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Last update 23 Jan 2025

Cadasil

Last update 23 Jan 2025

Basic Info

Synonyms

CADASIL, CADASIL, CADASIL (diagnosis)

+ [20]

Introduction

A familial, cerebral arteriopathy mapped to chromosome 19q12, and characterized by the presence of granular deposits in small CEREBRAL ARTERIES producing ischemic STROKE; PSEUDOBULBAR PALSY; and multiple subcortical infarcts (CEREBRAL INFARCTION). CADASIL is an acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. CADASIL differs from BINSWANGER DISEASE by the presence of MIGRAINE WITH AURA and usually by the lack of history of arterial HYPERTENSION. (From Bradley et al, Neurology in Clinical Practice, 2000, p1146)

Drugs associated with Cadasil

Cerebroprotein Hydrolysate

Target

TNF-α

Mechanism

TNF-α inhibitors [+1]

Active Org.

EVER Neuro Pharma GmbH [+1]

Originator Org.

EBEWE Pharma Ges.m.b.H. Nfg.KG

Active Indication

Brain Injuries, Traumatic [+6]

Inactive Indication

Acute Ischemic Stroke

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date03 Feb 1998

QRX-1204

Target-

Mechanism

RNA interference

Active Org.

ProQR Therapeutics NV

Originator Org.

ProQR Therapeutics NV

Active Indication

Cadasil

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

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 Cadasil

ChiCTR2400088550

/ SuspendedNot ApplicableIIT

Study on the relationship between sleep disorders and the cerebral lymphatic system in patients with autosomal dominant inherited cerebral artery disease (CADASIL) with subcortical infarction and white matter encephalopathy

Start Date01 Sep 2024

Sponsor / Collaborator

The Sixth Affiliated Hospital of Sun Yat-Sen University

NCT05755997

/ RecruitingPhase 2

A Randomized, Double-blind, Single-centre, Two-period Cross-over, Placebo-controlled Trial on Safety and Efficacy in Patients With Genetically Proven CADASIL

The objective of this trial is the global risk-benefit assessment of Cerebrolysin as compared to Placebo in patients with genetically proven CADASIL. In addition, a traditional approach will be taken based on an evaluation of the separate risk and benefit domains in comparison with placebo.

Start Date29 Nov 2023

Sponsor / Collaborator

EVER Neuro Pharma GmbH

NCT06148051

/ RecruitingNot ApplicableIIT

AusCADASIL: An Australian Cohort of CADASIL

The aim of this project is to establish an Australian cohort of patients diagnosed with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). This study will examine the clinical features and longitudinal course of CADASIL. Outcome measures include neuropsychological profile, neuroimaging, genetics, blood biomarkers, and retinal imaging.

Start Date25 Nov 2023

Sponsor / Collaborator

The University of New South Wales

[+4]

100 Clinical Results associated with Cadasil

100 Translational Medicine associated with Cadasil

0 Patents (Medical) associated with Cadasil

1,531

Literatures (Medical) associated with 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 Jan 2025·JAMA Neurology

Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL

Article

Author: Park, Ashley ; Jolly, Amy A. ; Cerfontaine, Minne N. ; Sukhonpanich, Nontapat ; Lee, Jung Seok ; Ishiyama, Hiroyuki ; Mele, Francesco ; Lee, Yi-Chung ; Guey, Stéphanie ; Shourav, Md Manjurul Islam ; Ihara, Masafumi ; Duering, Marco ; Muiño, Elena ; Pantoni, Leonardo ; Rutten, Julie W. ; Park, Jae-young ; Montanaro, Vinícus V. A. ; Poggesi, Anna ; Markus, Hugh S. ; Yuan, Yun ; Silva, Ana Rita ; Lesnik Oberstein, Saskia A. J. ; Meschia, James F. ; Choi, Jay Chol ; Pescini, Francesca ; De Stefano, Nicola ; Vonk, Sebastiaan J. J. ; Bersano, Anna ; Hack, Remco J. ; Rodríguez-Girondo, Mar ; Hsu, Shao-Lun ; Gravesteijn, Gido ; Santo, Gustavo ; Domínguez Mayoral, Ana ; Rifino, Nicola ; Nogueira, Renata ; Neilson, Sam J. ; Andersen, Pia ; Kalaria, Rajesh N. ; Saito, Satoshi ; Kim, Hyunjin ; Chabriat, Hugues ; Fernández-Cadenas, Israel ; Kopczak, Anna ; Ling, Chen ; Liao, Yi-Chu ; Muir, Keith W. ; Lopergolo, Diego ; Brodtmann, Amy ; Börjesson-Hanson, Anne

ImportanceTypical 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.ObjectiveTo design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.Design, Setting, and ParticipantsA 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 MeasuresPercentage 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.ResultsThe 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 RelevanceThe 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.

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