Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: NOTCH3 gene mutation and clinical features

Objective To investigate the NOTCH3 gene locus, clinical manifestation and MRI features of autosomal dominant hereditary cerebral arteriopathy with subcortical infarcts and white matter encephalopathy (CADASIL). Methods Genetic testing were performed in 831 cases of suspected CADASIL from 2009 to 2016, and 21 patients with CADASIL were selected as CADASIL group from NOTCH3 positive patients from Xinhui Hospital or Nanfang Hospital affliated to Southern Medical University. Another 32 patients with CADASIL score of more than 14 points served as CADASIL-like group. The clinical features and magnetic resonance imaging results of the two groups were analyzed. Results We have screened out 275 patients carrying NOTCH3 gene in 831 cases, with total of 71 mutant sites, in which 100 patients carried excon 4 mutant and 97 patients carried excon 11 mutant. Excon 11 p.R544C in Notch3 gene was found to be the maximum frequency of mutant site with mutation rate of 23.27%. White matter high signal intensity (WMHs) was the common expression in iconography and almost showed in all patients (95.2% in CADASIL group and 100% in CADASIL-like group). WMHs was always bilateral and symmetric. The rates of external capsule involvement in two groups were high with no statistically signifcant difference (71.4% in CADASIL group vs 71.9% in CADASIL-like group, P> 0.05). However, temporal pole involvement rate in CADASIL group was statistically signifcantly higher than that in CADASIL-like group (42.9% vs 12.5%, P< 0.05).The occurrence rates of multi-lacunar infarcts were 95.2% in CADASIL group and 90.6% in CADASIL-like group (P< 0.05). Cerebral microbleeds were observed in 76.2% (16/21) cases in CADASIL group and 46.9% (15/32) cases in CADASIL-like gruop with signifcant difference (P< 0.05). Conclusion In our study, NOTCH3 mutations most commonly occur in exon 4 and exon 11, and R544C in exon 11 accounted for nearly one fourth of the pedigrees, In CADASIL cases, bilateral, and symmetrical white matter lesions widely exist, with frequent involvement of temporal pole and cerebral microbleeds.