Cerebroretinal Vasculopathy Research Articles

Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant–based and single-gene–based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.

Defining retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

This scientific commentary refers to ‘Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’, by Stam et al. (doi:10.1093/brain/aww217) . Cerebral small vessel diseases refer to pathological processes that affect the structure or function of small vessels of the brain, including arteries, arterioles, capillaries, and occasionally venules (Pantoni, 2010). While the majority of small vessel diseases are sporadic age-related conditions driven by a complex interaction between genetic and cardiovascular risk factors or cerebrovascular amyloid deposition, inherited (familial) cerebral small vessel diseases have been increasingly reported in recent years (Joutel and Faraci, 2014). Of these inherited diseases, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and Fabry’s disease are among the most prevalent (Pantoni, 2010). The list of other, rarely observed single-gene small vessel diseases, often with systemic manifestations outside the brain, seems to be steadily increasing, posing diagnostic challenges in clinical practice. One such disorder is the fatal autosomal dominant condition caused by mutations in TREX1 (three prime repair exonuclease 1). TREX1 encodes a 3′-5′ DNA exonuclease involved in clearing cytosolic nucleic acids (Richards et al. , 2007). The disease was originally reported under different names, including hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), thought to represent distinct autosomal dominant neurovascular syndromes. The mapping of all three syndromes to a common locus on chromosome 3p21.1-p21.3 and the identification of pathogenic heterozygous C-terminal frame-shift mutations in TREX1 (Richards et al. , 2007 …

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.

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. * Abbreviations : AGS : Aicardi-Goutieres syndrome MC : mutation carrier RVCL(-S) : retinal vasculopathy with cerebral leukoencephalopathy (and systemic manifestations)

Neuropathology and Genetics of Cerebroretinal Vasculopathies

Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal-dominant disorders of early to middle-age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl-terminus of three prime exonuclease-1 (TREX1), the major mammalian 3' to 5' DNA exonuclease on chromosome 3p21.1-p21.3, result in a systemic vasculopathy that follows an approximately 5-year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes.

EVOLUTION OF A TUMOR-LIKE LESION IN CEREBRORETINAL VASCULOPATHY AND TREX1 MUTATION

Cerebroretinal vasculopathy (CRV) is an adult-onset autosomal dominant disorder involving the microvessels of the brain and retina due to frameshift mutations in the gene TREX1 .1,2 Patients present with vision loss, seizures, hemiparesis, apraxia, dysarthria, or memory loss. There is progression to blindness, a neurovegetative state, and death within 5 to 10 years.1 MRI reveals a tumor-like lesion in approximately half of patients, resembling a primary brain malignancy, while in the other half there are multiple small white matter lesions which may be misdiagnosed as demyelinating disease. The purpose of this report is to heighten awareness of this disease and to note near resolution of the tumor-like lesion. ### Case report. A 44-year-old woman had daily tension-type headaches and chronic sinusitis since 2006. In June 2007, she had transient right nasal visual field blurring. Visual acuity remained intact. Neurologic examination had normal results. In 2007, a multi-kindred study2 identified the causative mutation of CRV as frameshifts in the C-terminus of the TREX1 gene. The patient was found to carry the V235fs mutation (3688_3689insG). Her father, paternal grandmother, and extended kindred had CRV (n = 27, 4 with active disease, 23 died due to CRV, major family in reference 1). At the age of 43, her father presented with hemiparesis and a tumor-like lesion. He died of progressive disease complicated by steroid-associated bleeding from gastrointestinal ulcers at age 49. Her paternal grandmother had a brain lesion resected, believed to worsen after radiation, and died in …

Effects of intravitreal bevacizumab treatment on proliferative retinopathy in a patient with cerebroretinal vasculopathy

Effects of intravitreal bevacizumab treatment on proliferative retinopathy in a patient with cerebroretinal vasculopathy

Retinal Manifestations of Cerebroretinal Vasculopathy

We report a case of a 42-year-old woman who presented with a slowly progressive decrease in visual acuity and memory loss. Dilated fundus exam showed cotton-wool spots and parafoveal telangiectasias. Fluorescein angiography revealed foveal capillary nonperfusion, which was very similar to that of her father, who passed away from a similar illness. These two patients share the same clinical, angiographic and pathologic features as a pedigree that had autosomal dominant cerebroretinal vasculopathy. Hereditary small vessel disease of the brain and retina is a spectrum of different entities that has many manifestations in end organs outside of the central nervous system.

Novel ophthalmological features in hereditary endotheliopathy with retinopathy, nephropathy and stroke syndrome

The ophthalmic features are reported of a member of an Australian pedigree with three affected individuals spanning two generations with a hereditary endotheliopathy syndrome resulting in retinopathy, leukoencephalopathy and nephropathy. The index case initially presented with asymptomatic retinopathy, cerebral microvascular disease, nephropathy and raised inflammatory markers. The clinical, neuro-radiological, biochemical and histopathological findings in this patient are consistent with a diagnosis of hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS). Linkage analysis has identified a locus for HERNS on chromosome 3p21.1-p21.3. This locus is shared with two other diseases: hereditary vascular retinopathy (HVR) and cerebroretinal vasculopathy (CRV). Although peripheral retinal involvement is a feature of HVR, it has not previously been described in HERNS. This case represents a novel phenotype of HERNS, and serves to blur the distinction between the vasculopathies mapping to chromosome 3p21. Although previously thought to be distinct clinical entities, it is possible that HERNS, HVR and CRV simply represent different phenotypes of the same disease. This will only be clarified with the identification of the gene or genes. This case also raises the question of how best to manage rare forms of vascular retinopathy.

Mendelian and mitochondrial disorders associated with stroke

Several hereditary disorders induce angiopathy in the intracranial cerebrovasculature and thus cause ischemic strokes. MELAS is a maternally inherited mitochondrial disorder that produces stroke-like events. Sickle cell disease, which is the result of a single base pair substitution, is a major cause of strokes in children. Homocystinuria, an autosomal recessive syndrome, produces premature atherosclerosis. Hereditary cerebroretinal vasculopathy is an autosomal dominant disorder that causes retinal and brain infarctions. Fabry disease is an x-linked disorder that can cause stroke in adults. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an autosomal dominant syndrome that is associated with ischemic stroke and migraine-like headaches. The clinical presentation, stroke pathophysiology, and gene defects associated with these heritable disorders are reviewed.

Mendelian and mitochondrial disorders associated with stroke

Several hereditary disorders induced angiopathy in the intracranial cerebrovasculature and thus cause ischemic strokes. MELAS is a maternally inherited mitochondrial disorder that produces stroke-like events. Sickle cell disease, which is the result of a single base pair substitution, is a major cause of strokes in children. Homocystinuria, an autosomal recessive syndrome, produces premature atherosclerosis. Hereditary cerebroretinal vasculopathy is an autosomal dominant disorder that causes retinal and brain infarctions. Fabry disease is an x-linked disorder that can cause stroke in adults. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an autosomal dominant syndrome that is associated with ischemic stroke and migraine-like headaches. The clinical presentation, stroke pathophysiology, and gene defects associated with these heritable disorders are reviewed.

Hereditary Vascular Retinopathy, Cerebroretinal Vasculopathy, and Hereditary Endotheliopathy with Retinopathy, Nephropathy, and Stroke Map to a Single Locus on Chromosome 3p21.1-p21.3

We performed a genomewide search for linkage in an extended Dutch family with hereditary vascular retinopathy associated with migraine and Raynaud phenomenon. Patients with vascular retinopathy are characterized by microangiopathy of the retina, accompanied by microaneurysms and telangiectatic capillaries. The genome search, using a high throughput capillary sequencer, revealed significant evidence of linkage to chromosome 3p21.1-p21.3 (maximum pairwise LOD score 5.25, with D3S1578). Testing of two additional families that had a similar phenotype, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke, revealed linkage to the same chromosomal region (combined maximum LOD score 6.30, with D3S1588). Haplotype analysis of all three families defined a 3-cM candidate region between D3S1578 and D3S3564. Our study shows that three autosomal dominant vasculopathy syndromes with prominent cerebroretinal manifestations map to the same 3-cM interval on 3p21, suggesting a common locus.