A monogenic, age-related cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), causes accelerated vascular dementia, vision loss, and premature death. Given knowledge is limited regarding its pathophysiology, we examined the natural history of progression in imaging and cognitive endpoints to define the rate and variability of progression in a prospective RVCL-S cohort. We hypothesized that cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of cerebral hypoxia-ischemia, would be associated with neurologic disease progression. We performed sequential brain MRI and a cognitive battery in a prospective RVCL-S cohort. Arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal-appearing white matter (WM), respectively. Three neuroimaging endpoints of cSVD included the following: log-transformed, normalized fluid-attenuated inversion recovery WM hyperintensity (WMH) volume; WM microstructure using mean diffusivity; and normalized WM volume. Five cognitive and motor endpoints included Digit Symbol Substitution Test (DSST), category fluency, free recall, Montreal Cognitive Assessment (MoCA), and gait speed. Linear mixed-effects models examined age, CBF, and OEF in association with neuroimaging and cognitive progression. Twenty-five participants, aged 23-68 years (median 47 years, 56% female), underwent 151 scans over a median (25th, 75th) of 2.2 (1.8, 4.4) years. All neuroimaging and cognitive endpoints progressed over time, except for MoCA. Of neuroimaging endpoints, WMH volume demonstrated the largest rate of change (+31.3%/year, 95% CI 20.8%-42.3%). Of cognitive endpoints, DSST, a metric of processing speed, showed the steepest decline (-13.1 T-score points/decade, 95% CI -21.2 to -5.32), followed by free recall and category fluency (-5 [-7.9 to -2.4] and -4.1 [-7.2 to -1.2] T-score points per decade, respectively). The age at first brain lesion was estimated to be 30.6 (23.8, 35.8) years, modeled from individual WMH volume trajectories. In multivariable analysis, OEF, but not CBF, was independently associated with WMH growth (β = 3.73, 95% CI 0.63-6.83, p = 0.029) and change in WM microstructure (β = 0.175, 95% CI 0.029-0.32, p = 0.029). Neither OEF nor CBF was independently associated with cognitive decline. Elevated OEF in at-risk WM was associated with progression in WMH and impairment in WM microstructure, suggesting a role for tissue hypoxia-ischemia in underlying RVCL-S pathophysiology. Cerebral OEF holds promise as a predictive biomarker to risk-stratify patients with RVCL-S and other forms of cSVD.

Porto-sinusoidal vascular disorder (PSVD) is a rare liver disease. The pathophysiological mechanisms underlying the development of PSVD are unknown. Isolated cases of PSVD associated with gene mutations have been reported, but no overview is available. Therefore, we performed an extensive literature search to provide a comprehensive overview of gene mutations associated with PSVD. We identified 34 genes and 1 chromosomal abnormality associated with PSVD in the literature, and we describe here 1 additional gene mutation ( TBL1XR1 mutation, leading to Pierpont syndrome). These gene mutations are associated either with extrahepatic organ involvement as part of syndromes (Adams-Oliver, telomere biology disorders, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, immune deficiencies, cystic fibrosis, cystinosis, Williams-Beuren, Turner, Pierpont) or with isolated PSVD ( KCNN3 , DGUOK , FOPV , GIMAP5 , FCHSD1 , TRMT5 , HRG gene mutations). Most of the cases were revealed by signs or complications of portal hypertension. When analyzing the cell types in which these genes are expressed, we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of PSVD than previously thought. In addition, pathway analyses suggested that there may be 2 types of PSVD associated with gene mutations: those resulting directly from morphogenetic abnormalities and those secondary to immune changes.

Central nervous system involvement in vasculitis disorders, either primary or secondary, is a heterogeneous and challenging area in rheumatology clinical in terms of both diagnostics and therapeutics. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, difficult-to-diagnose, and ill-defined clinical entity caused by mutations at the TREX1 gene without effective treatment options. We hereby present a 50-year-old male patient with non-alcoholic fatty liver disease, hypertension, bilateral type III macular telangiectasia, and stage II chronic kidney disease with mild proteinuria presenting to the rheumatology clinic with various neurological symptoms accompanied by multiple contrast-enhancing cerebral lesions on magnetic resonance imaging. Even though RVCL-S is not an inflammatory vasculopathy, our patient has partially responded to high-dose corticosteroid and cyclophosphamide in terms of clinical status and radiological evaluation. This case report not only highlights the importance of consideration of RVCL-S in the differential diagnosis of central nervous system vasculitis-like disorders but also emphasises the potential use of certain immunosuppressive medications in the therapeutic perspective.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare small vessel disease marked by vision loss and neurocognitive deterioration. We sought to characterize the relatedness of the underlying retinal structure and cerebral disease. Participants with RVCL-S underwent optical coherence tomography (OCT) and brain MRI at baseline and 2 years. Total macular volume (TMV) and central subfield thickness (CST) were generated from OCT images. Neuroimaging metrics of ischemic brain injury included white matter hyperintensity (WMH) volume, white matter microstructure (mean diffusivity), and normalized white matter volume. Associations between retinal and neuroimaging metrics were assessed. Eleven RVCL-S participants were included. Reduction in TMV was associated with reduced normalized white matter volume (β = 0.021, 95% CI [0.006, 0.036], p = 0.0137), increased WMH volume (β = -11.0, 95% CI [-17.4, -4.0], p = 0.0046), and a near-significant increase in mean diffusivity (β = -0.017, 95% CI [-0.035, -0.001], p = 0.057). CST was not associated with neuroimaging metrics. Percent change in TMV was associated with percent change in mean diffusivity (β = -0.61, 95% CI [-1.14, -0.084], p = 0.028). A metric of retinal structure, TMV, may provide a marker of cerebral disease severity in RVCL-S. Additional studies are needed to demonstrate whether early measures of TMV predict cerebral disease progression.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets. We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity. In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.