Small Vessel Disease Phenotype Associated With Monoallelic Loss-of-Function Variants.

Background And Objectives: Monoallelic cysteine-altering () variants cause the adult-onset small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and biallelic loss-of-function () variants cause a rare, childhood-onset small vessel disease. Whether monoallelic variants also cause a small vessel disease is subject of debate. The aim of this study was to delineate the small vessel disease phenotype of individuals with a monoallelic variant and to compare it with CADASIL.

Association Between Vascular NOTCH3 Aggregation and Disease Severity in a CADASIL Cohort - Implications for NOTCH3 Variant-Specific Disease Prediction.

Objective: Vascular NOTCH3 protein ectodomain aggregation is a pathological hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease typically caused by cysteine-altering variants in NOTCH3. Given their high population frequency, these NOTCH3 variants are an important genetic contributor to stroke and vascular dementia worldwide. Disease severity in CADASIL is highly variable and is mainly determined by the position of the pathogenic NOTCH3 variant in the NOTCH3 ectodomain.

Topographic Localization of Chronic Cerebellar Ischemic Lesions: Implications for Underlying Cause.

Background: Chronic cerebellar lesions of presumed ischemic origin are frequently found in patients with ischemic stroke and as incidental findings. However, the differentiation of embolic lesions from lesions caused by cerebral small vessel disease (SVD) is unclear. We aimed to investigate whether the location of chronic cerebellar ischemic lesions (deep versus cortical) indicates the underlying cause (embolic versus SVD).

Association of Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

Background And Objectives: Pathogenic variants in are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Effect of EGFr Group, Sex, and Cardiovascular Risk Factors on CADASIL Clinical and Neuroimaging Outcomes.

Background: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of EGFr group. In this study, we determined the relative disease-modifying effects of EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Family Members With a Pathogenic Variant Can Have a Normal Brain Magnetic Resonance Imaging and Skin Biopsy Beyond Age 50 Years.

Background: To determine whether extremely mild small vessel disease (SVD) phenotypes can occur in variant carriers from Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) pedigrees using clinical, genetic, neuroimaging, and skin biopsy findings.

Methods: Individuals from CADASIL pedigrees fulfilling criteria for extremely mild -associated SVD (mSVD) were selected from the cross-sectional Dutch CADASIL cohort (n=200), enrolled between 2017 and 2020. Brain magnetic resonance imaging were quantitatively assessed for SVD imaging markers.

NOTCH3 variant position is associated with NOTCH3 aggregation load in CADASIL vasculature.

Aims: CADASIL, the most prevalent hereditary cerebral small vessel disease, is caused by cysteine-altering NOTCH3 variants (NOTCH3 ) leading to vascular NOTCH3 protein aggregation. It has recently been shown that variants located in one of NOTCH3 protein epidermal growth-factor like repeat (EGFr) domains 1-6, are associated with a more severe phenotype than variants located in one of the EGFr domains 7-34. The underlying mechanism for this genotype-phenotype correlation is unknown.

Broad phenotype of cysteine-altering variants in UK Biobank: CADASIL to nonpenetrance.

Objective: To determine the small vessel disease spectrum associated with cysteine-altering variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.

Methods: The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes.