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Last update 23 Jan 2025

Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

Last update 23 Jan 2025

Basic Info

Synonyms

Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL), 伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）, 常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病

Introduction-

Drugs associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

HOV-12020

Target-

Mechanism-

Active Org.-

Originator Org.

Hovid Bhd.

Active Indication-

Inactive Indication

Cadasil [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

DRKS00034054

/ RecruitingNot ApplicableIIT

Genetic Small Vessel Diseases (SVDs) Registry - GenSVDs-Registry

Start Date10 Apr 2024

Sponsor / Collaborator-

JPRN-jRCTs051220072

/ Not yet recruitingNot Applicable

Effect of Lomerizine Hydrochloride on Preventing Recurrence of Cerebral Ischemic Events in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy - LOMCAD

Start Date28 Nov 2022

Sponsor / Collaborator-

NCT05677880

/ RecruitingNot Applicable

Unraveling the Early Phases of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

This is an observational study to better understand the risk factors and progression of CADASIL, a leading cause of vascular cognitive impairment and dementia (VCID). 500 participants will be enrolled and can expect to be on study for up to 5 years.

Start Date03 Jun 2022

Sponsor / Collaborator

University of Wisconsin Madison

[+1]

100 Clinical Results associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

100 Translational Medicine associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

0 Patents (Medical) associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

948

Literatures (Medical) associated with Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

01 Feb 2025·Clinica Chimica Acta

Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort

Article

Author: Sutherland, Heidi G ; Maksemous, Neven ; Haupt, Larisa M ; Dunn, Paul J ; Griffiths, Lyn R ; Smith, Robert A

BACKGROUND AND AIMSCerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3. We hypothesise that other monogenic causes of CSVD may be causing a CADASIL-like CSVD phenotype.METHODSTo test this, we performed whole exome sequencing for 50 individuals suspected of having CADASIL, but did not exhibit a disease-causing mutation in NOTCH3, and applied targeted analysis of all monogenic forms of CSVD.RESULTSThis analysis identified three mutations affecting the Collagen type IV genes in three individuals likely to be causative of CSVD.CONCLUSIONSThis suggests that screening for all monogenic forms of CSVD when one monogenic form is clinically suspected may improve diagnosis in clinically suspected monogenic CSVD. However, despite these findings, the majority of NOTCH3 negative CSVD cases did not have candidate mutations in known CSVD genes, suggesting that additional genetic factors contributing to the disease are yet to be identified.

14 Jan 2025·Neurology

Determining Clinical Disease Progression in Symptomatic Patients With CADASIL

Article

Author: Reyes, Sonia ; Guey, Stéphanie ; Machado, Carla ; Chabriat, Hugues ; Kaisaridi, Sofia ; Tezenas Du Montcel, Sophie ; Jabouley, Aude ; Herve, Dominique ; Fernandes, Fanny ; Taleb, Abbas

BACKGROUND AND OBJECTIVESCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent small artery brain disease caused by pathogenic variants of the NOTCH3 gene. During the disease, we still do not know how the various deficits progress and develop with each other at different stages of the disease. We aim to model disease progression and identify possible progressive subgroups and the effects of different covariates on clinical worsening.METHODSData were obtained from patients followed in the French CADASIL referral center, who were aged 25-80 years and had completed at least 2 visits and one of 14 clinical scores. Progression and variability were assessed using a disease course model (Leaspy). A Gaussian mixture model was used to identify different progression subgroups. Logistic regressions were used to compare the characteristics between groups.RESULTSIn 395 patients along 2,007 visits, the follow-up ranged from 6 months to 19 years, with a mean of 7.5 years. They were 45% men with a mean age of 52.2 years. The evolution curves of the different scores showed that clinical manifestations develop heterogeneously and can vary considerably depending on the disease stage. We identified an early-onset, rapidly progressing subgroup of patients with earlier motor symptoms and focal neurologic deficits (median time shift 59 [Q1-Q3 48.9-66.3], median acceleration rate 0.84 [0.07-1.31]) and a late-onset slowly progressing group with earlier cognitive symptoms (median time shift 69.2 [63.4-75.1], median acceleration rate -0.18 [-0.48 to 0.14]). Male sex, lower education level, hypertension, and NOTCH3 pathogenic variant location within epidermal growth factor-like repeat (EGFr) 1-6 were found to be associated with this group difference.DISCUSSIONOur results suggest a gradual and heterogeneous decline in different clinical and cognitive performances over the lifetime of patients with CADASIL. Two progression profiles-one rapid and early and the other, more delayed and slower-are possible after the onset of symptoms. A major limitation of our study is that the clusters were assessed post hoc, which may induce some bias. Overall, male sex, low level of education, pathogenic variant location in EGFr 1 to 6 domains, smoking, and/or arterial hypertension may affect the clinical progression of the disease.

01 Dec 2024·Molecular Biology Reports

Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance

Article

Author: Tasharrofi, Behnoosh ; Keramatipour, Mohammad ; Najafi, Ali ; Tavasoli, Ali Reza ; Amirsalari, Susan ; Ashrafi, Mahmoud Reza ; Pourbakhtyaran, Elham ; Heidari, Morteza ; Khan, Golazin Shahbodagh

BACKGROUNDNOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance.METHODS AND RESULTSWhole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center.CONCLUSIONThe findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.

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Cerebral Autosomal Dominant Arteriopathy and Subcortical Infarcts and Leukoencephalopaty (CADASIL)

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