Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Nozaki, Hiroaki; Nishizawa, Masatoyo; Onodera, Osamu

doi:10.1161/strokeaha.114.004236

Cited by 85 publications

(85 citation statements)

References 40 publications

(97 reference statements)

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“…In contrast with monogenetic forms of cerebral SVD where mutations often lead to a loss of function of the respective proteins, we noticed increased expression levels of HTRA1 in the frontal cortex, COL4A1 in the frontal lobe, and COL4A1 and COL4A2 in the temporal and occipital lobes as well as in basal nuclei of SVD patients. Interestingly, mutations in HTRA1 , a serine protease inhibiting signaling by members of the TGF-β family, result in increased TGF-β signaling in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy and subsequently to vascular smooth muscle cell degeneration [18]. In this study, TGF-β signaling was found associated with downregulated genes in the basal ganglia of SVD patients, suggesting absence of TGF-β-induced detrimental effects on vascular smooth muscle cells in this area.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions

Ritz

Grond‐Ginsbach²,

Kloß³

et al. 2017

Neurodegener Dis

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Background/Aims: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights. Methods: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually. Results: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates. Conclusion: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions

Ritz

Grond‐Ginsbach²,

Kloß³

et al. 2017

Neurodegener Dis

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“…These features include fibrous proliferation of the intima, hyaline degeneration of the media, loss of vascular smooth muscle cells, and thickening and fragmentation of the internal elastic lamina [6]. There is dilatation of arterial lumen rather than luminal stenosis [7]; the ischemic brain insults are thought to be due to the disturbance of autoregulatory mechanisms for cerebral blood flow [8]. The findings are limited to the cerebral small arteries; skin biopsy is not helpful in diagnosis [1,9].…”

Section: Case Discussionmentioning

confidence: 99%

“…Spinal deformities, such as kyphosis and sclerosis of nuchal ligaments, as well as arthritic changes in elbows and knees have been described [1,11]; however, deformities of the skull have not been associated. Unlike CADASIL, migraines are not common [7]. …”

Section: Case Discussionmentioning

confidence: 99%

“…A diffuse bilaterally symmetrical, periventricular white matter abnormality appears as hypodense on CT. MRI is the preferred imaging modality, where the T2 and FLAIR hyperintensities are seen in the anterior temporal lobes, the external capsules, the brainstem, and cerebellum resembling [7] those seen in CADASIL. While lesions in the temporal lobes and external capsules are classic findings in CARASIL [12], those occurring in cerebral peduncles and middle cerebellar peduncles (Fig.…”

Section: Case Discussionmentioning

confidence: 99%

“…3b, c; Arc sign [12]) suggest a late stage [12] of the disease, and this is attributed to Wallerian degeneration [1,13]. U-fibers are relatively preserved, even during the late stage [7]. Microhemorrhages [3,7] have been identified; in late stages, diffuse brain atrophy is seen.…”

Section: Case Discussionmentioning

confidence: 99%

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A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review

et al. 2017

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Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced (“next generation”) sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. Conclusion: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-β1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included.

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Unusual causes of ischemic stroke and transient ischemic attack

Caprio

Lin

2019

Warlow's Stroke

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Features of Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Cited by 85 publications

References 40 publications

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review

Unusual causes of ischemic stroke and transient ischemic attack

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