Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3–6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.
Highlights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of ischemic stroke with characteristic manifestations of recurrent ischemic events, subcortical dementia, mood disturbance and migraine with aura [1]
Approximately 70% of CADASIL cases in Taiwan are resulting from the NOTCH3 R544C mutation, whereas mutations in exon 3–6 of NOTCH3 are responsible for approximately 90% of CADASIL patients in most Caucasian populations
CADASIL in Taiwan has an older age at symptom onset (54.1 years vs. 33.6–48.5 years), higher incidence of intracerebral hemorrhage (ICH) (16.2% vs. case reports) and rarer occurrence of migraine (2.7% vs. 42–75%) than those of CADASIL in most Caucasian populations
Summary
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of ischemic stroke with characteristic manifestations of recurrent ischemic events, subcortical dementia, mood disturbance and migraine with aura [1]. It is caused by mutations in the NOTCH3 gene (OMIM MIMÃ600276), which encodes a single-pass transmembrane receptor controlling cell fates during development [2]. Each EGFR domain contains 6 cysteine residues to form three disulfide bonds that are essential for stabilizing its structure. Most of NOTCH3 mutations are missense mutations, which usually lead to an odd number of cysteine residues and a disrupted EGFR conformation [1, 3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
