Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Family Members With a Pathogenic NOTCH3 Variant Can Have a Normal Brain Magnetic Resonance Imaging and Skin Biopsy Beyond Age 50 Years

• Published in: Stroke (1970) Vol. 53; no. 6; pp. 1964 - 1974
• Main Authors: Hack, Remco J, Gravesteijn, Gido, Cerfontaine, Minne N, Hegeman, Ingrid M, Mulder, Aat A, Lesnik Oberstein, Saskia A J, Rutten, Julie W
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01.06.2022
• Subjects: Original Contributions; biopsy; white matter; brain; capillaries; vascular dementia
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.121.036307

To determine whether extremely mild small vessel disease (SVD) phenotypes can occur in variant carriers from Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) pedigrees using clinical, genetic, neuroimaging, and skin biopsy findings. Individuals from CADASIL pedigrees fulfilling criteria for extremely mild -associated SVD (mSVD ) were selected from the cross-sectional Dutch CADASIL cohort (n=200), enrolled between 2017 and 2020. Brain magnetic resonance imaging were quantitatively assessed for SVD imaging markers. Immunohistochemistry and electron microscopy was used to quantitatively assess and compare NOTCH3 ectodomain (NOTCH3 ) aggregation and granular osmiophilic material deposits in the skin vasculature of mSVD cases and symptomatic CADASIL patients. Seven cases were identified that fulfilled the mSVD criteria, with a mean age of 56.6 years (range, 50-72). All of these individuals harbored a variant located in one of EGFr domains 7-34 and had a normal brain magnetic resonance imaging, except the oldest individual, aged 72, who had beginning confluence of WMH (Fazekas score 2) and 1 cerebral microbleed. mSVD cases had very low levels of NOTCH3 aggregation in skin vasculature, which was significantly less than in symptomatic EGFr 7-34 CADASIL patients ( =0.01). Six mSVD cases had absence of granular osmiophilic material deposits. Our findings demonstrate that extremely mild SVD phenotypes can occur in individuals from CADASIL pedigrees harboring EGFr 7-34 variants with normal brain magnetic resonance imaging up to age 58 years. Our study has important implications for CADASIL diagnosis, disease prediction, and the counseling of individuals from EGFr 7-34 CADASIL pedigrees.