New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan

Mizuta, Ikuko; Watanabe-Hosomi, Akiko; Koizumi, Takashi; Mukai, Makiko; Hamano, Ai; Tomii, Yasushi; Kondo, Masaki; Nakagawa, Masanori; Tomimoto, Hidekazu; Hirano, Teruyuki; Uchino, Makoto; Onodera, Osamu; Mizuno, Toshiki

doi:10.1016/j.jns.2017.08.009

Cited by 28 publications

(37 citation statements)

References 31 publications

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“…Other studies have also identified mutations located outside the EGFRs implicated as the cause for CADASIL and white matter disease, suggesting that there are other mechanisms which contribute or cause the CADASIL phenotype [41,42]. The increase in mutations that do not affect Cysteine residues or the EGFRs are reflected in updated proposed guidelines for CADASIL diagnosis which suggest that non-Cysteine-altering mutations should also be investigated carefully [43,44].…”

Section: Discussionmentioning

confidence: 99%

Investigating diagnostic sequencing techniques for CADASIL diagnosis

et al. 2020

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. More recently, next-generation sequencing (NGS)-based technologies such as a targeted gene panel and whole exome sequencing (WES) have been used for improved genetic diagnostic testing. In this study, data from 680 patient samples was analysed for 764 tests utilising 3 different sequencing technologies. Sanger sequencing was performed for 407 tests, a targeted NGS gene panel which includes NOTCH3 exonic regions accounted for 354 tests, and WES with targeted analysis was performed for 3 tests. In total, 14.7% of patient samples (n = 100/680) were determined to have a mutation. Testing efficacy varied by method, with 10.8% (n = 44/407) of tests using Sanger sequencing able to identify mutations, with 15.8% (n = 56/354) of tests performed using the NGS custom panel successfully identifying mutations and a likely non-NOTCH3 pathogenic variant (n = 1/3) identified through WES. Further analysis was then performed through stratification of the number of mutations detected at our facility based on the number of exons, level of pathogenicity and the classification of mutations as known or novel. A systematic review of NOTCH3 mutation testing data from 1997 to 2017 determined the diagnostic rate of pathogenic findings and found the NGS-customised panel increases our ability to identify disease-causing mutations in NOTCH3.

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Section: Discussionmentioning

confidence: 99%

Investigating diagnostic sequencing techniques for CADASIL diagnosis

et al. 2020

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“…While immunostaining is considered both sensitive (85-95%) and specific (95-100%), electron-microscopic testing has variable sensitivity and specificity (Joutel et al, 2001;Markus et al, 2001). However, the presence of GOMs is the pathological hallmark of CADASIL, being one of the criteria for the diagnosis, therefore its specificity can be considered 100%, while its sensitivity varies between operators (Mizuta et al, 2017).…”

Section: Diagnosismentioning

confidence: 99%

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

2020

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary small-vessels angiopathy caused by mutations in the NOTCH 3 gene, located on chromosome 19, usually affecting middleages adults, whose clinical manifestations include migraine with aura, recurrent strokes, mood disorders, and cognitive impairment leading to dementia and disability. In this review, we provide an overview of the current knowledge on the pathogenic mechanisms underlying the disease, focus on the corresponding therapeutic targets, and discuss the most promising treatment strategies currently under investigations. The hypothesis that CADASIL is an appropriate model to explore the pathogenesis of sporadic cerebral small vessel disease is also reviewed.

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“…CADASIL is an inherited cerebrovascular disorder, whose main clinical features are migraine with aura, recurrent subcortical ischemic attacks, strokes, vascular dementia, cognitive impairment, psychiatric disturbances, and apathy [8][9][10][11][12][13][14][15][16]. Due to the rarity of the disease, CADASIL is often overlooked and misdiagnosed; nevertheless, the combined symptomatic and asymptomatic prevalence of CADASIL is estimated at least 10.7 per 100,000 adults [11,12,[17][18][19][20].…”

Section: Clinical Picturementioning

confidence: 99%

“…However, because affected family members may have been misdiagnosed [80] and de novo cases have been described [69,81], the lack of an apparent family history of CADASIL does not preclude the diagnosis. Several groups of clinicians [13,14,82] proposed suitable diagnostic strategies to be used in the clinical setting for the selection of patients to be subjected to NOTCH3 gene analysis. In fact, in order to establish a correct diagnosis, clinical signs, neuroimaging findings, and family history need to be evaluated.…”

Section: Diagnosismentioning

confidence: 99%

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Ungaro¹,

Sprovieri²

2020

Rare Diseases

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease whose key features are recurrent transient ischemic attacks (TIA), strokes, migraine with aura, vascular dementia, and diffuse white matter abnormalities detectable through neuroimaging. The disease results from mutations in the NOTCH3 gene, encoding a transmembrane receptor involved in cellular signaling and fate during embryonic development. Genetic testing is the gold standard for diagnosing this condition, but the syndrome can be suspected clinically based on family history and characteristic findings of white matter changes. Nevertheless, different individual symptom types, onset, and disease severity, even among individuals in the same family, have been increasingly recognized. The molecular mechanisms by which NOTCH3 mutations lead to vascular degeneration remain unclear. Most CADASIL-associated mutations result in either a gain or loss of cysteine residue in one of the 34 EGF-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. More than 200 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Although it has been suggested that some mutations may be associated with a milder or more severe phenotype, so far no clear genotype-phenotype correlation has been found. To date, no disease-modifying treatment is available for this condition.

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New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan

Abstract: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

Cited by 28 publications

References 31 publications

Investigating diagnostic sequencing techniques for CADASIL diagnosis

Investigating diagnostic sequencing techniques for CADASIL diagnosis

Pathophysiological Mechanisms and Potential Therapeutic Targets in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

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