PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations

TREX1 p.A129fs and p.Y305C variants in a large multi-ethnic cohort of CADASIL-like unrelated patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.</p

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies

Portuguese Consensus on the Diagnosis and Management of Lewy Body Dementia (PORTUCALE)

Lewy body dementia is a common cause of dementia leading to the progressive deterioration of cognitive function and motor skills, behavioral changes, and loss of autonomy, impairing the quality of life of patients and their families. Even though it is the second leading cause of neurodegenerative dementia, diagnosis is still challenging, due to its heterogenous clinical presentation, especially in the early stages of the disease. Accordingly, Lewy body dementia is often misdiagnosed and clinically mismanaged. The lack of diagnostic accuracy has important implications for patients, given their increased susceptibility to the adverse effects of certain drugs, such as antipsychotics, which may worsen some symptoms associated with Lewy body dementia. Therefore, a specialist consensus based on the analysis of the most updated and relevant literature, and on clinical experience, is useful to all professionals involved in the care of these patients. This work aims to inform and provide recommendations about the best diagnostic and therapeutic approaches in Lewy body dementia in Portugal. Moreover, we suggest some strategies in order to raise the awareness of physicians, policy makers, and the society at large regarding this disease.A demência com corpos de Lewy é uma causa comum de demência, provocando a perda progressiva de funções cognitivas e capacidades motoras, alterações comportamentais, e perda de autonomia, com compromisso da qualidade de vida dos doentes e seus familiares. Apesar de ser a segunda causa mais frequente de demência neurodegenerativa, o diagnóstico mantém-se um desafio, devido à sua apresentação clínica heterogénea, sobretudo nas fases iniciais da doença. Por conseguinte, a demência com corpos de Lewy é frequentemente mal diagnosticada e clinicamente gerida de forma insuficiente. A falta de acuidade diagnóstica tem implicações significativas para os doentes, dada a maior suscetibilidade aos efeitos adversos de determinados fármacos, tais como os antipsicóticos, que podem agravar alguns sintomas associados à demência com corpos de Lewy. Por conseguinte, um consenso de especialistas, baseado na análise da literatura mais atual e relevante, e na experiência clínica, é útil para todos os profissionais envolvidos no cuidado destes doentes. O objetivo deste trabalho é informar e gerar recomendações acerca das melhores abordagens diagnóstica e terapêutica da demência com corpos de Lewy em Portugal. Além disso, sugerimos estratégias para aumentar a sensibilização dos médicos, dos decisores políticos e da sociedade em geral em relação a esta doença.Este trabalho foi parcialmente financiado pela GE Healthcare Espanha para apoio à logística da realização da reunião de consenso e para apoio de medical writing no âmbito da preparação deste artigo. A GE Healthcare Espanha não teve qualquer papel no desenho do consenso, recolha, análise e interpretação de literatura, redação do manuscrito, nem na decisão de submeter o artigo para publicação. As opiniões expressas no artigo são da responsabilidade dos autores e não são necessariamente as da GE Healthcare Espanha.info:eu-repo/semantics/publishedVersio

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies