The spectrum of Notch3 mutations in 28 Italian CADASIL families

Dotti, Maria Teresa; Federico, Antonio; Mazzei, R.; Bianchi, Silvia; Scali, O.; Conforti, Francesca Luisa; Sprovieri, T.; Guidetti, Donata; Aguglia, Umberto; Consoli, Domenico; Pantoni, Leonardo; Sarti, Cristina; Inzitari, Domenico; Quattrone, Aldo

doi:10.1136/jnnp.2004.048207

Cited by 74 publications

(53 citation statements)

References 13 publications

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“…For the same reason a genetic analysis limited to a few exons in association with clinical and neuroimaging data as proposed by Markus and coworkers 8 seems dated today. 14,33 In CADASIL, a pregenetic screening is needed because the analysis of the NOTCH3 gene is costly and time-consuming. Furthermore, one must consider the emotional distress of patients and their relatives related to the performance of a genetic test for an autosomal-dominant disease; the time before the result is achieved can be very long, and the negativity of the test does not exclude the presence of other inherited diseases and therefore is not entirely reassuring for the patients.…”

Section: Discussionmentioning

confidence: 99%

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

Pescini

Nannucci

Bertaccini

et al. 2012

Stroke

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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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Section: Discussionmentioning

confidence: 99%

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

Pescini

Nannucci

Bertaccini

et al. 2012

Stroke

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“…Interestingly, previous reports have described a clustering of CADASIL-related NOTCH3 mutations in exon 4 ( Fig. 7B; Joutel et al, 1997), or in exon 11 (Dotti et al, 2005), but the mapping of missense mutations, normalized to exon size (this Review), reveals four 'hotspots' for CADASIL mutations, rather than one or two (Fig. 7A).…”

Section: Notch3 In Development: a Cornucopia Of Congenital Disordersmentioning

confidence: 99%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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“…In contrast, in 28 unrelated CADASIL families from central and south Italy, the highest mutations rate was found in exon 11 (21%), and only 18% were in exon 4. 29 Tang et al 30 report the first known Taiwanese family affected by CADASIL (Arg332Cys at exon 6). The results suggest that limited scanning of exons 3 and 4 is inadvisable in CADASIL cases of Italian origin.…”

Section: Cadasilmentioning

confidence: 99%

Advances in Vascular Cognitive Impairment 2005

Chui

Skoog

2006

Stroke

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VaD is purported to be more common than AD in Asia. In a study of 34 807 persons, aged 65 or older, living in several Chinese communities, Zhang et al 4 reported a prevalence of 4.8% for AD and 1.1% for VaD. These results suggest that the prevalence of dementia subtypes in China is similar to Western countries. It should be noted, however, that the application of NINDS-AIREN criteria and the absence of brain imaging may underestimate the extent of underlying CVD.Costs related to VCI for society and individuals have been examined. According to 2 studies 5,6 annual utilization of health care resources and primary caregivers are higher for VaD than AD. In the CHS cohort, 7 median survival from dementia onset to death was shorter in VaD (3.9 year) than in AD (7.1 years) and cognitively normal controls (11.0 years). This is not surprising, because VaD would be associated with higher cardiovascular mortality.The role of inflammation, infection, and antioxidants have been explored. In the Rotterdam Study 8 levels of fibrinogen, but not C-reactive protein, were associated with an increased risk of AD and VaD. In a Japanese case-control study, 9 antibodies against Chlamydia pneumoniae were found more often in VaD than in AD. In the Canadian Study of Health and Aging, 10 subjects reporting any antioxidant vitamin-use at baseline showed a significantly lower risk for incident VCI, but not dementia or AD. These data are intriguing but preliminary. NeuroimagingAssociations between WMH, neuropsychological impairment and brain atrophy have been studied. The prospective, population-based Rotterdam Scan Study 11 observed periventricular WMH, generalized brain atrophy, and brain infarcts on MRI to be associated with steeper decline in information processing speed and executive function during 5.2 yearsmean follow-up. In a clinical study on 69 patients with dementia, those with severe WMH displayed greater executive/visuoconstructional impairment relative to memory/language disabilities, whereas those with milder white matter abnormalities displayed relatively more memory/language disabilities. 12 In a sample of 50 AD, 13 mixed AD/subcortical vascular dementia (SVD) and 77 cognitively-intact controls, WMH correlated with cortical gray matter atrophy, but not with hippocampal or entorhinal atrophy. 13 Assuming that medial temporal atrophy is a marker for AD, whereas WMH is a marker for SVD, these findings suggest AD and SVD are independent processes and that both contribute to cortical gray matter atrophy. Thus, WMH appears to contribute to cognitive decline and loss of brain volume in the elderly. PathologyHeterogeneity and overlap pose ongoing challenges for the pathological classification of VaD. Among 175 autopsied VaD cases, only 49 (28%) were classified as "pure" VaD (ie, with only 1 type of vascular brain lesion and without AD pathology). 14 Of these, 36 had small vessel disease, 7 large vessel disease, and 6 hypoxic-hypoperfusion injury. The remaining 126 cases (72%) showed, in addition to Alzheimer pathology, a mixture of ...

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The spectrum of Notch3 mutations in 28 Italian CADASIL families

Cited by 74 publications

References 13 publications

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

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

The developmental biology of genetic Notch disorders

Advances in Vascular Cognitive Impairment 2005

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