Genotype and Phenotype Differences in CADASIL from an Asian Perspective.

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease linked to NOTCH3 gene mutations.
• While classical mutations involve cysteine alterations, cysteine-sparing variants are emerging as potential pathogens.
• Significant clinical and genetic differences exist between Asian and Western CADASIL patients.

Purpose of the Study:

• To review and compare CADASIL characteristics in Asian versus Western populations.
• To explore the spectrum of NOTCH3 mutations from an Asian perspective.
• To emphasize the need for further investigation into novel NOTCH3 variants and their pathogenic roles.

Main Methods:

• Literature review and comparative analysis of existing studies on CADASIL.
• Focus on NOTCH3 mutation loci, clinical presentation, and neuroimaging findings.
• Synthesis of data to highlight ethnic and founder effects on the NOTCH3 spectrum.

Main Results:

• Asian CADASIL patients exhibit different prevalent NOTCH3 mutation loci (exons 2-6, especially exon 4) compared to Western patients (exon 11).
• Variations observed in age of onset, prevalence of cerebral microbleeds, stroke types, clinical symptoms, and MRI findings (white matter hyperintensities, anterior temporal pole involvement).
• Ethnicity and founder effects significantly influence the clinical manifestation of NOTCH3 mutations.

Conclusions:

• The clinical spectrum of CADASIL varies significantly across different ethnic groups, particularly between Asian and Western populations.
• Understanding these ethnic-specific differences in NOTCH3 mutations is crucial for accurate diagnosis and management.
• Further functional studies on diverse populations are essential to elucidate the pathogenicity of novel NOTCH3 variants.