Yimin Sun, MD, PhD1; Jianying Xi, MD, PhD;1 Yue Zhang, MD, PhD1Patient
61 years, male
A 61-year-old male was admitted for progressive apathy, limb weakness and lower body edema for 4 years. No obvious visual disturbance was complained. He presented slow reaction and weakness in the lower limbs 4 years ago, while he could walk by himself. The brain MRI revealed a left frontal ring-enhanced mass (Figure 1). He was diagnosed as tuberculous meningoencephalitis and treated by the antituberculous therapy, accompanied with corticosteroid. After short-term improvement, his condition continued to deteriorate, during which the patient developed edema in the lower limbs. At admission, the physical examination showed he was: alert and oriented. His cognition was impaired (MMSE:15/30. MoCA: 12/30). Muscle strength was measured 3/5 in the lower extremities. Babinski sign was positive bilaterally. Brain MRI and CT showed leukoencephalopathy with calcifications (Figure 2). Estimated glomerular filtration rate (eGFR) was measured 45ml/(min*1.73m2) (reference range: 80-120). He had a history of renal dysfunction, hypothyroidism and mild elevation of liver enzyme. No biopsy was performed.
Figure 1. Brain MRI and CT images obtained 4 years ago A. T1WI shows a hyperintense lesion in the left frontal lobe surrounded by oedema. B and C. T2WI and T2-FLARE show a hypointense mass with remarkable surrounding oedema. Periventricular white matter abnormalities were less obvious than those seen now. D. DWI shows prominent restricted diffusion within the left frontal lesion. E. Post contrast T1WI shows ring enhancement. F. CT shows multiple punctate calcifications (arrows), which become more prominent later.
Figure 2. T2-FLAIR, DWI and CT images performed at this admission. A. T2-FLAIR shows unspecific white matter lesions near lateral ventricular horns and lateral ventricular dilation. B. DWI shows punctate restricted diffusion near right lateral ventricle (arrow).C. CT shows multiple punctate calcifications near lateral ventricular horns (arrows).
Although this patient had no visual disturbance, systematic involvement and typical radiological manifestations suggest retinal vasculopathy with cerebral leukoencephalopathy (RVCL). RCVL is an autosomal dominant microvasculopathy caused by C-terminal frameshift mutations in TREX1 gene(1). Different type of mutations in the same gene can cause Aicardi-Goutiéres syndrome or hereditary systemic lupus erythematosus(2). RVCL, as the name suggests, mainly affects brain and retina, but it may also cause systemic impairment such as renal dysfunction. In 2016, RVCL was renamed to RVCL-S (S stands for systemic manifestations) to stress the systemic features(3). But in this article, we still use the term of RVCL.
Clinical Perspective RVCL affects both genders. Vascular retinopathy begins from age 20 onwards with severity ranging from decreased visual acuity or visual field defects to blindness(4). Retinal haemorrhage and cotton wool spots may be present on fundoscopy. Neurological problems start around age 50(4). Symptoms include focal neurologic deficit, cognitive impairment, migraine and seizures. Half patients have elevated serum creatinine and proteinuria. Liver impairment may be present. Other symptoms include anaemia, hypertension, hypothyroidism and Raynaud’s phenomenon(3). Our patient did not report visual disturbance probably because he had cognitive problem and was uncooperative. Fundoscopy examination was unable to be performed due to severe cataract.
Three types of lesions can be present on brain MRI.
Focal non-enhancing T2 weighted hypertense periventricular and deep white matter lesions (Figure 2).
Punctate T2-hyperintense white matter lesions with nodular enhancement.
Large white matter ring enhancing mass with perilesional oedema and mass effect. Lesions are most frequently located in frontoparietal lobe. It may demonstrate high diffusion signal on DWI. This type may easily be taken for brain neoplasm, vasculitis or other conditions. (Figure 1) It is among the major diagnostic criteria proposed by Stam AH(3).
The first manifestation is a supportive feature in the diagnostic criteria proposed by Stam AH(3). The next two are included in the major diagnostic criteria(3).
Brain CT is non-specific. It may show low density in white matter. Half of all patients demonstrate multiple intracerebral calcifications on CT. It is also a supportive feature in the diagnostic criteria(3)
Outcome A heterozygous mutation p.V235Gfs*6 was identified in TREX1 gene. There is no cure available currently, so no further measure was taken.
Take Home Message / Teaching Points
 Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, et al. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39(9):1068-70. Epub 2007/07/31. doi: 10.1038/ng2082. PubMed PMID: 17660820.
 Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235-43. Epub 2015/03/04. doi: 10.1007/s10875-015-0147-3. PubMed PMID: 25731743.
 Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016;139(11):2909-22. Epub 2016/09/09. doi: 10.1093/brain/aww217. PubMed PMID: 27604306; PubMed Central PMCID: PMCPMC5091044.
 Pelzer N, Hoogeveen ES, Haan J, Bunnik R, Poot CC, van Zwet EW, et al. Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease. Journal of internal medicine. 2019;285(3):317-32. Epub 2018/11/10. doi: 10.1111/joim.12848. PubMed PMID: 30411414.