Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese.
OBJECTIVE
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, most clinical, molecular and neuroimaging information has come from Caucasians. Therefore, we investigated the spectrum of NOTCH3 mutations and MRI features in CADASIL patients of Chinese origin on Taiwan.


METHODS
Mutational analysis of NOTCH3 exons 2 to 23 by direct nucleotide sequencing was performed in patients with clinically suspected CADASIL. MRI findings were retrospectively evaluated and scored using a modified Schelten's scale.


RESULTS
Nine different point mutations of NOTCH3 were identified in 21 unrelated patients. Intriguingly, 47.6 % were in exon 11, and 19 % in each of exon 4 and 18. R544C was very common and present in all patients with a mutation in exon 11. Many patients with NOTCH3 R544C share the same haplotype linked to the mutation using markers D19S929 and D19S411, which flank the NOTCH3. The sensitivity of T2-weighted MRI detecting anterior temporal abnormality was only 42.9 %. Furthermore, the neuroimaging evidence of intracerebral hemorrhage (ICH) was present in 23.8 % of the 21 patients.


CONCLUSIONS
A population-specific mutational spectrum of CADASIL was found in the Chinese patients on Taiwan. The Chinese patients carrying NOTCH3 R544C may descend from a common ancestor. Anterior temporal hyperintensity on T2-weighted MRI may not be a sensitive marker for CADASIL. ICH is a relatively common manifestation of CADASIL in East Asians, especially in the presence of hypertension.
Lee
Yi-Chung
YC
Dept. of Neurology, National Yang-Ming University, School of Medicine, #155, Sec.2, Li-nung St., Peitou District, Taipei, Taiwan 112, Republic of China.
Liu
Chin-San
CS
Chang
Ming-Hong
MH
Lin
Kon-Ping
KP
Fuh
Jong-Ling
JL
Lu
Yi-Chu
YC
Liu
Ya-Fen
YF
Soong
Bing-Wen
BW
D000328:Adult; D000368:Aged; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D046589:CADASIL / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D013624:Taiwan
D005819:Genetic Markers; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch