Border-Zone Cerebral Infarcts Associated with COVID-19 in CADASIL: A Report of 3 Cases and Literature Review

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

Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease

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

Molecular bases and pathophysiological mechanisms of moyamoya angiopathy

L’angiopathie moyamoya (MMA) est une affection cérébro-vasculaire rare dont la physiopathologie est mal connue. Elle est caractérisée par l’association d’une sténose des terminaisons des carotides internes et d’un réseau de néovaisseaux à la base du crâne. Il en existe une forme pure (MoyaMoya Disease ou MMD) et une forme syndromique (MoyaMoya Syndrome ou MMS). Dix pourcents des cas de MMA sont familiaux. En Asie, une très forte association a été démontrée entre MMD et un variant de susceptibilité unique dans le gène RNF213, variant totalement absent chez les Caucasiens. Par ailleurs, une douzaine de gènes impliqués dans des formes mendéliennes de MMS ont été identifiés à ce jour mais ne concernent qu’un très faible nombre de patients. La pénétrance de la MMA dans ces formes est le plus souvent très faible et aucun modèle animal n’a de ce fait pu être établi. L’identification d’autres gènes impliqués dans la MMA pourrait permettre, au-delà des applications cliniques immédiates, de mieux caractériser les pathways impliqués et d’aider ainsi à la compréhension des mécanismes physiopathologiques. L’objectif de cette thèse était de poursuivre le démantèlement moléculaire de cette affection par l’analyse moléculaire d’une cohorte multiethnique de 126 index MMA (80% MMD/ 20% MMS) et 66 de leurs apparentés pour lesquels nous disposions de données phénotypiques détaillées et d’un séquençage exome entier (WES, Whole Exome Sequencing). Treize de ces index appartenaient à des familles multiplex et 113 étaient des formes sporadiques (dont 15 trios et 6 index issus d’unions consanguines). Nous avons tout d’abord réalisé une analyse d’association de type « burden-test » visant à comparer la charge en variants rares de RNF213 entre 73 index MMA caucasiens et une cohorte de573 contrôles de même origine ethnique. Nous avons démontré l’existence d’une association significative entre variants rares non-synonymes de RNF213 et MMA chez les Caucasiens, association encore plus marquée lorsque l’analyse était restreinte aux cas familiaux et/ou de début précoce. Les variants identifiés chez les patients se regroupaient dans un hotspot C-terminal englobant le domaine RING-finger.D’autre part, nous avons conduit une « analyse individuelle ou familiale » des données de WES des familles multiplex, trios, index consanguins et index sporadiques de début précoce. Les gènes candidats identifiés ont ensuite été criblés dans l’ensemble de la cohorte de 126 index à la recherche d’une récurrence génétique. L’analyse des trios a mis en évidence l’implication de variants rares de novo du gène CBL (un gène majeur de la voie RAS-MAPK connu à la fois pour son implication dans un syndrome Noonan-like et dans une forme particulière de leucémie de l’enfant) dans des formes mendéliennes de MMA de début pédiatrique ne présentant ni phénotype Noonan-like, ni leucémie. L’analyse des index consanguins a permis d’identifier une nouvelle forme mendélienne de MMA liée à des mutations récessives perte de fonction dans le gène NOS3 codant pour la Nitric oxide(NO) synthase endothéliale, pointant le rôle de la voie du NO dans la physiopathologie de la MMA.Ce travail souligne l’architecture complexe de la MMA, avec l’intervention d’une part de variants de susceptibilité et d’autre part de variants mendéliens impliqués dans une très petite proportion de patients. L’analyse en cours des données cette cohorte par une approche de tests de charge exome-wide, devrait permettre d’identifier de nouveaux gènes de susceptibilité. Enfin l’analyse de modèles murins KO pour NOS3 pourrait aider à l’obtention d’un premier modèle murin de MMA.Moyamoya angiopathy (MMA) is a rare condition characterized by a stenosis of the terminal part of the internal carotid arteries and a deep network of neovessels. Pathophysiology of MMA is unknown. Moyamoya disease (MMD) refers to the isolated MMA; when MMA is associated to other systemic manifestations, the term of moyamoya syndrome (MMS) is used. 10% of MMA are familialcases. In Asia, a strong association has been shown between MMD and a unique susceptibility variantin RNF213, variant totally absent in Caucasians. On the other hand, twelve genes are known to be involved in various Mendelian MMS, but are involved in a minority of patients and the penetrance of their mutations is in most cases very low. Beyond the immediate clinical applications, the identification of new MMA genes could allow a better characterization of MMA pathways and thus improve our understanding of MMA pathophysiology. In this thesis, we aimed to pursue the molecular dismantling of MMA through the analysis of whole exome sequencing (WES) data generated for a multiethnic cohort of 126 well phenotyped probands (80% MMD/ 20% MMS) and 66 of their relatives. 13 out of these 126 probands were familial cases and 113 were sporadic cases (including 15 trios and 6 consanguineous probands). We first performed a RNF213 gene burden-test to compare the burden in RNF213 rare variants between 73 Caucasian MMA probands and 573 French Caucasian controls. This analysis showed a significant association between rare non-synonymous RNF213 variants and MMA in Caucasians, especially in early-onset of familial cases. MMA variants significantly clustered in Cterminal hotspot encompassing the RING-finger domain.On the other hand, we performed an “individual or familial” analysis of WES data from multiplex families, trios, consanguineous probands and early-onset sporadic cases. Candidate genes identified through this strategy were then screened in the whole cohort of 126 MMA probands in order toidentify a genetic recurrence. Trios’ analysis demonstrated the involvement of de novo mutation inCBL gene (a RAS-MAPK pathway gene involved in Noonan-like syndromes and in a rare form of childons et leukemia) in infant-onset MMA in two unrelaled young girls without any overt symptom of Noonan-like syndrome and without hematologic malignancy. Consanguineous probands’ analysis ledto identification of a new Mendelian MMA due to recessive loss-of-function mutations in the NOS3 gene that encodes the endothelial Nitric Oxide (NO) synthase, pointing out the crucial role of the NO pathway in MMA pathophysiology.This thesis highlights the complexity of MMA genetic architecture, with the involvement of both susceptibility genetic variants and variants involved in Mendelian forms of this disease, thelatter being involved in a minority of patients. An ongoing exome wide burden test analysis of this cohort should lead to the identification of additional MMA genes. The analysis of mouse models KO for genes involved in the NO pathway has been started with the hope to get a relevant MMA mouse model

Cerebral Amyloid Angiopathy Related Inflammation With Prominent Meningeal Involvement. A Report of 2 Cases

International audienceCerebral 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

White Matter Hyperintensities progression over 2 years in CADASIL is associated with age, sex, migraine status, initial hyperintensities volume and diastolic blood pressure: a longitudinal study in 214 patients

International audienceWhite Matter Hyperintensities are the 1st markers of CADASIL and progress differently across patients. The exact determinants of their progression during the course of this genetic disease are unknown. We aimed to investigate their main predictors over 2 years in a longitudinal study of 214 patients

Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians

International audienceMoyamoya 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\textless10-3). 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

Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the alpha 1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble alpha 1 beta 1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and non-syndromic moyamoya

Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease.

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 etiology 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 analyzed 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 harboring these gain-of-function ANO1 variants had classic features of MMD, 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