Hereditary Systemic Angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy

Winkler, David T.; Lyrer, Philippe; Probst, Andreas; Devys, Didier; Haufschild, Timo; Haller, Sven; Willi, Niels; Mihatsch, M. J.; Steck, Andrea; Tolnay, Markus

doi:10.1007/s00415-008-0675-3

Cited by 29 publications

(38 citation statements)

References 28 publications

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“…Reports on electron microscopic study of RVCL are insufficient; double contour of the capillary wall and widening subendothelial spaces seem common findings. However, a multilayered endothelial basement membrane of the glomerulus was described in one report [6], although we, and two other reports, [9,10] did not confirm this finding.…”

Section: Discussioncontrasting

confidence: 53%

“…Segmental mesangial changes, mesangiolysis, and proliferation of mesangial cell may be the result of severe endothelial damage and repair processes. Previously reported RVCL histological findings resembled those at a certain stage of case 1 [6,7,[9][10][11].…”

Section: Discussionmentioning

confidence: 85%

“…Neurological disorders and visual disturbance are highlighted as manifestations leading to the diagnosis of RVCL [7,8]. According to a recent report [2], 61% of mutation carriers have features of nephropathy, but there are only brief descriptions on renal histopathological changes [6,7,[9][10][11]. Herein, we describe two cases of RVCL and their unique and various histopathological findings found at renal biopsy.…”

Section: Introductionmentioning

confidence: 99%

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Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

et al. 2018

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease. Neurological disorders and visual disturbance are highlighted as manifestations of RVCL; however, there are few reports focused on nephropathy. Herein, we describe detailed renal histopathological findings in a daughter and father with RVCL, proven by TREX1 genetic analysis. A kidney biopsy of the daughter, 35-year-old with asymptomatic proteinuria, revealed unique and various glomerular changes. Atypical double contour (not tram track-like) of the capillary wall was widely found, an apparent characteristic finding. Glomerular findings were varied due to a combination of new and old segmental mesangial proliferative changes, mesangiolysis, and segmental glomerulosclerosis-like lesions; these changes may be related to endothelial cell damage. Collapsed tufts were also found and thought to be the result of ischemia due to arterial changes. Glomerular findings in a kidney biopsy of the father revealed similarity to the daughter's glomerulus at a relatively advanced stage, but the degree of variety in the glomerular findings was much less. Kidney biopsy findings suggesting endothelial cell damage of unknown etiology need to be considered for possible RVCL.

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Section: Discussioncontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

et al. 2018

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“…The genetic screening of TREX1 led to the identification of the causative mutations of the disease, both in our patient and in the family previously described with HSA (Table 1) [16].…”

Section: Introductionmentioning

confidence: 94%

“…A variant of RVCL with peculiar multiorgan involvement and unknown genetic cause is termed hereditary systemic angiopathy (HSA), characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, nephropathy and hepatopathy, variably spread among the affected members of the unique family reported so far [16].…”

Section: Introductionmentioning

confidence: 99%

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

et al. 2014

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

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A 44‐year‐old man with eye, kidney, and brain dysfunction

Vodopivec

Oakley

Perugino

et al. 2016

Annals of Neurology

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of the three-prime repair exonuclease-1 (TREX1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient’s multisystem presentation, retinal involvement interpreted as “retinal vasculitis”, and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet’s disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy.

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Hereditary Systemic Angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy

Cited by 29 publications

References 28 publications

Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy

A 44‐year‐old man with eye, kidney, and brain dysfunction

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