Diagnostic strategies in CADASIL

H. S. Markus, R. J. Martin, M. A. Simpson, Yanbin Dong, N. Ali, A. H. Crosby, J. F. Powell

Research output: Contribution to journalReview article

257 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1134-1138
Number of pages5
JournalNeurology
Volume59
Issue number8
DOIs
StatePublished - Oct 22 2002
Externally publishedYes

Fingerprint

CADASIL
Exons
Biopsy
Skin
Mutation
Sensitivity and Specificity
Temporal Lobe
Migraine Disorders
Point Mutation
Dementia
Stroke
Magnetic Resonance Imaging
Population
Genes

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Markus, H. S., Martin, R. J., Simpson, M. A., Dong, Y., Ali, N., Crosby, A. H., & Powell, J. F. (2002). Diagnostic strategies in CADASIL. Neurology, 59(8), 1134-1138. https://doi.org/10.1212/WNL.59.8.1134

Diagnostic strategies in CADASIL. / Markus, H. S.; Martin, R. J.; Simpson, M. A.; Dong, Yanbin; Ali, N.; Crosby, A. H.; Powell, J. F.

In: Neurology, Vol. 59, No. 8, 22.10.2002, p. 1134-1138.

Research output: Contribution to journalReview article

Markus, HS, Martin, RJ, Simpson, MA, Dong, Y, Ali, N, Crosby, AH & Powell, JF 2002, 'Diagnostic strategies in CADASIL', Neurology, vol. 59, no. 8, pp. 1134-1138. https://doi.org/10.1212/WNL.59.8.1134
Markus HS, Martin RJ, Simpson MA, Dong Y, Ali N, Crosby AH et al. Diagnostic strategies in CADASIL. Neurology. 2002 Oct 22;59(8):1134-1138. https://doi.org/10.1212/WNL.59.8.1134
Markus, H. S. ; Martin, R. J. ; Simpson, M. A. ; Dong, Yanbin ; Ali, N. ; Crosby, A. H. ; Powell, J. F. / Diagnostic strategies in CADASIL. In: Neurology. 2002 ; Vol. 59, No. 8. pp. 1134-1138.
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abstract = "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.",
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N2 - 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.

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