Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Family Members With a Pathogenic
 NOTCH3
 Variant Can Have a Normal Brain Magnetic Resonance Imaging and Skin Biopsy Beyond Age 50 Years

Hack, Remco J; Gravesteijn, Gido; Cerfontaine, Minne N; Mulder, Aat A.; Oberstein, Saskia A J Lesnik; Rutten, Julie W.

doi:10.1161/strokeaha.121.036307

Cited by 14 publications

(16 citation statements)

References 38 publications

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“…9 Some elderly individuals having mutations in EGFr domains 7-34 were even found to present with very limited cerebral lesions. 10 This does not rule out that patients with variants located in EGFr domain 1-6 cannot remain neurologically intact (N int ) or stable. 11 In parallel, during the recent decade and with the spread of genetic testing, diagnosis of CADASIL has been broadened to include patients with more atypical symptoms or much less severe clinical picture.…”

Section: Introductionmentioning

confidence: 99%

Elderly CADASIL patients with intact neurological status

et al. 2022

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Background and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most devastating cerebral small vessel diseases. However, despite its progression with aging, some patients remain neurologically intact (Nint) even when they get older. Their main characteristics are poorly known. We aimed to delineate their clinical, imaging, and molecular features.Methods Individuals aged over 65 years were selected from a cohort of 472 CADASIL patients. Subjects who had no focal deficit, cognitive impairment, or disability were considered Nint. Their demographic, genetic, clinical, and imaging features were compared to those with permanent neurological symptoms (Nps).Results Among 129 patients, 23 (17.8%) individuals were considered Nint. The frequency of vascular risk factors and NOTCH3 cysteine mutations in epidermal growth factor-like repeat (EGFr) domains 7-34 did not differ between Nint and Nps patients but Nint patients had less stroke events and were more likely to have migraine with aura. The number of lacunes and microbleeds and degree of brain atrophy were lower in the Nint group, but the volume of white matter hyperintensities did not differ between the two groups.Conclusions Nearly one in five CADASIL patients can remain Nint after the age of 65 years. Their clinical and imaging profile differed from that of other age-matched CADASIL patients. The location of NOTCH3 mutation inside or outside EGFr domains 1-6 cannot fully explain this discrepancy. The factors involved in their relative preservation of brain tissue from severe damage despite aging remain to be determined.

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Section: Introductionmentioning

confidence: 99%

Elderly CADASIL patients with intact neurological status

et al. 2022

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“…These marked degenerative changes lead to cerebrovascular dysfunction, which further causes white matter tract damage [ 24 ] . Interestingly, mutant NOTCH3 occurs in both the brain and peripheral arterial vessels [ 8 ] . Conversely, peripheral arteriopathy is subclinical, and small arterial function is not impaired [ 8 ] .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, mutant NOTCH3 occurs in both the brain and peripheral arterial vessels [ 8 ] . Conversely, peripheral arteriopathy is subclinical, and small arterial function is not impaired [ 8 ] . In addition, the white matter region is most vulnerable to cerebrovascular dysfunction in CADASIL.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both cerebral and extracerebral small arteries, such as skin vasculature, present these degenerative changes [ 6 – 7 ] . However, only cerebral small vessels have primarily compromised function in the early stage of CADASIL [ 8 ] , suggesting that cerebrovascular dysfunction may play an important role in the pathogenesis of CADASIL. Conversely, white matter hyperintensity (WMH) is the radiological hallmark of CADASIL [ 9 ] .…”

Section: Introductionmentioning

confidence: 99%

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Effects of different regional cerebral blood flow on white matter hyperintensity in CADASIL patients

Wang¹,

Zhang²,

Shang³

et al. 2022

J Biomed Res

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an early-onset inherited small vessel disease. Decreased cerebral blood flow (CBF) may contribute to white matter hyperintensity (WMH) severity in CADASIL, but more evidence is needed to support this hypothesis. This study comprised six patients with CADASIL who harbored mutations in the coding sequence of NOTCH3 and twelve age-matched neurologically healthy controls. We collected clinical and imaging data from patients with CADASIL and divided the brain into four regions: WMH, normal-appearing white matter (NAWM), gray matter (GM), and global brain. We analyzed the relationship between CBF of each region and the WMH volume. Compared with the control group, CBF was significantly decreased in all four regions in the CADASIL group. Lower CBF in these regions was correlated with higher WMH volume in CADASIL. CBF in the NAWM, GM and global regions was positively correlated with that in WMH region. However, after correction tests, only CBF in the WMH region but not in NAWM, GM and global regions was associated with WMH volume. Our findings suggest that CBF in the WMH region is an influencing factor of the WMH severity in CADASIL.

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“…More recently, the clinical phenotype in CADASIL cases with typical NOTCH3 variants has been shown to be widely variable, with some individuals suffering early onset stroke while other remain stroke free at least until the eighth decade. 5 A number of factors have been suggested to modulate the phenotype including variant location (with variants in proximal EGF repeats 1-6 being associated with more severe disease), 2 the presence of cardiovascular risk factors, 6 and modifying genes. 7 The UK Biobank resource also includes data on vascular risk factors and imputed genome-wide genotyping, allowing cardiovascular risk factor and polygenic risk scores to be calculated to investigate the importance of such modifying factors.…”

Section: Introductionmentioning

confidence: 99%

Both vascular risk factors and common genetic variants influence penetrance of variants causing monogenic stroke

Cho

Harshfield

Al-Thani

et al. 2022

Preprint

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Monogenic forms of stroke have been thought to be rare with high penetrance. However, recent studies have reported typical monogenic stroke pathogenic variants are much commoner than expected in the general population. Whether such variants are associated with disease, and why the phenotype of these variants varies so widely remain unclear. In 454,787 individuals in UK Biobank, we identified typical pathogenic variants in NOTCH3, HTRA1 and COL4A1/2 genes in 1 in 467, 1 in 832 and 1 in 1353 subjects, respectively. Variants in all three genes were associated with stroke risk, and NOTCH3 and HTRA1 with dementia risk. Cardiovascular risk (assessed by Framingham cardiovascular risk score), polygenic risk (assessed by a polygenic stroke risk score), and variant location within each gene, were all associated with penetrance of NOTCH3 and HTRA1 variants. Our results suggest intensive cardiovascular risk factor modification may reduce stroke and dementia risk in individuals with such variants.

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Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Family Members With a Pathogenic NOTCH3 Variant Can Have a Normal Brain Magnetic Resonance Imaging and Skin Biopsy Beyond Age 50 Years

Cited by 14 publications

References 38 publications

Elderly CADASIL patients with intact neurological status

Elderly CADASIL patients with intact neurological status

Effects of different regional cerebral blood flow on white matter hyperintensity in CADASIL patients

Both vascular risk factors and common genetic variants influence penetrance of variants causing monogenic stroke

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