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Related Experiment Videos

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.

Neurology
|October 25, 2002
PubMed
Summary

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.

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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.

Related Experiment Videos

  • 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.