Evaluation of diagnostic NOTCH3 immunostaining in CADASIL

• Published in: Acta neuropathologica Vol. 106; no. 2; pp. 107 - 111
• Main Authors: OBERSTEIN, Saskia A. J. Lesnik, VAN DUINEN, Sjoerd G, VAN DEN BOOM, Rivka, MAAT-SCHIEMAN, Marion L. C, VAN BUCHEM, Mark A, VAN HOUWELINGEN, Hans C, HEGEMAN-KLEINN, Ingrid M, FERRARI, Michel D, BREUNING, Martijn H, HAAN, Joost
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.08.2003; Springer Nature B.V
• Subjects: Adult; Aged; Amyloidosis - complications; Amyloidosis - diagnosis; Amyloidosis - metabolism; Antibodies; Asymptomatic; Biological and medical sciences; Biopsy; Case-Control Studies; Cerebral Hemorrhage - complications; Cerebral Hemorrhage - diagnosis; Cerebral Hemorrhage - genetics; Cerebral Hemorrhage - metabolism; Dementia, Multi-Infarct - diagnosis; Dementia, Multi-Infarct - metabolism; Dementia, Multi-Infarct - pathology; Diagnostic tests; Disability Evaluation; Disease control; False Negative Reactions; Family medical history; Genetic Carrier Screening; Humans; Immunologic Techniques; Investigative techniques, diagnostic techniques (general aspects); Magnetic Resonance Imaging; Medical sciences; Middle Aged; Miscellaneous. Technology; Mutation; Nervous system involvement in other diseases. Miscellaneous; Neurology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch; Sensitivity and Specificity; Single-Blind Method; Skin - pathology; Staining and Labeling; Netherlands; Performance evaluation; Human; Immunohistochemistry; Nervous system diseases; Leucoencephalopathy; Nuclear magnetic resonance imaging; Cerebral disorder; Pathology; CADASIL; Diagnostic test; Magnetic resonance imaging; Biopsy; Central nervous system disease; CADASIL syndrome; Medical imagery; Genetics; Skin; Diagnosis; Mutation; Technique
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-003-0701-6

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.