Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Year: 2016

Type: article

Abstract: See Charidimou (doi:10.1093/aww253) for a scientific commentary on this article. Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies. See Charidimou (doi:10.1093/aww253) for a scientific commentary on this article. Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations is a newly recognised and often misdiagnosed neurovascular syndrome caused by mutations in TREX1. Stam et al. provide the first comprehensive clinical, pathological and radiological characterization of RVCL-S, and highlight cerebral mass lesions, impaired liver and kidney function, and premature death.

Source: Brain

DOI: 10.1093/brain/aww217

Institutions: Leiden University, Leiden University Medical Center, Washington University in St. Louis, LMU Klinikum, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, University of California, Los Angeles, Liverpool Hospital, The University of Sydney, Concord Repatriation General Hospital, Monash Medical Centre, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam UMC Location University of Amsterdam, Mercy Hospital, Retina Institute, Cleveland Clinic, Munich Cluster for Systems Neurology, Alrijne Ziekenhuis

Language: English

Topic: Cerebrovascular and genetic disorders

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: European Commission, Deutsche Forschungsgemeinschaft, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Centre for Medical Systems Biology, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke

Awards: G1300016734, G161284949, Mechanisms and Treatment of Migraine and its Chronification, Nuclease Immune Mediated Brain and Lupus-like conditions (NIMBL): natural history, pathophysiology, diagnostic and therapeutic modalities with application to other disorders of autoimmunity, Pre-doctoral Research Training in Human Genetic Epidemiology, G3345700492, Pathobiology of Retinal Vasculopathy with Cerebal Leukodystrophy (RVCL), G3916079629, G4093014502, G4598234423, G5651375637, G784065502, G8450831549

OpenAlex ID: W2513620161