Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles

Area of Science:

• Neurology
• Genetics
• Vascular Neurology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic cerebrovascular disorder.
• NOTCH3 gene mutations, particularly in exons 3-6, are the primary cause.
• Previous studies highlighted anterior temporal pole involvement and specific mutation clusters.

Purpose of the Study:

• To investigate the genotypic and phenotypic spectrum of CADASIL in Taiwan.
• To identify common and novel NOTCH3 mutations in the Taiwanese Han-Chinese population.
• To compare Taiwanese CADASIL characteristics with those reported in Caucasian populations.

Main Methods:

• Sanger sequencing of NOTCH3 exons 2-24 in 112 Taiwanese CADASIL patients from 95 families.
• Identification and characterization of NOTCH3 mutations.
• Haplotype analysis for families with the R544C mutation.
• Clinical data analysis comparing Taiwanese patients with Caucasian cohorts.

Main Results:

• Twenty NOTCH3 mutations were identified, including three novel mutations.
• The R544C mutation in exon 11 was the most frequent (70.5% of pedigrees).
• Taiwanese CADASIL patients exhibited less anterior temporal involvement, later onset, higher intracerebral hemorrhage incidence, and rarer migraines compared to Caucasians.
• The R544C mutation correlated with reduced anterior temporal involvement, later onset, and increased cognitive dysfunction.

Conclusions:

• The study expands the known spectrum of NOTCH3 mutations associated with CADASIL.
• Distinct clinical and genotypic features of CADASIL in Taiwanese Han-Chinese descent were identified.
• These findings offer valuable insights for diagnosing and managing CADASIL in this population.