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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.

Résumé: Les maladies des petits artères cérébrales (MPAC) sont une cause fréquente d'accidents vasculaires cérébraux (AVC), qu'ils soient ischémiques ou hémorragiques. Une petite proportion des MPAC résulte de pathologies monogéniques. Bien qu'elles soient rares, l'identification de ces formes monogéniques est cruciale, permettant d'offrir une prise en charge adaptée à ces patients et à leurs apparentés. Dans cette revue, les principales situations devant conduire le clinicien à évoquer une forme monogénique de MPAC sont listées, et les principales caractéristiques des différentes MPAC connues à ce jour sont résumées. Cerebral small vessel diseases (cSVD) represent a common cause of stroke, either ischemic or hemorrhagic. Only a small proportion of cSVD results from monogenic conditions. Although they are involved in a minority of patient, the accurate identification by physicians of hereditary forms of cSVD is crucial for the medical care of these patients and their relatives. In this paper, the main situations that must lead physicians to suspect a hereditary cSVD are listed, and the key characteristics of the monogenic cSVD known to date are summarized. [ABSTRACT FROM AUTHOR]

Résumé: Nous rapportons le cas d'une patiente présentant un accident vasculaire cérébral (AVC) ischémique, secondaire à un thrombus de la carotide interne, sur plaque d'athérome. La taille du thrombus et son association à une embolie pulmonaire sont inhabituels et le seul facteur favorisant potentiel identifié est le contexte de Covid-19, sans signe de gravité de l'infection. La survenue de volumineuses thromboses artérielles au cours de la maladie liée au coronavirus est largement rapportée depuis le début de l'épidémie. Ce phénomène, responsable notamment d'AVC ischémiques sévères, ne survient pas nécessairement chez des patients présentant une forme grave de l'infection, mais semble associé à un moins bon pronostic fonctionnel. We report a case of ischemic stroke characterized by unusual large thrombosis of the internal carotid, origin associated to pulmonary embolism in a patient without any prothrombotic factor except from mild signs of Covid-19. The high incidence of thrombotic phenomens observed among patients with coronavirus during the last months does not seem to systematically occur among patients with severe presentation of the infection, but seems associated to a worst functional prognosis. [ABSTRACT FROM AUTHOR]

Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being "idiopathic" according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/ MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Intravascular lymphoma is a rare subtype of B‐cell lymphoma characterized by a clonal proliferation restricted to the lumen of small vessels. Over 50% of patients exhibit central nervous system (CNS) involvement, but diagnosis is often delayed due to the lack of distinctive features. We aimed to identify key phenotypic features for early diagnosis of intravascular lymphoma with CNS involvement through an in‐depth cohort study.We built up a multicenter retrospective cohort of 17 patients recruited in collaboration with the French Expert Network for Oculo‐Cerebral Lymphomas (LOC network), and retrospectively analyzed data from medical records.In this cohort, 15 of 17 (88%) patients developed focal neurological episodes, often fluctuating and/or recurrent, with a sudden onset in 68% of episodes, suggesting a vascular origin. Rapid cognitive deterioration occurred in 15 of 17 (88%) patients, psychiatric manifestations in 8 of 17 (47%), and “B signs” in 14 of 17 (82%). Brain MRI showed polymorphic FLAIR hyperintensities in 14 of 16 (87%) patients, and DWI‐positive lesions in 13 of 16 (81%) of patients, which accumulated over time and had unusual characteristics for ischemic lesions (progressive growth, persistent DWI‐hyperintensity over 1 month, surrounded by a wider FLAIR hyperintensity). Early‐onset inflammatory syndrome, and elevated lactate dehydrogenase (LDH) levels were observed in over 90% of cases. Mild and inconsistent meningitis contrasted with a nearly‐constant hyperproteinorachia. An increased interleukin 10/6 ratio over 0,7 was found in 4 of 7 (57%) patients, and skin biopsy led to a pathological diagnosis in 3 of 6 (50%) patients.The results of this study highlight “red flags” that could help accelerate the diagnosis of intravascular lymphoma involving the CNS. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Importance: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking., Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum., Design, Setting, and Participants: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024., Main Outcomes and Measures: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level., Results: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival., Conclusions and Relevance: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Cerebral small vessel disease (cSVDs) account for 25% of stroke and are a frequent cause of cognitive or motor disability in adults. In a small number of patients, cSVDs result from monogenic diseases, the most frequent being cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An early disease onset, a suggestive family history, and a low vascular risk profile contrasting with a high load of cSVD imaging markers represent red flags that must trigger molecular screening. To date, a dozen of genes is involved in Mendelian cSVDs, most of them are responsible for autosomal dominant conditions of variable penetrance. Some of these mendelian cSVDs (CADASIL, HTRA1-related cSVD, pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), cathepsin-A related arteriopathy with strokes and leukoencephalopathy (CARASAL), and cSVD related to LAMB1 mutations) are causing ischemic stroke. Others (COL4A1/COL4A2-related angiopathy and hereditary cerebral amyloid angiopathy) preferentially lead to intracerebral hemorrhages. The clinical features of different Mendelian cSVDs can overlap. Therefore, the current approach is based on simultaneous screening of all genes involved in these conditions through a panel-targeted sequencing gene or exome sequencing. Nevertheless, a pathogenic variant is identified in less than 15% of patients with a suspected genetic cerebrovascular disease, suggesting that many additional genes remain to be identified., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Children with untreated biotinidase deficiency can experience variable symptoms depending on their age of presentation. Older children and adolescents can exhibit predominant neurological deficits including para- or tetraparesis and vision loss., Methods: We report the first case of delayed-onset biotinidase deficiency in a young adult., Results: A 22-year-old man presented with a disabling extensive myelopathy and bilateral optic neuropathy which mimicked the findings of a (seronegative) neuromyelitis optica. Imaging investigations were characterized by an MRI T2 hyper-intensity involving the spinal cord, the optic nerves, the fornix and the mammillar bodies, together with an increased (18)F-FDG uptake on positron emission tomography. He was ultimately shown to have profound biotinidase deficiency due to a novel missense mutation and was partly improved by oral biotin therapy., Conclusion: This individual exemplifies the need to include biotinidase deficiency in the differential diagnosis of patients with extensive myelopathy and/or bilateral optic neuropathy and argues for newborn screening for the disorder., (© The Author(s), 2015.)