Genotype and Phenotype Differences in CADASIL from an Asian Perspective

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small-vessel disease caused by mutations in the NOTCH3 gene. Classical pathogenic mechanisms are associated with cysteine gain or loss, but recent studies suggest that cysteine-sparing mutations might have a potential role as a pathogen. In comparison with CADASIL patients in Western countries, there are several differences in Asian patients: (1) prevalent locus of NOTCH3 mutations (exons 2-6 [particularly exon 4] vs. exon 11), (2) age at symptom onset, (3) prevalence of cerebral microbleeds and hemorrhagic stroke, (4) clinical symptoms, and (5) severity of white matter hyperintensities and typical involvement of the anterior temporal pole in magnetic resonance imaging. Both ethnicity and founder effects contribute to these differences in the clinical NOTCH3 spectrum in different cohorts. More functional investigations from diverse races are needed to clarify unknown but novel variants of NOTCH3 mutations. This review may broaden the spectrum of NOTCH3 variants from an Asian perspective and draw attention to the hidden pathogenic roles of NOTCH3 variants.

Automated summary

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Asian patients differs from that in Western patients in terms of NOTCH3 mutation sites, age at symptom onset, prevalence of cerebral microbleeds and hemorrhagic stroke, clinical symptoms, and severity of white matter hyperintensities. Ethnicity and founder effects contribute to these differences in the clinical spectrum of NOTCH3 mutations.