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Diagnostic strategies in CADASIL
H S Markus1, R J Martin, M A Simpson
1Department of Clinical Neuroscience, St. George's Hospital Medical School, London, UK.
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) diagnosis can be aided by screening notch3 gene mutations, particularly in exon 4. Anterior temporal pole MRI involvement is a sensitive diagnostic marker.
Area of Science:
- Neurology
- Genetics
- Medical Diagnostics
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder causing stroke and dementia.
- Molecular diagnosis of CADASIL is challenging due to mutations occurring at multiple sites within the NOTCH3 gene.
- Granular osmiophilic material (GOM) on skin biopsy and specific MRI findings may aid CADASIL diagnosis.
Purpose of the Study:
- To identify the spectrum of NOTCH3 mutations in the British population.
- To evaluate the diagnostic utility of MRI and skin biopsy in CADASIL.
- To propose optimized molecular screening protocols for CADASIL.
Main Methods:
- Screening of exons 2-23 of the NOTCH3 gene in 83 potential index cases.
- MRI analysis using a modified Scheltens scale, focusing on anterior temporal lobe and external capsule.
- Skin biopsy performed on a subgroup of patients to detect granular osmiophilic material (GOM).
Main Results:
- Fifteen distinct NOTCH3 point mutations were found in 48 families, with 73% located in exon 4.
- Anterior temporal pole MRI involvement showed 89% sensitivity and 86% specificity for CADASIL.
- Skin biopsy had 45% sensitivity and 100% specificity, while external capsule MRI had 93% sensitivity and 45% specificity.
Conclusions:
- A targeted screening protocol focusing on NOTCH3 exon 4, followed by exons 3, 5, and 6, is recommended.
- Granular osmiophilic material (GOM) on skin biopsy is a definitive but not always present diagnostic sign.
- Anterior temporal pole involvement on MRI is a valuable and sensitive biomarker for CADASIL diagnosis.
Background:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis.
Methods:
The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup.
Results:
Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%.
Conclusions:
The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.