RESUMO
AIMS: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a life-threatening, inherited, nonhypertensive arteriole disease of the brain. Therapeutic strategy for CARASIL is limited because its pathogenesis is not clear. We previously reported the first family with CARASIL in China, which involves a high-temperature requirement serine protease gene mutation (HtrA1L364P ). Based on this previous study, we constructed a CARASIL mouse model (Mut-hHtrA1L364P mouse, hereinafter referred to as Mut). This paper aimed to systematically study the behavior, pathology, and molecular biology of Mut mice and explore the pathogenesis and possible therapeutic strategies of CARASIL. METHODS: Food maze and water maze experiments were used in the behavioral studies. Pathological studies were carried out by arteriole labeling staining and electron microscopy. The mRNA and protein expression levels of the key factors of TGF-ß/Smad signaling pathway (TGF-ß, Smad2, Smad3, and Smad4) in the brain of the model mice were detected by immunohistochemistry, real-time quantitative polymerase chain reaction (RT-PCR), and Western blot assay. RESULTS: The food maze and water maze experiment data showed significant differences between the Mut and wild-type (WT) mice in the first time to find food, the time to contact the escape table for the first time, and the number of times to travel in the escape table quadrant (p < 0.001). The results of vascular labeling staining showed that some small arteries in the brain of Mut mice lost normal structure. The results of electron microscopy showed that the cell morphologies in the cortex and hippocampus of Mut mice were abnormal; the number of synapses was reduced; the walls of capillaries, venules, and arterioles thickened; lumen stenosis and other abnormal phenomenon occurred; and lipofuscin deposition and autophagosomes were found in the hippocampus. Immunohistochemistry, RT-PCR, and Western Blot results showed that the mRNA and protein expression levels of TGF-ß, Smad2, and Smad3 in the brain of Mut mice increased to different degrees. CONCLUSIONS: The most significant innovation of this study is the first study on the pathogenesis of CARASIL disease using model animals. The Mut mice can well simulate the pathogenesis of CARASIL in behavioral and pathological aspects. The TGF-ß/Smad signaling pathway, which is involved in the pathogenesis of CARASIL, is abnormally upregulated in the brain of Mut mice.
Assuntos
Doenças Arteriais Cerebrais , Infarto Cerebral/genética , Disfunção Cognitiva , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Alopecia , Animais , Doenças Arteriais Cerebrais/genética , Infarto Cerebral/metabolismo , Transtornos Cerebrovasculares , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Leucoencefalopatias , Camundongos , RNA Mensageiro , Transdução de Sinais , Doenças da Coluna Vertebral , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Mutations in ACTA2 gene can lead to multisystemic smooth muscle dysfunction, including cerebrovascular disease. Treatment strategies for this rare entity remain controversial, and patients are at increasing risk of neurological sequelae. We herein present the case of an 11-year-old boy previously diagnosed with an ACTA2 gene mutation who developed repetitive transient ischemic attacks and treated with bosentan, an oral endothelin receptor antagonist. Magnetic resonance imaging revealed bilateral, periventricular white matter T2 hyperintensities, and magnetic resonance angiography identified several abnormalities including fusiform dilatation in the proximal segments of internal cerebral arteries, together with followed by terminal segmental stenosis. The distal branches showed a markedly straightened course with no increase in lenticulostriate collaterals. Magnetic resonance imaging also revealed an increase in the number and size of large periventricular white matter lesions located in the left frontal lobe with the progression of ischemic symptoms. Instead of revascularization surgery, the administration of bosentan was started due to the high risk of perioperative ischemic sequelae. After bosentan initiation, the patient's repetitive episodes of cerebral ischemia ceased, and there has been no increase in the number of white matter lesions for 7 years. Bosentan might be beneficial for treating cerebral ischemia associated with ACTA2 cerebral arteriopathy by maintaining the dilatation of stenotic vessels and adequate systemic blood flow and should be considered before performing revascularization surgery.
Assuntos
Isquemia Encefálica , Doenças Arteriais Cerebrais , Transtornos Cerebrovasculares , Actinas , Bosentana/uso terapêutico , Angiografia Cerebral , Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/cirurgia , Infarto Cerebral , Criança , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
We investigated the effect of CYP2C19 polymorphisms on the clinical outcomes of clopidogrel therapy in patients after stenting procedure for cerebral artery stenosis in northeast China. 568 patients performed CYP2C19 genotype screening in the neurosurgery department of our hospital; 154 patients were finally recruited according to the inclusion and exclusion criteria, and followed-up for 6 months. Ischemic events including (1) transient ischemic attack (TIA); (2) stent thrombosis; (3) ischemic stroke; and (4) death were defined as primary clinical endpoints. The frequencies of CYP2C19*1, *2 and *3 alleles in 568 patients were 63.1%, 31.1% and 5.8%, respectively. 154 patients were classified into extensive (65 patients; 42.2%), intermediate (66 patients; 42.9%), and poor (23 patients; 14.9%) metabolizer groups. A χ2 test showed a significant difference in primary clinical endpoints at 6 months (P = 0.04), and a multivariate Cox regression analysis indicated that the CYP2C19 loss-of-function (LOF) alleles associated with post-procedure prognosis. The Kaplan-Meier curve revealed that there was no significant difference in ischemic events between *2 and *3 alleles carriers. Our study verifies that CYP2C19 *2 and *3 have significant impact on the clinical outcomes of clopidogrel therapy in patients with stenting procedure for cerebral artery stenosis in China.
Assuntos
Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/mortalidade , Constrição Patológica/etiologia , Constrição Patológica/patologia , Citocromo P-450 CYP2C19 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Doenças Arteriais Cerebrais/patologia , Doenças Arteriais Cerebrais/cirurgia , Comorbidade , Constrição Patológica/cirurgia , Gerenciamento Clínico , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fatores de Risco , StentsRESUMO
BACKGROUND: Incontinentia pigmenti (IP) is an X-linked neurocutaneous disorder that can present with cerebral arteriopathy during early infancy. However, no previous reports have demonstrated arteriopathic manifestations during postinfantile childhood in patients with IP. PATIENT DESCRIPTION: We describe a case of IP in a 2-year-old girl who developed encephalopathic manifestations associated with influenza A infection. She presented diffuse magnetic resonance imaging abnormalities involving the cortices, subcortical white matter, corpus callosum, basal ganglia, and thalami, resembling the findings in early infantile cases reported in the previous literatures. Magnetic resonance angiography demonstrated attenuation of the cerebral arteries. Proinflammatory cytokines and chemokines were upregulated in the cerebrospinal fluid. Left hemiplegia remained following the remission of the arteriopathic manifestations. Genetic analyses revealed a novel type of mutation in the IKBKG gene. CONCLUSION: Our findings indicate that patients with IP can develop destructive cerebral arteriopathy even after early infancy. The similarities in magnetic resonance imaging abnormalities between our patient and the previously reported infantile patients may be explained by the underlying immunologic pathophysiology of IP.
Assuntos
Encéfalo/diagnóstico por imagem , Doenças Arteriais Cerebrais/complicações , Incontinência Pigmentar/complicações , Doenças Arteriais Cerebrais/diagnóstico por imagem , Doenças Arteriais Cerebrais/genética , Pré-Escolar , Análise Mutacional de DNA , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Quinase I-kappa B/genética , Incontinência Pigmentar/diagnóstico por imagem , Incontinência Pigmentar/genética , Angiografia por Ressonância Magnética , Mutação , Substância Branca/diagnóstico por imagemRESUMO
Until recently, cerebral arteriopathy due to heterozygous mutations of the ACTA2 gene was considered a variant of moyamoya disease. However, radiographic analysis of patients with these mutations reveals a distinctive angiographic appearance from that seen in moyamoya disease. Several heterozygous missense ACTA2 mutations have been implicated in the development of this distinct cerebrovascular entity; however, the penetrance and systemic manifestations of these mutations vary based on the location of the amino acid replacement within the α-smooth muscle actin protein. The severity of the phenotype may also differ among patients within a single mutation type. There is limited literature on the safety and efficacy of revascularization procedures for ACTA2 arteriopathy, which have been limited to those patients with known Arg179His mutations. The authors provide a review of the breadth of mutations within the ACTA2 literature and report a case of two siblings with de novo ACTA2 Arg258Cys mutations with differing clinical courses, highlighting the utility of indirect revascularization with 8-year follow-up data. This case highlights the importance of early recognition of the angiographic appearance of ACTA2 cerebral arteriopathy and performance of genetic testing, as the location of the mutation impacts clinical presentation and outcomes.
Assuntos
Actinas/genética , Doenças Arteriais Cerebrais/genética , Adolescente , Criança , Humanos , Masculino , Mutação de Sentido Incorreto , Penetrância , IrmãosRESUMO
Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up- and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.
Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , RNA Circular/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Linhagem Celular , Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/metabolismo , Biologia Computacional , Humanos , Masculino , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , RNA Circular/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.
Assuntos
Adenosina Trifosfatases/genética , Arteriopatias Oclusivas/genética , Doenças Arteriais Cerebrais/genética , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases/genética , Idoso , Arteriopatias Oclusivas/diagnóstico por imagem , Doenças Arteriais Cerebrais/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man-based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively. Allele - 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70-0.96; P = 0.016). The model-based multifactor dimensionality reduction method has revealed 21 two-order, 124 three-order, and 474 four-order gene-gene (G×G) interactions models meaningfully (Pperm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.
Assuntos
Doenças Arteriais Cerebrais/genética , Redes Reguladoras de Genes , Arteriosclerose Intracraniana/genética , Metaloproteinase 8 da Matriz , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Idoso , Doenças Arteriais Cerebrais/enzimologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Arteriosclerose Intracraniana/enzimologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The potential effect of matrix metalloproteinase-9 (MMP-9) variants and these variants interactions on hemorrhagic transformation (HT) risk after ischemic stroke (IS) remain unclear. The aims of present study were to investigate the associations of six variants in MMP-9 with HT, and these variants interactions whether related to increased HT risk. METHOD: A total of 705 patients with IS who were admitted to the participating hospitals within 48 hr of symptom onset were consecutively enrolled between March 2014 and December 2016. HT was confirmed by brain computed tomography (CT) scan during 14 days from stroke onset. Six variants of MMP-9 gene were measured by mass spectrometry. Interactions of gene variant-gene variant were assessed through generalized multifactor dimensionality reduction method (GMDR). RESULTS: HT occurred in 104 (14.8%) patients. There were no differences in genotypes for the six variants between patients with and without HT using univariate analysis (all p > 0.05). GMDR analysis revealed that there was a synergistic effect of gene variant-gene variant interactions between rs3918242 and rs3787268 in MMP-9 gene. Cox regression analysis showed that high-risk interactions of rs3918242 and rs3787268 were associated with increased risk of HT after adjusting for covariates (hazard ratio: 2.08; 95% confidence interval: 1.34-7.85; p = 0.016). CONCLUSION: Incidence of HT is common in acute IS in Chinese population. The mechanisms leading to HT are most likely multifactorial. Two-loci interactions of rs3918242 and rs3787268 in MMP-9 gene may confer a higher risk for HT.
Assuntos
Isquemia Encefálica/genética , Hemorragia Cerebral/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Idoso , Povo Asiático/genética , Aterosclerose/genética , Isquemia Encefálica/complicações , Angiografia Cerebral , Doenças Arteriais Cerebrais/genética , Artérias Cerebrais , Angiografia por Tomografia Computadorizada , Epistasia Genética/genética , Feminino , Genótipo , Heterozigoto , Humanos , Embolia Intracraniana/genética , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/complicações , Trombose/genéticaRESUMO
This review will discuss important developments in childhood arterial ischemic stroke over the past decade, focusing on improved understanding of the causes, consequences, and targets for intervention. Risk factors for childhood arterial ischemic stroke are different to adults. Infections, particularly herpes group viruses, are important precipitants for stroke. Non-atherosclerotic arteriopathies are the most common cause of childhood arterial ischemic stroke and an important predictor of recurrent events. Recent advances include the identification of serum biomarkers for inflammation and endothelial injury, and imaging biomarkers to monitor for vascular progression. Multicenter trials of immunotherapies in focal cerebral arteriopathies are currently in development. Recognition of clinical and radiological phenotypic patterns has facilitated the discovery of multisystem disorders associated with arterial ischemic stroke including ACTA2 arteriopathy and adenosine deaminase 2 deficiency. Identification of these Mendelian disorders provide insights into genetic mechanisms of disease and have implications for medical and surgical management. In contrast to adults, there are long diagnostic delays in childhood arterial ischemic stroke. Refinement of pediatric Code Stroke protocols and clinical decision support tools are essential to improve diagnostic certainty and improve access to reperfusion therapies. Children do not recover better than adults following arterial ischemic stroke, with more than half of survivors having long-term impairments. The physical, cognitive, and behavioral consequences of childhood arterial ischemic stroke are increasingly reported but further research is required to understand their impact on participation, quality of life, psychosocial, and family functioning. Longitudinal studies and the use of advanced imaging techniques, to understand neurobiological correlates of functional reorganization, are essential to developing targeted intervention strategies to facilitate recovery.
Assuntos
Isquemia Encefálica/terapia , Doenças Arteriais Cerebrais/terapia , Endotélio Vascular/imunologia , Acidente Vascular Cerebral/terapia , Actinas/genética , Adenosina Desaminase/genética , Biomarcadores , Isquemia Encefálica/genética , Doenças Arteriais Cerebrais/genética , Criança , Predisposição Genética para Doença , Humanos , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fatores de Risco , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. SUMMARY: We performed a literature search using PubMed with the key words "ACTA2 mutation," "ACTA2 cerebral arteriopathy," and "multisystemic smooth muscle dysfunction syndrome." Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.
Assuntos
Actinas/genética , Doenças Arteriais Cerebrais/genética , Doença de Moyamoya/genética , Músculo Liso Vascular , Mutação de Sentido Incorreto , Adolescente , Adulto , Angiografia Digital , Angiografia Cerebral/métodos , Doenças Arteriais Cerebrais/diagnóstico por imagem , Doenças Arteriais Cerebrais/fisiopatologia , Doenças Arteriais Cerebrais/cirurgia , Artérias Cerebrais/fisiopatologia , Artérias Cerebrais/cirurgia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Angiografia por Ressonância Magnética , Masculino , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/fisiopatologia , Doença de Moyamoya/cirurgia , Músculo Liso Vascular/diagnóstico por imagem , Músculo Liso Vascular/fisiopatologia , Músculo Liso Vascular/cirurgia , Procedimentos Neurocirúrgicos , Fenótipo , Prognóstico , Fatores de RiscoRESUMO
OBJECTIVES: Stenosis of the intracranial large arteries, especially the middle cerebral artery (MCA), is common in the Chinese population. We conducted a case-control study to investigate clinical and apolipoprotein E (ApoE) gene polymorphism of MCA atherosclerosis in the Chinese population. MATERIALS AND METHODS: Polymerase chain reaction-based protocols were used to identify the genotypes of polymorphisms in ApoE genes. Clinical parameters and the genotypes of polymorphisms in the ApoE genes were compared in patients with and without MCA stenosis. The ApoE exon ε4 genotypes with risk factors were compared in the patients with and without MCA stenosis. RESULTS: In total, 337 ischemic stroke patients were recruited, 156 cases with and 181 without MCA stenosis. Univariate analysis showed that the levels of systolic blood pressure and pulse pressure were higher in the MCA-stenosis group. There were no significant differences in the genotype and allele frequencies of the ApoE polymorphism observed between patients with and without MCA stenosis. However, there was a trend that the MCA-stenosis group tended to have more of genotype ε4/ε4 (3.8% vs. 0.6%, P=0.052) than the non-MCA-stenosis group. There was no effect of ApoE genotype and genotype-by-environment interactions on ischemic stroke susceptibility. CONCLUSIONS: This present study indicated that the hypertension (ie, systolic blood pressure and pulse pressure) and the ApoEε4/ε4 genotype may be associated with the occurrence of MCA stenosis in the ischemic stroke Chinese patients.
Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Isquemia Encefálica/genética , Doenças Arteriais Cerebrais/genética , Artéria Cerebral Média/patologia , Acidente Vascular Cerebral/genética , Idoso , Estudos de Casos e Controles , China , Constrição Patológica/patologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de RiscoRESUMO
BACKGROUND: Previous data have shown that the 20210G>A polymorphism of the Factor II gene is related to an increased prothrombin level, which may in turn lead to a procoagulant state. The heterogeneous and multifactorial character of arterial ischemic stroke often results in contradictory reports describing the association between the 20210G>A polymorphism and arterial ischemic stroke in different populations. We performed a meta-analysis of available data addressing the relation between the FII 20210G>A polymorphism and arterial ischemic stroke, both in young adults and children. METHODS: We searched PubMed using appropriate keywords. The inclusion criteria for the study were as follows: case-control study, study population consisting of children, study population consisting of young adults, arterial ischemic stroke confirmed by magnetic resonance imaging or computed tomography, and English language. The exclusion criteria included lack of genotype or allele frequencies, study design other than a case-control study, outcome definition other than arterial ischemic stroke, and previously overlapped patient groups. Finally, 30 case-control studies (14 in children and 16 in young adults) were included. Statistical analyses were conducted using R software. Heterogeneity between the studies was evaluated using the Dersimonian and Laird's Q test. In the case of significant between-studies heterogeneity, the pooled odds ratio was estimated with a random-effects model, otherwise a fixed-effects model was used. RESULTS: The pooled analysis showed that carriers of 20210A allele (GA+AA genotypes) of the prothrombin gene are more common in arterial ischemic stroke patients, both in children and young adults, than in control subjects (P = 0.006; odds ratio, 1.83; 95% confidence interval, 1.19 to 2.80 and P = 0.001; odds ratio, 1.69; 95% confidence interval, 1.25 to 2.28, respectively). CONCLUSIONS: The results of the present meta-analysis have proven that the FII 20210G>A polymorphism is associated with arterial ischemic stroke in both pediatric and young adult patients.
Assuntos
Isquemia Encefálica/genética , Doenças Arteriais Cerebrais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Eicosanoids may play a role in ischemic stroke (IS). However, the association of variants in eicosanoid genes with symptomatic carotid artery or intracranial arterial stenosis and neurologic deterioration (ND) is not fully understood. The aim of the present study was to investigate the association of 11 variants in eicosanoid genes with symptomatic carotid artery or intracranial arterial stenosis and ND. METHODS: Eleven variants in eicosanoid genes were examined using mass spectrometry method in 297 IS patients. The symptomatic carotid artery or intracranial arterial stenosis was assessed by computed tomographic angiography. Platelet aggregation and platelet-leukocyte aggregates were measured. The primary outcome was ND within 10 days of admission. ND was defined as an increase of 2 or more points in National Institutes of Health Stroke Scale score. RESULTS: Among 297 IS patients, 182 (61.3%) cases had symptomatic carotid artery or intracranial arterial stenosis, and 88 (29.6%) patients experienced ND within 10 days after admission. Symptomatic carotid artery or intracranial arterial stenosis was significantly associated with higher ND (P < .001). Rs20417CC, rs41708TT, and rs5629CC were independent risk factors for symptomatic carotid artery or intracranial arterial stenosis and ND, and associated with higher platelet aggregation and platelet-leukocyte aggregates. CONCLUSIONS: Symptomatic carotid artery or intracranial arterial stenosis was associated with higher ND. Rs20417CC, rs41708TT, and rs5629CC were not only independent risk factors for symptomatic carotid artery or intracranial arterial stenosis, but also independent risk predictors for ND.
Assuntos
Isquemia Encefálica/genética , Estenose das Carótidas/genética , Doenças Arteriais Cerebrais/genética , Ciclo-Oxigenase 2/genética , Sistema Enzimático do Citocromo P-450/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Tromboxano-A Sintase/genética , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/fisiopatologia , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/enzimologia , Estenose das Carótidas/fisiopatologia , Doenças Arteriais Cerebrais/diagnóstico por imagem , Doenças Arteriais Cerebrais/enzimologia , Doenças Arteriais Cerebrais/fisiopatologia , China , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
Mutations in the smooth muscle-specific isoform of alpha actin (ACTA2) cause smooth muscle dysfunction in arteries. This rare loss-of-function mutation may cause a diffuse occlusive cerebral arteriopathy, resulting in stroke. While ACTA2 arteriopathy is often described as moyamoya-like, it has a distinct phenotype characterized by dilation of the proximal internal carotid artery (ICA) and occlusion of the terminal ICA and proximal middle cerebral artery. Intracranial arteries have an abnormally straight course, often with small aneurysms. There is limited experience with revascularization procedures for ACTA2 arteriopathy, and the safety and efficacy of these procedures are unknown. In this paper the authors present a symptomatic 6-year-old patient with ACTA2 cerebral arteriopathy who underwent both indirect revascularization and direct cerebrovascular bypass. Postoperatively, the patient suffered an ischemic infarct in a neighboring vascular territory. While direct cerebrovascular bypass is technically feasible, patients with ACTA2 arteriopathy may be at increased risk for perioperative stroke compared with patients with moyamoya disease.
Assuntos
Actinas/genética , Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/cirurgia , Revascularização Cerebral/efeitos adversos , Revascularização Cerebral/métodos , Artéria Cerebral Anterior/cirurgia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Isquemia Encefálica/genética , Doenças Arteriais Cerebrais/diagnóstico por imagem , Criança , Orelha/irrigação sanguínea , Estudos de Viabilidade , Feminino , Humanos , Mutação , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/genética , Artérias Temporais/cirurgiaRESUMO
Spontaneous cervico-cerebral artery dissection (CCAD) is a common condition found among young patients with ischemic stroke. We examined the possible association between the polymorphism of methylenetetrahydrofolate reductase (MTHFR)-C677T and the gene mutation in transforming growth factor beta receptor II (TGFBR2) in a cohort of CCAD patients. One-hundred CCAD cases (65 males; mean age: 38.08 ± 10.68 years) and 100 matching controls were included. Ancestry informative markers (AIMs) were used to increase internal validity of the genetic analysis. Genotypes of the C677T polymorphism in the MTHFR gene were determined by polymerase chain reaction and restriction fragment length polymorphism; direct sequencing was used for a mutation analysis of the TGFBR2 gene. Associations were evaluated using a multivariate statistics, and Hardy-Weinberg equilibrium was analyzed. We also incorporated our data into a meta-analysis of the MTHFR-C677T. Sixty-three patients presented with vertebral and 37 with carotid artery dissection. Ancestry markers found a call rate on each over 95 %. All AIMs did not deviate from Hardy-Weinberg equilibrium (p > 0.05). The homozygous TT genotype was more frequent in cases (OR 2.04, CI 95 % 1.53-2.72, p = 0.005), whereas no significant difference was found on heterozygous CT genotype. TGFBR2 mutation was not present in our samples. In the meta-analysis of MTHFR/C677T variant, a total 613 cases and 1547 controls were analyzed; we found a moderate association for the recessive model genotype (OR 2.04, CI 95 % 1.53-2.72; p = 0.342; Z = 4.83; I (2) = 11.3). This study supports a positive association between the MTHFR-C677T polymorphism and genetically confirmed Mexican mestizo CCAD patients.
Assuntos
Dissecção Aórtica/genética , Doenças Arteriais Cerebrais/genética , Indígenas Norte-Americanos/genética , Aneurisma Intracraniano/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Dissecção Aórtica/etnologia , Doenças Arteriais Cerebrais/etnologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Aneurisma Intracraniano/etnologia , Masculino , México , Mutação , Polimorfismo de Nucleotídeo Único , Receptor do Fator de Crescimento Transformador beta Tipo IIRESUMO
The influence of toll-like receptor 4 on neurogenesis and inflammation has been scarcely explored so far by using neuroimaging techniques. For this purpose, we performed magnetic resonance imaging and positron emission tomography with 3'-deoxy-3'-[(18)F]fluorothymidine and [(11)C]PK11195 at 2, 7, and 14 days following cerebral ischemia in TLR4(+/+)and TLR4(-/-)mice. MRI showed similar infarction volumes in both groups. Despite this, positron emission tomography with 3'-deoxy-3'-[(18)F]fluorothymidine and [(11)C]PK11195 evidenced an increase of neurogenesis and a decrease of inflammation in TLR4(-/-)mice after ischemia. These results evidence the versatility of neuroimaging techniques to monitor the role of toll-like receptor 4 after cerebral ischemia.
Assuntos
Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/genética , Proliferação de Células , Inflamação/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Doenças Arteriais Cerebrais/genética , Doenças Arteriais Cerebrais/patologia , Infarto Cerebral/genética , Infarto Cerebral/patologia , Didesoxinucleosídeos , Inflamação/genética , Inflamação/patologia , Isoquinolinas , Ventrículos Laterais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptor 4 Toll-Like/genéticaRESUMO
ACTA2 mutations have recently been shown to cause a multisystem smooth muscle dysfunction syndrome that may result in pediatric stroke. We report a case of ACTA2 mutation in a 3-year-old girl presenting with acute ischemic stroke and provide high resolution imaging of the cerebral arteries demonstrating novel findings of multiple tiny aneurysms (particularly in the posterior circulation), as well as the more characteristic imaging phenotype of straightened and narrowed proximal intracranial vessels, dilated cervical vessels and occlusion of the M1 MCA segment without lenticulostriate collateral formation. This newly identified disease should be added to the differential diagnosis of pediatric stroke and cerebral vasculopathy. Neuroradiologists, interventionalists, surgeons and neurologists should become familiar with this rare disease and its clinical sequelae.
Assuntos
Actinas/genética , Isquemia Encefálica/genética , Doenças Arteriais Cerebrais/genética , Mutação/genética , Acidente Vascular Cerebral/genética , Substituição de Aminoácidos/genética , Doenças Arteriais Cerebrais/patologia , Pré-Escolar , Feminino , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/genética , Imageamento por Ressonância Magnética , NeuroimagemRESUMO
BACKGROUND AND PURPOSE: The c.14576G>A variant in ring finger protein 213 (RNF213) was recently identified as a susceptibility gene variant for moyamoya disease (MMD). The occurrence of c.14576G>A variant was evaluated in patients with intracranial major artery stenosis/occlusion (ICASO) without signs of MMD (non-MMD ICASO), as well as in patients with MMD and other cerebrovascular diseases as controls. METHODS: This single-hospital-based case-control study was completed in 7 months (from October 2011-April 2012) at Department of Neurosurgery, The University of Tokyo Hospital. The occurrence of c.14576G>A variant was analyzed in 41 patients with non-MMD ICASO, in 48 with MMD, in 21 with cervical disease, in 61 with cerebral aneurysm, and in 25 normal subjects. RESULTS: Nine of 41 patients (21.9%) with non-MMD ICASO and 41 of 48 (85.4%) with MMD had the c.14576G>A variant. One of 61 patients (1.6%) with cerebral aneurysm and no patients with cervical disease or normal subjects had the variant. Comparison of each phenotype group with the normal subjects showed that presence of c.14576G>A variant had significant associations with MMD (odds ratio [OR], 292.8; 95% confidence interval [CI], 15.4-5153.0; P<0.0001) and with non-MMD ICASO (OR, 14.9; 95% CI, 0.82-268.4; P=0.01), but no association with either cerebral aneurysm (OR, 1.2; 95% CI, 0.04-32.0; P=1.00) or cervical disease (OR, 1.1; 95% CI, 0.02-62.3; P=1.00). CONCLUSIONS: The present study indicates that a particular subset of Japanese patients with non-MMD ICASO has a genetic variant associated with MMD. Therefore, we propose the existence of a new entity of ICASO caused by the c.14576G>A variant in RNF213.