3T MRI study discloses high intrafamilial variability in CADASIL due to a novel NOTCH3 mutation

• Published in: Journal of clinical neuroscience 2018-12, Vol.58, p.25-29
• Main Authors: La Piana, Roberta, Leppert, Ilana R., Pike, G. Bruce, Lanthier, Sylvain, Brais, Bernard, Tampieri, Donatella
• Format: Article
• Language: English
• Subjects: Adult; Aged; Brain - diagnostic imaging; CADASIL; CADASIL - complications; CADASIL - diagnostic imaging; CADASIL - genetics; Female; Genetic Variation - genetics; Humans; Leukoencephalopathy; Magnetic Resonance Imaging - methods; Male; Middle Aged; Migraine with Aura - complications; Migraine with Aura - diagnostic imaging; Migraine with Aura - genetics; MRI; Mutation - genetics; NOTCH3; Pedigree; Receptor, Notch3 - genetics; Risk Factors
• ISSN: 0967-5868; 1532-2653
• DOI: 10.1016/j.jocn.2018.10.080

•CADASIL is sometimes misdiagnosed with multiple sclerosis.•CADASIL can present with high intrafamilial MRI and clinical variability.•The degree of leukoencephalopathy may not correlate with the clinical severity.•Full NOTCH3 gene testing should be performed when CADASIL is suspected.•Familial MR studies are crucial in leukoencephalopathies of suspected genetic origin. In order to evaluate the usefulness of presymptomatic MRI, we performed 3T brain MRI and Sanger gene sequencing in a proband with suspected but not confirmed CADASIL and her apparently asymptomatic father. The 35-year-old proband presented with migraine with visual aura. Brain MRI showed diffuse leukoencephalopathy, suggesting CADASIL. NOTCH3 gene sequencing (exons 3–6) was negative. Family history was unclear. The MRI study of the father documented severe, diffuse leukoencephalopathy, with involvement of the temporal poles and external capsules (not observed in the proband), and lacunar infarcts in the absence of cardiac disease or risk factors. The MRI findings were in favour of an autosomal dominant mode of transmission and reinforced the hypothesis of CADASIL. Full NOTCH3 gene sequencing uncovered a novel exon 8 mutation (c.1337G>A; p.Cys446Tyr) outside the most commonly mutated region of NOTCH3. The novel mutation leads to a typical MRI pattern but a variable overall phenotype. The study underlines the usefulness of combining full gene sequencing with familial MRI studies.