M.D.
Updated on 19/06/2024, published on 13/06/2024
  • Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a very rare, autosomal dominant (AD) vasculopathy caused by mutations in TREX1
  • in earlier reports, the following terms were used to describe RVCL-S
    • cerebroretinal vasculopathy (CRV)
    • hereditary vascular retinopathy (HVR)
    • hereditary systemic angiopathy (HSA)
    • hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS)
  • RVCL-S is a multisystemic disease presenting with:
    • leukoencephalopathy (stroke)
    • progressive visual loss
    • systemic manifestations, including Raynaud’s phenomenon, anemia, and liver and kidney disease
  • RVCL-S leads to premature death, typically due to terminal pneumonia
  • the TREX1 gene (also known as Three Prime Repair Exonuclease 1) encodes a DNA exonuclease that plays a critical role in DNA repair
  • it helps maintain genomic stability and prevents the accumulation of single-stranded DNA (ssDNA) in the cytoplasm, which could potentially trigger autoimmunity
  • mutations in this gene result in:
    • RVCL-S
    • Aicardi-Goutieres syndrome (early-onset neonatal form)
    • Familial Chilblain Lupus (FCL) – TREX1 mutations can cause a form of monogenic lupus characterized by skin lesions, arthritis, and other systemic manifestations
    • cryofibrinogenemia – an association with heterozygous mutations in TREX1 has been reported (Paradis, 2019)

Pathology and pathophysiology

  • RVCL-S is caused by mutations in the TREX1 gene, which encodes a DNA exonuclease; this mutation leads to widespread endothelial dysfunction due to the accumulation of intracellular DNA debris
    • the basement membrane abnormalities can be seen on electron microscopy (ELM)
    • there is no evidence of either abnormal mitochondria or accumulation of mitochondria in any tissue examined
  • the brain lesions are caused by cerebral infarction due to the altered capillaries and arterioles (arteriolopathy)
  • fresh lesions may show contrast enhancement on MRI, indicating a breakdown of the blood-brain barrier (BBB)

Clinical presentation

  • progressive visual loss
    • RVCL-S typically begins in the 3rd or 4th decade of life, followed by focal neurological deficits within 4–10 years
    • visual loss affects the central vision with reduced visual acuity; blind spots in the visual field are also common
  • long-term psychiatric symptoms, such as depression, anxiety, and paranoia, begin as early as the second decade of life
  • stroke-like episodes
    • strokes or TIAs that typically occur in young adults without traditional cardiovascular risk factors
    • stroke typically progresses over several days before reaching a plateau
    • signs of multifocal cortico-subcortical involvement, such as dysarthria, hemiparesis, apraxia, ataxia, and dementia, are typical in advanced stages
  • migraine headaches
  • nephropathy (50% of cases) – may manifest as proteinuria and hematuria; HERNS can also lead to progressive renal failure
  •  other (liver disease,  anemia, hypothyroidism, Raynaud’s phenomenon

Diagnostic evaluation

Ophthalmologic evaluation

  • retinal vasculopathy is most prominent in the macular area
  • fluorescein angiogram (FAG) shows juxtafoveal capillary obliteration with tortuous telangiectatic microaneurysms
  • peripheral retinopathy, including telangiectasias, may occur later


  • CT – nonspecific arteriolopathic changes, possible calcifications
  • MR:
    • multifocal T2 hyperintense lesions in the deep white matter and basal ganglia (lacunes) (Stam, 2016)
      • lesions are non-specific but remarkable for relatively young patients
    • tumefactive lesions surrounded by edema (in 75% of RVCL-S patients, most often in later stages) (Raynowska, 2018)
      • T2 hyperintense
      • T1 hypointense
    • lesions spare the cortex
    • lesions show long-lasting nodular or rim enhancement after gadolinium contrast
  • some of the above-stated neuroimaging characteristics may be observed in other small-vessel diseases; the pattern and evolution of the findings are typical for RVCL-S (the long-term contrast enhancement with long-term diffusion restriction)  (Hedderich, 2020)
  • neuroimaging findings in RVCL-S have been mistaken for vasculitis, multiple sclerosis, or neoplasms in the past

Genetic testing

  • confirmatory testing for mutations in the TREX1 gene
Main features
  • vascular retinopathy
  • punctate T2 hyperintense white matter lesions with nodular enhancement
  • larger T2 hyperintense white matter mass lesions with rim-enhancement, mass effect, and surrounding edema
  • family history of autosomal dominant inheritance with middle-age onset of disease manifestations.
Supportive features
  • CT – focal white matter calcifications
  • MRI – non-enhancing punctate T2 hyperintense white matter lesions at young age 
  • liver disease
  • kidney disease
  • anemia consistent with blood loss and/or chronic disease
  • microscopic gastrointestinal bleeding
  • subclinical hypothyroidism
  • Raynaud’s phenomenon
  • migraine with or without aura


  • currently, there is no known causal treatment
    • a clinical trial with crizanlizumab is ongoing; crizanlizumab  targets a protein called P-selectin, which captures blood cells and can contribute to blockages in small blood vessels
    • CRISPR-based editing technologies are developed
  • antiplatelet therapy
  • corticosteroid therapy can be considered for tumefactive lesions with surrounding edema
  • treatment of retinopathy (laser/anti-VEGF therapy) and glaucoma

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Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations