Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.
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ABSTRACT:
SUBMITTER: Stam AH
PROVIDER: S-EPMC5091044 | biostudies-literature | 2016 Nov
REPOSITORIES: biostudies-literature
Publications
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.
Stam Anine H AH Kothari Parul H PH Shaikh Aisha A Gschwendter Andreas A Jen Joanna C JC Hodgkinson Suzanne S Hardy Todd A TA Hayes Michael M Kempster Peter A PA Kotschet Katya E KE Bajema Ingeborg M IM van Duinen Sjoerd G SG Maat-Schieman Marion L C MLC de Jong Paulus T V M PTVM de Smet Marc D MD de Wolff-Rouendaal Didi D Dijkman Greet G Pelzer Nadine N Kolar Grant R GR Schmidt Robert E RE Lacey JoAnne J Joseph Daniel D Fintak David R DR Grand M Gilbert MG Brunt Elizabeth M EM Liapis Helen H Hajj-Ali Rula A RA Kruit Mark C MC van Buchem Mark A MA Dichgans Martin M Frants Rune R RR van den Maagdenberg Arn M J M AMJM Haan Joost J Baloh Robert W RW Atkinson John P JP Terwindt Gisela M GM Ferrari Michel D MD
Brain : a journal of neurology 20161101 11
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Project description:PurposeTo describe a case of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) to enhance early recognition of this often-missed diagnosis.MethodsA case report is presented.ResultsA 50-year-old woman with a history of Raynaud phenomenon, memory difficulties, and a family history of strokes was referred for evaluation of a bilateral, small-vessel, occlusive disease refractory to immunosuppressive therapy. An extensive workup for treatable causes was unrevealing. Fifteen months after presentation, brain imaging showed white-matter lesions and dystrophic calcification, which led to the discovery of a pathogenic variant in TREX1 and the diagnosis of RVCL-S.ConclusionsRetina specialists play a critical role in the timely diagnosis of RVCL-S. Although the findings in this condition can mimic those in other common retinal vascular disorders, there are key characteristics that increase the suspicion for RVCL-S. Early recognition might decrease unnecessary therapies and procedures.
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Project description:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, underrecognized, systemic small vessel disease caused by heterozygous C-terminal truncating TREX1 mutations. The disease is characterized by vascular retinopathy, focal neurological complaints, cognitive decline and a wide range of systemic manifestations, including Raynaud's phenomenon, anemia and liver and kidney disease. Eventually, RVCL-S leads to premature death. The underlying pathological finding in RVCL-S is a nonatherosclerotic, amyloid-negative angiopathy involving small arteries and capillaries. However, the exact mechanisms by which the truncated TREX1 protein causes angiopathy remains unknown. Timely recognition of this disease is important to slow down and treat complications of the disorder, but also to prevent unnecessary (invasive) diagnostic or therapeutic procedures. As we move forward, translational research combining basic science advances and clinical findings as well as studies focusing on natural history following RVCL-S patients at different disease stages, will be critical to help elucidate RVCL-S pathophysiology. These studies will also provide the tools to identify appropriate biomarkers and therapeutic agent options for RVCL-S patients.
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Project description:BackgroundBeing a newly defined disease, RVCL-S is underrecognized by clinicians globally. It is an autosomal dominantly inherited small vessel disease caused by the heterozygous C-terminal frameshift mutation in TREX1 gene. RVCL-S is featured by cerebral dysfunction, retinopathy, and vasculopathy in multiple internal organs. Misdiagnosis may cause devastating consequences in patients, such as iatrogenic PML caused by misuse of immunosuppressants. Thus, increasing awareness of this disease is in urgent need.ResultsWe uncovered a large Chinese origin RVCL-S pedigree bearing the TREX1 mutation. A comprehensive characterization combining clinical, genetic, and neuropathological analysis was performed. The Intrafamilial comparison showed highly heterogeneous clinical phenotypes. Mutation carriers in our pedigree presented with retinopathy (8/13), seizures (2/13), increased intracranial pressure (1/13), mild cognitive impairment (3/13), stroke-like episode (3/13), mesenteric ischemia (1/13), nephropathy (9/13), ascites (3/13), hypertension (9/13), hyperlipidemia (3/8), hypoalbuminemia (3/8), normocytic anemia (3/8), subclinical hypothyroidism (1/8), hyperfibrinogenemia (1/8), hyperparathyroidism (2/8), and abnormal inflammatory markers (4/8). The constellation of symptoms is highly varied, making RVCL-S a challenging diagnosis. Comparison with reported RVCL-S pedigrees further revealed that the mesenteric ischemia is a novel clinical finding and the MRS pattern of brain lesions is emulating neoplasm and tumefactive demyelination.ConclusionOur reports characterize a highly heterogeneous RVCL-S pedigree, highlight the probability of misdiagnosis in clinical practice, and broaden the clinical spectrum of RVCL-S.
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Project description:BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S.MethodsvWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls.ResultsWhile vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056).ConclusionsThese findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.
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Project description:PurposeTo report a case of occlusive retinal vasculopathy, secondary to hyperhomocysteinemia.ObservationsA 43-year-old male was examined at the retina outpatient clinic due to complaints of bilateral decrease in visual acuity. The patient underwent a comprehensive ophthalmological examination, wide-field fundus photographs and fluorescein angiography, as well as spectral domain optical coherence tomography with enhanced-deep imaging. The patient had a significant medical history of chronic kidney disease and progressive bilateral vision loss over the last two years, which worsened in the left eye during the past 3 months. Fundus examination revealed a vitreous hemorrhage in the left eye and bilateral proliferative retinopathy. Blood glucose and systemic blood pressure were unremarkable. Plasma homocysteine was reported at >500 μmol/L, which is higher than the corrected reference range by age.Conclusion and importanceHyperhomocysteinemia is a rare but well-known disease, capable of accelerating atherosclerotic disease and generating a prothrombotic state that can lead to multiple systemic complications. Despite its low incidence, the disease should be part of the differential diagnosis in patients with bilateral proliferative retinopathy, in the absence of diabetes mellitus and systemic hypertension.
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