Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous <i>TREX 1</i> Mutation

Saito, Rie; Nozaki, Hiroaki; Kato, Taisuke; Toyoshima, Yasuko; Tanaka, Hajime; Tsutsumi, Yutaka; Morioka, Toshio; Horikawa, Yo; Oyanagi, Kiyomitsu; Morita, Takashi; Onodera, Osamu; Kakita, Akiyoshi

doi:10.1093/jnen/nly115

Cited by 19 publications

(20 citation statements)

References 16 publications

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“…This possibility was shown in a recent histopathologic study, in which focal calcifications associated with WMLs and granular calcifications in the walls of several vessels were described. 18 In the current study, punctiform SWI artifacts were also seen in the basal ganglia and cerebellum. Proof of calcifications in the basal ganglia and cerebellar hemispheres would be a new finding in RVCL-S. 9 In the past, neuroimaging findings of RVCL-S have been mistaken for multiple sclerosis, vasculitis, or neoplasms, and unnecessary brain biopsies have been performed in some cases.…”

Section: Discussionsupporting

confidence: 57%

Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

Hoogeveen¹,

Pelzer

Boer

et al. 2021

AJNR Am J Neuroradiol

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Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is caused by TREX1 mutations. Highquality systematic follow-up neuroimaging findings have not been described in presymptomatic and symptomatic mutation carriers. We present MR imaging findings of 29 TREX1 mutation carriers (20-65 years of age) and follow-up of 17 mutation carriers (30-65 years of age). Mutation carriers younger than 40 years of age showed a notable number of punctate white matter lesions, but scan findings were generally unremarkable. From 40 years of age onward, supratentorial lesions developed with long-term contrast enhancement (median, 24 months) and diffusion restriction (median, 8 months). In these lesions, central susceptibility artifacts developed, at least partly corresponding to calcifications on available CT scans. Some lesions (n ¼ 2) additionally showed surrounding edema and mass effect (pseudotumors). Cerebellar punctate enhancing lesions developed mainly in individuals older than 50 years of age. These typical neuroimaging findings should aid neuroradiologic recognition of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, which may enable early treatment of manifestations of the disease. ABBREVIATIONS: Gd ¼ gadolinium; MC ¼ mutation carrier; RVCL-S ¼ retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; WML ¼ white matter lesion R etinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a dominantly inherited disease caused by mutations in the TREX1 gene. 1 RVCL-S is histologically characterized by a systemic vasculopathy of mediumand small-caliber arteries as well as veins. 2,3 Clinically, the disease manifests from 35 to 40 years of age onward and is characterized by vascular retinopathy, Raynaud phenomenon, migraine, and dysfunction of multiple internal organs (including kidney disease, liver disease, anemia, and subclinical hypothyroidism). 4 So far, few studies have described neuroimaging findings, mostly in symptomatic RVCL-S patients with advanced disease. 2,5-17 A previous study described 3 types of lesions: 1) focal-to-confluent nonenhancing white matter lesions (WMLs), 2) WMLs with punctate enhancement, and 3) rim-enhancing lesions with surrounding T2-hyperintensity (edema/gliosis) and/or diffusion restriction. 9 These lesions with surrounding edema may become large with mass effect and are referred to as pseudotumors.RVCL-S remains a frequently missed diagnosis, partly due to lack of recognition by radiologists. We systematically studied the neuroimaging characteristics of RVCL-S and describe the frequency and evolution of these findings in a large set of presymptomatic and symptomatic carriers.

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Section: Discussionsupporting

confidence: 57%

Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

Hoogeveen¹,

Pelzer

Boer

et al. 2021

AJNR Am J Neuroradiol

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“…Patients ultimately diagnosed with RVCL-S often undergo brain biopsy (sometimes more than once) to exclude malignancy. The most common pathological features of RVCL-S are vasculopathy of medium and small vessels, sparing leptomeningeal and extraparenchymal arteries, with medial mural hyalinization and concentric wall thickening, along with ischemic and fibrinoid necrosis of the white matter sparing the gray matter (Raynowska et al, 2018;Saito et al, 2019;Stam et al, 2016). Duplication of basement membranes can be seen on electron microscopy, as was the case in our patient (Stam et al, 2016).…”

Section: Discussionsupporting

confidence: 67%

Novel de novo TREX1 mutation in a patient with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations mimicking demyelinating disease

Macaron

Khoury

Hajj‐Ali

et al. 2021

Multiple Sclerosis and Related Disorders

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“…High-penetrance COL4A1 mutations lead to a variety of rare monogenic brain infarction phenotypes which include severe B-ASC, and more common COL4A1 single nucleotide polymorphisms (SNPs) are also associated with brain cSVD [41,134]. TREX1 mutations are another interesting cause of degenerative microvascular lesions in the eye, brain, and elsewhere, implicating inflammatory dysfunction at the basement membrane of arterioles and other small vessels [171,176]. Other genes associated with monogenic B-ASC phenotype include HTRA1 and FOXC1/FOXF2 [108,125,213].…”

Section: Genetics and Agingmentioning

confidence: 99%

Brain arteriolosclerosis

et al. 2020

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Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as A a a b c-predominant age-related TDP-43 encephalopathy (LATE).There may also be complex physiologic interactions between metabolic syndrome (e.g. hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that include consideration of comorbid diseases, B-ASC is independently associated with impairments in global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

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Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation

Cited by 19 publications

References 16 publications

Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

Neuroimaging Findings in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

Novel de novo TREX1 mutation in a patient with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations mimicking demyelinating disease

Brain arteriolosclerosis

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