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BACKGROUND AND OBJECTIVES: Cerebrospinal fluid (CSF) collections extending longitudinally at the anterior aspect of the spinal dura have been reported in association with various conditions and under multiple names. The aim of this study was to report cases associated with brachial amyotrophy (BA) and examine its relationship with other clinical variants. METHODS: We conducted a retrospective cohort study including patients who presented with a motor deficit of the upper limbs and an anterior interdural CSF collection on spinal MRI. We performed a systematic review of the literature to include cases revealed by BA. RESULTS: Seven patients presenting with BA and a confirmed dural dissection on spinal MRI were included. All patients were male with a slowly progressing history of asymmetrical and proximal motor deficit of the upper limbs. Chronic denervation affecting mostly C5 and C6 roots was found on electroneuromyography. Spinal MRI demonstrated an anterior CSF collection dissecting the interdural space and exerting a traction on cervical motor roots. Dynamic computed tomography myelogram localized the dural defect every time it was performed (4/7 cases), and surgical closure was possible for 3 patients, leading to resolution of the collection. Literature review yielded 18 other published cases of spinal dural dissections revealed by BA, including 4 in association with spontaneous intracranial hypotension and 4 others in association with superficial siderosis. CONCLUSION: We propose a unifying diagnosis termed "spinal anterior dural dissection" (SADD) to encompass spinal dural CSF collections revealed by BA (SADD-BA), spontaneous intracranial hypotension (SADD-SIH), or superficial siderosis (SADD-SS).
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INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is a cause of early onset ischemic lacunar stroke. COVID-19 infection may lead, in addition to acute respiratory syndrome, to vascular complications including stroke. Herein, we report three CADASIL patients presenting with cerebral border-zone infarcts concomitant to COVID-19 infection and summarize similar cases previously published in literature. METHODS: Clinical and radiological features of the 3 patients were collected and described. A narrative review of literature was performed in PubMed and Google Scholar by the end of 2022 using the "CADASIL" AND "COVID-19" AND "stroke" terms. RESULTS: In our 3 patients, aged 40-58 years, stroke symptoms occurred one to 11 days after the first COVID-19 manifestations. Pulmonary symptoms were mild or absent. One patient presented with hemodynamic failure presumably related to acute cardiomyopathy. Brain magnetic resonance imaging revealed in all cases, ischemic lesions within border-zone areas in both cerebral hemispheres, lesions in the genu of the corpus callosum or in the medium cerebellar peduncles in two cases. The watershed pattern of ischemic lesions was detected in two cases despite any blood pressure drop or severe respiratory dysfunction. Seven CADASIL patients presenting with acute brain infarcts (multiple in 4/7) in context of SARS-CoV-2 infection were identified in literature, despite no fall in blood pressure except for one of them. CONCLUSION: Our observations, in line with previous reports, further suggest that COVID-19 infection may alter blood flow autoregulation in the deepest cerebral white matter in CADASIL patients. The thrombocytopathy and endotheliopathy developing during COVID-19 infection may participate to the underlying vascular processes.
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CADASIL , COVID-19 , Acidente Vascular Cerebral , Humanos , CADASIL/diagnóstico , CADASIL/diagnóstico por imagem , COVID-19/complicações , SARS-CoV-2 , Imageamento por Ressonância Magnética , Infarto Cerebral , Acidente Vascular Cerebral/complicaçõesRESUMO
Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.
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Anoctamina-1 , Doença de Moyamoya , Criança , Humanos , Adulto Jovem , Anoctamina-1/genética , Canais de Cloreto/genética , Doença de Moyamoya/genética , Proteínas de Neoplasias/genéticaRESUMO
BACKGROUND: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. METHODS: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. RESULTS: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. CONCLUSIONS: We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.
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Doença de Moyamoya , Óxido Nítrico Sintase Tipo III , Óxido Nítrico , Guanilil Ciclase Solúvel , Adulto , Humanos , Doença de Moyamoya/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Transdução de Sinais/genética , Guanilil Ciclase Solúvel/genéticaRESUMO
The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major effect on the phenotype of the disease. The exact impact of such mutations locations on the multiple facets of the disease has not been fully evaluated. We aimed to describe the phenotypic spectrum of a large population of CADASIL patients and to investigate how this mutation location influenced various clinical and imaging features of the disease. Both a supervised and a non-supervised approach were used for analysis. The results confirmed that the mutation location is strongly related to clinical severity and showed that this effect is mainly driven by a different development of the most damaging ischemic tissue lesions at cerebral level. These effects were detected in addition to those of aging, male sex, hypertension and hypercholesterolemia. The exact mechanisms relating the location of mutations along the NOTCH3 receptor, the amount or properties of the resulting NOTCH3 products accumulating in the vessel wall, and their final consequences at cerebral level remain to be determined.
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CADASIL , Receptor Notch3 , Humanos , Masculino , Mutação , Receptor Notch3/genética , Fatores de Risco , CADASIL/genéticaRESUMO
COL4A1 and COL4A2 genes encode the alpha1 and the alpha2 chains of type IV collagen, a key component of basement membranes. Mutations located in the coding sequence of COL4A1/COL4A2 genes are responsible for an autosomal dominant (AD) cerebral angiopathy that manifest in either adults, children or fetuses. The most typical among such mutations are missense glycine mutations in the triple helix. They increase the susceptibility to brain hemorrhage but can also promote the occurrence of multiple other types of systemic manifestations that can involve the eyes, kidneys or muscles. This condition is characterized by a very incomplete penetrance, and a wide phenotypic variability even among members of the same family. Recently, mutations in the COL4A1 3'UTR non-coding region that upregulate COL4A1 expression, and COL4A1/COL4A2 duplications, have been shown to cause AD forms of ischemic cerebral small vessel disease in adults. Herein, we summarize the genetic and pathophysiological aspects of these conditions, detail their clinical and imaging characteristics and discuss some principles in their clinical management.
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BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most devastating cerebral small vessel diseases. However, despite its progression with aging, some patients remain neurologically intact (Nint) even when they get older. Their main characteristics are poorly known. We aimed to delineate their clinical, imaging, and molecular features. METHODS: Individuals aged over 65 years were selected from a cohort of 472 CADASIL patients. Subjects who had no focal deficit, cognitive impairment, or disability were considered Nint. Their demographic, genetic, clinical, and imaging features were compared to those with permanent neurological symptoms (Nps). RESULTS: Among 129 patients, 23 (17.8%) individuals were considered Nint. The frequency of vascular risk factors and NOTCH3 cysteine mutations in epidermal growth factor-like repeat (EGFr) domains 7-34 did not differ between Nint and Nps patients but Nint patients had less stroke events and were more likely to have migraine with aura. The number of lacunes and microbleeds and degree of brain atrophy were lower in the Nint group, but the volume of white matter hyperintensities did not differ between the two groups. CONCLUSIONS: Nearly one in five CADASIL patients can remain Nint after the age of 65 years. Their clinical and imaging profile differed from that of other age-matched CADASIL patients. The location of NOTCH3 mutation inside or outside EGFr domains 1-6 cannot fully explain this discrepancy. The factors involved in their relative preservation of brain tissue from severe damage despite aging remain to be determined.
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BACKGROUND: Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4 gene. The natural history of MS remains incompletely understood. METHODS: We recruited in a longitudinal retrospective study patients with molecular confirmed MS from the French reference center for rare skeletal dysplasia. We described natural history by chaining data from medical reports, clinical data warehouse, medical imaging and photographies. RESULTS: We included 12 patients. The median age was 22 years old (y/o). Intrauterine and postnatal growth retardation were consistently reported. In preschool age, neurodevelopment disorders were reported in 80% of children. Specifics facial and skeletal features, thickened skin and joint limitation occured mainly in school age children. The adolescence was marked by the occurrence of pulmonary arterial hypertension (PAH) and vascular stenosis. We reported for the first time recurrent strokes from the age of 26 y/o, caused by a moyamoya syndrome in one patient. Two patients died at late adolescence and in their 20 s respectively from PAH crises and mesenteric ischemia. CONCLUSION: Myhre syndrome is a progressive disease with severe multisystemic impairement and life-threathning complication requiring multidisciplinary monitoring.
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Deformidades Congênitas da Mão , Deficiência Intelectual , Adolescente , Adulto , Criança , Pré-Escolar , Criptorquidismo , Fácies , Transtornos do Crescimento/genética , Humanos , Deficiência Intelectual/genética , Masculino , Estudos Retrospectivos , Proteína Smad4 , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: The course and pattern of cognitive decline in ischemic cerebral small vessel disease (cSVD) remains poorly characterized. We analysed the trajectory pattern of cognitive decline from age 25 to 75 years in CADASIL. METHODS: We applied latent process mixed models to data obtained from CADASIL patients who were repeatedly scored during follow-up using 16 selected clinical scales or cognitive tests. RESULTS: The modelled evolutions of these scores obtained from 1243 observations in 265 patients recruited at the French National Referral Centre (50.1 years on average and 45.3% males) showed wide and heterogeneous variations in amplitude along the age-related progression of the disease. While the Backward Digit Span remained essentially stable, a linear deterioration of scores obtained using the Symbol Digit Numbers or Number of Errors of Trail Making Test B was detected from 25 to 75 years. In contrast, the largest score changes were observed at midlife using the Digit Cancellation Task. All other tests related to executive functions, memory performances, or global cognitive efficiency showed a rate of change accelerating especially at the advanced stage of the disease. Male gender, the presence of gait disorders or of some disability at baseline were found to predict earlier or large changes of 4 scores (Index of Sensitivity to Cueing, Delayed Total Recall, Initiation/Perseveration and Barthel Index) in a subgroup of individuals distinct form the rest of the sample. DISCUSSION: Cognitive alterations develop heterogeneously during the progression of CADASIL and vary largely according to the stage of the disease. These results suggest that not only the target population, study duration but also the stage of disease progression should be considered in preparing future clinical trials aimed at reducing cognitive decline in any such condition.
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BACKGROUND: There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). OBJECTIVE: To describe the CSF levels of Aß42, Aß40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. METHODS: We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman's correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. RESULTS: We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aß42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aß42 level and 14.3% patients with normal Aß42 level. Compared to AD, CAA showed lower levels of Tau (pâ=â0.008), p-Tau (pâ=â0.004), and Aß40 (pâ=â0.001) but similar Aß42 level (pâ=â0.07). No correlation between Aß42 or Aß40 levels and neuroimaging was found. CONCLUSION: CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aß40 appears as an interesting selective biomarker in differential diagnosis.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Angiopatia Amiloide Cerebral/complicações , Humanos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos Retrospectivos , Proteínas tau/líquido cefalorraquidianoRESUMO
Cerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic conditions. Since the characterization in the late 1990s of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, several other monogenic conditions leading to adult-onset ischemic or hemorrhagic stroke have been described. In this practical guide, we summarize the key features that should elicit the differential diagnosis of a hereditary cerebral small vessel diseases in adult stroke patients, describe the main clinical and imaging characteristics of the major hereditary cerebral small vessel diseases that can manifest as stroke, and provide general recommendations for the clinical management of affected patients and their relatives.
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Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Acidente Vascular Cerebral/etiologia , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , HumanosRESUMO
BACKGROUND: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients. OBJECTIVE: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya. METHODS: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs. RESULTS: Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced. CONCLUSION: The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
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Proteínas de Ligação a DNA/genética , Dosagem de Genes/genética , Predisposição Genética para Doença , Doença de Moyamoya/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Feminino , Duplicação Gênica/genética , Genoma Humano/genética , Humanos , Lactente , Masculino , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/patologia , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do ExomaRESUMO
PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. METHODS: Exome sequencing from 39 trios were analyzed. RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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Transtornos Cerebrovasculares/genética , Doença de Moyamoya/genética , Adulto , Proteínas de Ciclo Celular/genética , Transtornos Cerebrovasculares/metabolismo , Criança , Pré-Escolar , DNA Helicases/genética , Deficiências do Desenvolvimento/genética , Exoma/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Deficiência Intelectual/genética , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Pessoa de Meia-Idade , Mutação/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sequenciamento do Exoma/métodosRESUMO
Cerebral amyloid angiopathy related inflammation (CAA-RI) is a rare form of CAA characterized by subacute encephalitic symptoms (cognitive decline, seizures, focal deficits) associated with extensive and confluent white matter lesions co-localizing with lobar microbleeds on brain MRI. We report two cases of unusual CAA-RI mimicking meningoencephalitis but without typical brain lesions on FLAIR and T2* sequences. These 2 cases may extend the clinical spectrum of CAA-RI by suggesting the possible occurrence of quite purely meningeal forms of CAA-RI.
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Moyamoya angiopathy is a rare vasculopathy with stenosis and/or occlusion of bilateral intracranial parts of internal carotid arteries and/or proximal parts of middle and anterior cerebral arteries. PHACE syndrome is characterized by large segmental hemangiomas in the cervical-facial region. Both conditions are known to be associated in rare cases. Recently, it was discussed in the literature that RNF213 variants could be etiologically involved in this association. Here, we describe a childhood case with this rare co-occurrence in which we did not identify any rare RNF213 variant. The clinical and genetic backgrounds are discussed.
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Adenosina Trifosfatases/genética , Coartação Aórtica/complicações , Anormalidades do Olho/complicações , Doença de Moyamoya/complicações , Síndromes Neurocutâneas/complicações , Ubiquitina-Proteína Ligases/genética , Adulto , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/genética , Encéfalo/diagnóstico por imagem , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/genética , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genéticaRESUMO
Genetic association studies have provided new insights into the genetic variability of human complex traits with a focus mainly on continuous or binary traits. Methods have been proposed to take into account disease heterogeneity between subgroups of patients when studying common variants but none was specifically designed for rare variants. Because rare variants are expected to have stronger effects and to be more heterogeneously distributed among cases than common ones, subgroup analyses might be particularly attractive in this context. To address this issue, we propose an extension of burden tests by using a multinomial regression model, which enables association tests between rare variants and multicategory phenotypes. We evaluated the type I error and the power of two burden tests, CAST and WSS, by simulating data under different scenarios. In the case of genetic heterogeneity between case subgroups, we showed an advantage of multinomial regression over logistic regression, which considers all the cases against the controls. We replicated these results on real data from Moyamoya disease where the burden tests performed better when cases were stratified according to age-of-onset. We implemented the functions for association tests in the R package "Ravages" available on Github.
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Transtornos Cerebrovasculares/genética , Simulação por Computador/normas , Estudos de Associação Genética , Variação Genética , Modelos Genéticos , Doença de Moyamoya/genética , Herança Multifatorial/genética , Idade de Início , Estudos de Casos e Controles , Interpretação Estatística de Dados , Humanos , Modelos Logísticos , Fenótipo , Prognóstico , Índice de Gravidade de DoençaRESUMO
Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.
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Adenosina Trifosfatases/genética , Predisposição Genética para Doença , Doença de Moyamoya/diagnóstico , Mutação , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Criança , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/genética , Linhagem , Fosfoproteínas Fosfatases/genética , Sequenciamento do Exoma , Adulto JovemRESUMO
Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
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Adenosina Trifosfatases/genética , Doença de Moyamoya/genética , Mutação de Sentido Incorreto , Ubiquitina-Proteína Ligases/genética , Adenosina Trifosfatases/química , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Exoma , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/etnologia , Domínios RING Finger/genética , Ubiquitina-Proteína Ligases/química , População Branca/genéticaRESUMO
BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.
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Mutação em Linhagem Germinativa , Doença de Moyamoya/enzimologia , Doença de Moyamoya/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/patologia , Sequenciamento do ExomaRESUMO
PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).