Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors

Dupé, Charlotte; Guey, Stéphanie; Biard, Lucie; Dieng, Sokhna; Lebenberg, Jessica; Grosset, Lina; Alili, Nassira; Hervé, Dominique; Tournier‐Lasserve, Elisabeth; Jouvent, Éric; Chevret, Sylvie; Chabriat, Hugues

doi:10.1177/0271678x221126280

Cited by 20 publications

(16 citation statements)

References 68 publications

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“…We observed a similar point prevalence of ICH to that previously reported from European CADASIL cohorts, which ranged from 0.5% to 2.7% [ 42 – 44 ]; however, ICH was more commonly observed in the Asian cohorts. A recent meta-analysis reported the pooled prevalence of ICH in CADASIL of 10.1%, with 17.7% and 2.0% within the Asian and European subgroups, respectively [ 45 – 47 ].…”

Section: Discussionsupporting

confidence: 88%

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review

Sukhonpanich,

Markus

2024

J Neurol

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Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is characterised by early onset stroke and dementia. Most strokes are lacunar ischaemic strokes, but intracerebral haemorrhage (ICH) has also been reported, although there are limited published data on its frequency and characteristics. Methods A retrospective review of a prospectively recruited CADASIL register from the British National Referral clinic was performed to identify acute ICH cases and their characteristics. In addition, a systematic review of ICH in CADASIL was performed. MEDLINE (Pubmed), Embase, and Web of Science were searched for articles published from inception until 31/05/2023. Results Ten cases of ICH were identified from the National clinic register of 516 symptomatic patients, giving an estimated point prevalence of 1.9%. An additional 119 cases were identified from the systematic review, comprising 129 cases and 142 ICH events in total. Including all identified cases, the mean age at onset of ICH was 56.6 ± 15.7 (SD) years, and 74 (57.4%) were male. ICH was the first manifestation of the disease in 32 patients (38.1%), and ICH recurrence occurred in 16 (12.4%). Most ICHs were subcortical, with the thalamus, 58 (40.8%), and basal ganglia, 34 (23.9%), being the commonest sites. Anticoagulation, but not antiplatelet agents, was associated with an increased risk of ICH (20.0% vs. 1.9%, p = 0.006). Conclusions ICH is a relatively rare manifestation of CADASIL, occurring in about 2% of symptomatic cases. Most of the haemorrhages occurred in the subcortical regions.

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Section: Discussionsupporting

confidence: 88%

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review

Sukhonpanich,

Markus

2024

J Neurol

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“…5 Similarly, modifiable vascular risk factors such as hypertension and hypercholesterinemia were associated with stroke penetrance in a French CADASIL study. 20 To date, no randomized controlled trials have been conducted to examine whether reducing cardiovascular risk can effectively mitigate the risk of stroke in individuals with NOTCH3 variants.…”

Section: Discussionmentioning

confidence: 99%

Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank

Lin

Chen

et al. 2023

International Journal of Stroke

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Background and aim Previous studies have suggested cardiovascular risk factors increase the risk of not only common sporadic stroke, but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the Taiwanese population. Methods This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke. The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3 R544C in stroke. Results From the 114,282 participants with both genotype and questionnaire results, 1,080 (0.95%) harbored the pathogenic NOTCH3 R544C variant. When compared to the matched controls (n=10,800), the carriers presented with a history of stroke (OR: 2.52, 95% CI [1.45, 4.37]), dementia (OR: 30.1, 95% CI [3.13, 289.43]), and sibling history of stroke (OR: 2.48, 95% CI [1.85, 3.34]) phenotypes. The risk of stroke increased with every 10-year increase in age (p = 0.006, Cochran–Mantel–Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1,080 carriers with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI [3.54, 43.3]) and diabetes mellitus (OR: 4.10, 95% CI [1.31, 12.4]) were independently associated with stroke. Harboring the NOTCH3 R544C variant in the Taiwan biobank is comparable with 6.74 standard deviations increase in individual’s polygenic risk score for stroke. Conclusion While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also played a role in the occurrence of stroke in Taiwanese community-dwelling individual carrying NOTCH3 variant.

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“…Data obtained in patients and controls were compared after adjustment for age and sex. Association between clinical or imaging parameters and each retinal vascular parameter was assessed by multivariable analyses using generalised linear models and adjustment for age, presence of hypertension (HT), presence of other vascular risk factors, location of mutation in EGFR domains of the Notch3 protein, from 1 to 6 vs 7 to 34, which has been shown to influence the severity of the CADASIL phenotype 7 8…”

Section: Methodsmentioning

confidence: 99%

Retinal vascular density in CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

et al. 2023

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Background and objectiveRetinal vascular density (VD) measured using optical coherence tomography with angiography (OCTA) has been suggested as a potential marker of intracerebral vascular changes in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). We aimed to determine whether VD is related to the clinical and imaging manifestations of the disease.MethodsOCTA was performed in 104 CADASIL patients (parallel to their clinical and imaging assessment) and in 83 healthy individuals.ResultsA significant reduction of VD related to age was detected in patients and controls in the superficial and deep vascular plexus of the whole foveal or parafoveal retinal area (p<0.0001). After adjustment for age, these parameters were found significantly lower in patients than in controls (p<0.03). Multivariable analysis did not show any association between retinal VD and history of stroke, modified Rankin Scale or Mini-Mental Status Examination scores. No significant association was found with MRI lesions either .ConclusionIn CADASIL, retinal VD is decreased early and progresses with ageing but does not appear related to the severity of clinical or imaging manifestations.

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Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors

Cited by 20 publications

References 68 publications

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review

Prevalence, clinical characteristics, and risk factors of intracerebral haemorrhage in CADASIL: a case series and systematic review

Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank

Retinal vascular density in CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

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