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Evaluation of diagnostic NOTCH3 immunostaining in CADASIL

Acta Neuropathologica volume 106, pages 107–111 (2003)Cite this article

Abstract

CADASIL is caused by mutations in the NOTCH3 gene. Although increasingly recognized as a disease entity, the diagnostic confirmation can be lengthy or inconclusive. Recently, NOTCH3 immunostaining of skin biopsy specimens has been introduced as a new diagnostic test. The aim of this study was to independently assess the diagnostic value of NOTCH3 immunostaining, and determine whether the degree of immunostaining correlates with other disease parameters. We determined NOTCH3 mutation carrier status in 62 symptomatic and asymptomatic individuals from 15 CADASIL families. Skin biopsy specimens of these individuals, as well as of a disease control group, were immunostained with NOTCH3 antibody and blindly analyzed by two independent observers to determine sensitivity and specificity. A semiquantitative NOTCH3 immunostaining score was correlated with clinical, genetic and MRI parameters. The sensitivity was 90.2% and 85.4%, respectively, for the two observers, the specificity 95.2% and 100%; both lower than previously reported. Certain NOTCH3 mutations may underlie false-negative results. False-positive results were found in a non-mutated control, and also in one disease control. There was no difference in immunostaining between symptomatic and asymptomatic NOTCH3 mutated individuals. Furthermore, the NOTCH3 immunostaining score did not correlate with clinical or MRI parameters. NOTCH3 immunostaining is a supportive, but not definitive, CADASIL diagnostic test, and should be interpreted in the context of clinical and radiological data. Confirmation by DNA analysis is requisite for positive results, and when there exists high clinical suspicion, also for negative results.

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Acknowledgements

S.A.J. Lesnik Oberstein is financially supported by NWO, reg. number 940-37-006. The authors wish to thank Dr. A. Joutel and Prof. Dr. E. Tournier-Lasserve for kindly providing the NOTCH3 1E4 antibody, Ms. E. Vollebregt for genetic analysis, Mrs. C. Welling-Graafland for assisting in NOTCH3 antibody staining, members of the Dutch CADASIL research group for patient referral, and the CADASIL families for their committed participation.

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Affiliations

  1. Department of Clinical Genetics, K5-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC , Leiden, The Netherlands

    Saskia A. J. Lesnik Oberstein & Martijn H. Breuning

  2. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Sjoerd G. van Duinen, Marion L. C. Maat-Schieman & Ingrid M. Hegeman-Kleinn

  3. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

    Rivka van den Boom & Mark A. van Buchem

  4. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

    Hans C. van Houwelingen

  5. Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

    Michel D. Ferrari & Joost Haan

  6. Department of Neurology, Rijnland Hospital, Leiderdorp, The Netherlands

    Joost Haan

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  1. Saskia A. J. Lesnik Oberstein
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  2. Sjoerd G. van Duinen
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  3. Rivka van den Boom
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  4. Marion L. C. Maat-Schieman
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  5. Mark A. van Buchem
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  6. Hans C. van Houwelingen
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  7. Ingrid M. Hegeman-Kleinn
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  8. Michel D. Ferrari
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  9. Martijn H. Breuning
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  10. Joost Haan
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Correspondence to Saskia A. J. Lesnik Oberstein.

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Lesnik Oberstein, S.A.J., van Duinen, S.G., van den Boom, R. et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol 106, 107–111 (2003). https://doi.org/10.1007/s00401-003-0701-6

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  • DOI: https://doi.org/10.1007/s00401-003-0701-6

Keywords

  • CADASIL
  • Diagnostic test
  • Pathology
  • Magnetic resonance imaging
  • Genetics