Mutations of the Notch3 Gene in Non-Caucasian Patients with Suspected CADASIL Syndrome

Kotorii, Satoshi; Takahashi, K.; Kamimura, Kohei; Nishio, Takeshi; Arima, Kunimasa; Yamada, Haruki; Uyama, Eiichiro; Uchino, Makoto; Suenaga, Akihito; Matsumoto, Masayasu; Kuchel, George A.; Rouleau, Guy A.; Tabira, Takeshi

doi:10.1159/000051256

Cited by 34 publications

(21 citation statements)

References 29 publications

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“…Genetic examination of Notch3 in this case was performed by Kotorii et al, 7 and a missense mutation (nucleotide substitution 716G3 A; Arg213Lys) was recognized in the EGF5 domain of exon 4.…”

Section: Methodsmentioning

confidence: 91%

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

Okeda

Arima

Kawai

2002

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104

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Background and Purpose-There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods-We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results-We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions-These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO 2 levels and systemic blood pressure in CADASIL.

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Section: Methodsmentioning

confidence: 91%

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

Okeda

Arima

Kawai

2002

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104

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“…Previously, a few attempts of diagnostic strategies for CADASIL have been made, 8,31,32 but they have been seldom used and never validated. Some of the items of the Davous criteria 31 (ie, age, presence or absence of vascular risk factors, neuroimaging findings) that were proposed at a time when the knowledge about the disease was more limited may be questionable on the basis of the currently available data.…”

Section: Discussionmentioning

confidence: 99%

The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale

Pescini

Nannucci

Bertaccini

et al. 2012

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Overall, the recognition of the disease before the development of the full clinical-neuroimaging picture may be challenging. Moreover, as we recently reported, none of the Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype is highly variable, and, although the full clinical-neuroimaging picture may be suggestive of the disease, no characteristic is pathognomonic. Thus, a genetic test remains the diagnostic gold standard, but because it is costly and time-consuming, a pregenetic screening appears desirable. We aimed at developing the CADASIL scale, a screening tool to be applied in the clinical setting. Methods-A preliminary scale was created assigning weighted scores to common disease features based on their frequencies obtained in a pooled analysis of selected international CADASIL series. The accuracy of the scale versus the genetic diagnosis was tested with receiver operating characteristic analysis after the application of this scale to 61 CADASIL and 54 NOTCH3-negative patients (no pathogenic mutation on exons 2-23 of the NOTCH3 gene). To improve the scale accuracy, we then developed an ad hoc optimization algorithm to detect the definitive scale. A third group of 39 patients affected by sporadic small-vessel disease was finally included in the algorithm to evaluate the stability of the scale. Results-The cutoff score of the definitive CADASIL scale had a sensitivity of 96.7% and a specificity of 74.2%. This scale was robust to contamination of patients with sporadic small-vessel disease. Conclusions-The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and therefore to be subjected to the genetic testing.

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“…17,19 In addition, two Japanese patients have been reported as carrying a noncysteine mutation. 20,21 CADASIL is found worldwide and in many ethnic groups. The number of patients is growing with the increasing knowledge of the disease, yet CADASIL is thought to be markedly underdiagnosed.…”

Section: Introductionmentioning

confidence: 99%

Detection of the founder effect in Finnish CADASIL families

et al. 2004

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Mutations of the Notch3 Gene in Non-Caucasian Patients with Suspected CADASIL Syndrome

Cited by 34 publications

References 29 publications

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale

Detection of the founder effect in Finnish CADASIL families

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