Diagnostic strategies in CADASIL

Markus, Hugh S.; Martin, Ruvie; Simpson, Michael A.; Dong, Yanbin; Ali, Nadira; Crosby, Andrew H.; Powell, John

doi:10.1212/wnl.59.8.1134

Cited by 291 publications

(270 citation statements)

References 20 publications

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“…All mutations occur in extracellular domains, more specifically the epidermal growth-like factor-repeats (EGF-repeats), from a non-paired cysteine 4,7 . Most mutations occur in codons of exon 4, followed by exons 3, 5, 6 and 11 7,9,10 ( Fig 1B). The exon 3 seems to be the second most commonly affected site in French, English and German families 7,9 ; exon 11 could, however, be the second most prevalent in Dutch families 11 .…”

Section: Genetics and Pathogenesismentioning

confidence: 99%

“…Most mutations occur in codons of exon 4, followed by exons 3, 5, 6 and 11 7,9,10 ( Fig 1B). The exon 3 seems to be the second most commonly affected site in French, English and German families 7,9 ; exon 11 could, however, be the second most prevalent in Dutch families 11 . The Notch proteins constitute a family of surface receptors that promote transduction of signals between neighboring cells.…”

Section: Genetics and Pathogenesismentioning

confidence: 99%

“…Most mutations are found in gene exon 4: this site should be investigated first in suspected cases. In a British study prospectively evaluating different diagnostic strategies, 15 different mutations were identified in 48 families, 73% of them in exon 4 (less than 10% each in exons 3, 5 and 6) 9 . A case in which the molecular diagnosis was made in a fetus whose father was affected by CADASIL has been published 34 .…”

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

“…In the study of Markus et al 9 , the diagnostic value of characteristic MRI changes was also evaluated. Moderate to severe white matter changes in the anterior temporal regions exhibited slightly lower sensitivity (89% vs. 93%), but much higher specificity than those in the external capsule (86% vs. 45%).…”

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

“…Specificity is high, approaching 100%, but sensitivity is low (less than 50%); the involvement is often focal, and thourough assessment of the material is necessary to make the diagnosis 9,35 .…”

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

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CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of ischemic strokes and a most important model for the study of subcortical vascular dementia. This unrelentlessly progressive disease affects many hundreds of families all over the world but is not well studied in Brazil. This manuscript reviews pathogenetic, clinical, radiological and therapeutic features of CADASIL. The causal mutations are now very well known, but the same can not be said about its intimate pathogenetic mechanisms. The variable clinical presentation should lead physicians to actively pursue the diagnosis in many settings and to more thouroughly investigate family history in first degree relatives. A rational approach to genetic testing is however needed. Treatment of CADASIL is still largely empiric. Highquality therapeutic studies involving medications and cognitive interventions are strongly needed in CADASIL. Key words: CADASIL, etiology, genetics, diagnosis, therapeutics.cADAsIL: patogênese, achados clínicos e radiológicos e tratamento resumo CADASIL é a causa genética mais freqüente de infartos cerebrais e constitui modelo importante de estudo de demências vasculares subcorticais. De natureza inexoravelmente progressiva, afeta milhares de pessoas em todo o mundo. Sua importância é pouco reconhecida entre nós, o que nos levou à presente revisão dos principais aspectos patogenéticos, clínicos, neuroradiológicos e terapêuticos da doença. As mutações causais são hoje bem conhecidas, mas os mecanismos patogenéticos íntimos ainda permanecem misteriosos. A apresentação clínica variável deve fazer com que os médicos considerem o diagnóstico em vários contextos clínicos e investiguem de forma mais extensa que o usual a história familial deparentes de primeiro grau. Além disso, uma abordagem racional é necessária para reduzir custos e aumentar a eficiência do diagnóstico genético. O tratamento atual de pacientes com CADASIL é basicamente empírico. Estudos clínicos sobre medicamentos e intervenções cognitivas de alto nível metodológico constituem uma necessidade urgente.

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Section: Genetics and Pathogenesismentioning

confidence: 99%

Section: Genetics and Pathogenesismentioning

confidence: 99%

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

Section: Diagnosis Of Cadasilmentioning

confidence: 99%

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CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Spectrum of Mutations in Biopsy-Proven CADASIL

Peters¹,

Opherk²,

Bergmann³

et al. 2005

Arch Neurol

137

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Background: Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an important cause of stroke in young adults. Mutations are typically located within epidermal growth factorlike repeat domains in the extracellular part of the Notch3 receptor. Identification of the mutation is critical for genetic counseling and testing of relatives at risk. Objectives: To identify the spectrum of NOTCH3 mutations in CADASIL and to discuss the implications for diagnostic strategies. Design: Screening for NOTCH3 mutations was performed in 125 unrelated German CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for epidermal growth factor-like repeats. Results were compared with those of previously published studies. Results: We detected 54 distinct mutations (117 missense mutations and 3 in-frame deletions) in 120 (96.0%) of the 125 patients. Of the mutations, 58.3% were located in exon 4 and 85.8% in exons 2 through 6. In 5 patients (4.0%), no mutation was identified.

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