Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Abstract

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 (AE standard deviation) age at diagnosis was 42.9 AE 8.3 years and at death 53.1 AE 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 AE 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

Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

“…A review of 78 mutation carriers of a C-terminal frame-shift in TREX1 from 11 unrelated families reported the manifestations in RVCL [2]. At diagnosis, 92% of mutation carriers presented with retinopathy.…”

“…One was detected as nephropathy prior to retinopathy. It differs by individual in terms of how the manifestations present [2,[4][5][6]8] and nephropathy can be the first manifestation found, as in this case. Therefore, clarifying the histopathology of the kidney assists in providing early RVCL diagnosis.…”

“…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.…”

“…Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease caused by mutations of the three-prime repair exonuclease − 1 (TREX1) [1,2]. TREX1 is a 3′-5′ DNA exonuclease ubiquitously expressed in human organs, including kidney [1,3].…”

“…RVCL patients typically exhibit visual disturbance and neurological disorders in middle age, often accompanied by renal and liver dysfunction. The disease is currently fatal within 5-10 years of diagnosis [2]. Neurological disorders and visual disturbance are highlighted as manifestations leading to the diagnosis of RVCL [7,8].…”