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Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis
Yanbin Dong1, Ahamad Hassan, Zhongyi Zhang
1Department of Clinical Neurosciences, St George's Hospital Medical School, London, United Kingdom.
Insights
Screening for Notch3 mutations in stroke patients yielded few results, indicating these mutations are rare in cerebral small-vessel disease. The study found Notch3 mutations uncommon in typical stroke cases without classic CADASIL features.
Area of Science:
- Genetics and Neurology
- Molecular Medicine
- Cerebrovascular Diseases
Background:
- Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder causing early strokes and dementia.
- Notch3 gene mutations are the known cause of CADASIL.
- Atypical presentations suggest CADASIL may be underdiagnosed in stroke patients.
Purpose of the Study:
- To evaluate the diagnostic yield of screening for Notch3 gene mutations in patients presenting with lacunar stroke.
- To assess the frequency of Notch3 mutations in patients with lacunar stroke, with or without leukoaraiosis.
Main Methods:
- Studied 218 consecutive patients undergoing brain and carotid imaging.
- Employed polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) to screen key exons of the Notch3 gene.
- Focused on exons 3, 4, 5, and 6 for mutation and polymorphism detection.
Main Results:
- Identified a single Notch3 mutation (C697T in exon 4) in one young patient, resulting in an overall carrier frequency of 0.05%.
- In patients with lacunar stroke onset at or before 65 years and leukoaraiosis, the mutation detection rate was 2.0%.
Conclusions:
- Notch3 mutations are infrequent in patients with common strokes linked to cerebral small-vessel disease.
- Genetic screening for Notch3 mutations has a low diagnostic yield in stroke patients lacking classic CADASIL indicators.
Background And Purpose:
Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis.
Methods:
Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms.
Results:
A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at < or =65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9).
Conclusions:
Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.