{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:30:28Z","timestamp":1789579828783,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,11,8]],"date-time":"2018-11-08T00:00:00Z","timestamp":1541635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["VIDI 91711319"],"award-info":[{"award-number":["VIDI 91711319"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Intern Med"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (<jats:styled-content style=\"fixed-case\">RVCL<\/jats:styled-content>\u2010S) is a small vessel disease caused by C\u2010terminal truncating <jats:italic><jats:styled-content style=\"fixed-case\">TREX<\/jats:styled-content>1<\/jats:italic> mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a cross\u2010sectional study, we compared the clinical characteristics of 33 <jats:italic><jats:styled-content style=\"fixed-case\">TREX<\/jats:styled-content>1<\/jats:italic> mutation carriers (<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>+) from three Dutch <jats:styled-content style=\"fixed-case\">RVCL<\/jats:styled-content>\u2010S families with those of 37 family members without <jats:italic><jats:styled-content style=\"fixed-case\">TREX<\/jats:styled-content>1<\/jats:italic> mutation (<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\u2010). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain <jats:styled-content style=\"fixed-case\">MRI<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60\u201365.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death.<\/jats:p><\/jats:sec>","DOI":"10.1111\/joim.12848","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T07:29:18Z","timestamp":1541748558000},"page":"317-332","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease"],"prefix":"10.1111","volume":"285","author":[{"given":"N.","family":"Pelzer","sequence":"first","affiliation":[{"name":"Department of Neurology Leiden University Medical Centre Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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