Prevalence and Clinical Characteristics of Stroke Patients with p.R544C Notch3 Mutation in Taiwan
Sung-Chun Tang,1 Yih-Ru Chen,2 Nai-Fang Chi,3 Chih-Hao Chen,1 Yu-Wen Cheng,4 Fang-I Hsieh, 2 Yi-Chen Hsieh,5 Hsu-Ling Yeh,6 Pi-Shan Sung,7 Chaur-Jong Hu,3 Chang-Ming Chern, 8 Huey-Juan Lin, 9 Li-Ming Lien,6 Giia-Sheun Peng,10 Hung-Yi Chiou,2 Jiann-Shing Jeng1

From the 1Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei; 2School of Public Health, College of Public Health, Taipei Medical University, Taipei; 3Department of Neurology, Taipei Medical University Hospital and Shuang Ho Hospital, Taipei;4partment of Neurology, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu; 5Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei; 6Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei; 7Department of Neurology, National Cheng Kung University Hospital, Tainan; 8Department of Neurology, Taipei Veteran General Hospital, Taipei; 9Department of Neurology, Chi-Mei Medical Center, Tainan; 10Department of Neurology, Tri-Service General Hospital, Taipei, Taiwan.

Abstract
Objective- Features of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations vary between ethnicities and regions. In Taiwan, more than 70% of CADASIL patients carry the mutation hot spot of p.R544C. We investigated the prevalence of NOTCH3 p.R544C mutation in acute stroke patients in Taiwan.

Methods- This prospective, multi-centers study recruited patients with acute stroke within 10 days of symptom onset. The p.R544C mutation was identified by polymerase chain reaction with confronting two-pair primers and sequencing. Clinical parameters, vascular risk factors, stroke subtypes, and stroke outcomes were analyzed.

Results- Of the 1970 stroke patients (mean age 61.1±13.6 years, male 69.5%) included, 1705 (86.5%) had ischemic stroke and 265 (13.5%) had intracerebral hemorrhage. The prevalence of R544C (+) in the study population was 2.8% (95% confidence interval [CI] = 2.1%–3.5%). The prevalence was highest in patients with small vessel occlusion type of ischemic stroke (5.6%), followed by intracerebral hemorrhage (5.3%), and infarct of undetermined etiology (2.7%), and was low in patients with cardioembolism (0.8 %) and large artery atherosclerosis (0.7%). All R544C (+) patients with intracerebral hemorrhage were non-lobar hemorrhage. Sibling history of stroke (odds ratio [OR] = 4.50, 95% CI = 1.67–12.14 in ischemic stroke; OR = 6.03, 95% CI = 1.03–35.47 in ICH, respectively) and small vessel occlusion (OR, 4.03, 95% CI, 1.26–12.92) were significantly associated with p.R544C(+).

Interpretation- p.R544C NOTCH3 mutation is underdiagnosed in stroke patients in Taiwan, especially in those with small vessel occlusion and sibling history of stroke. 

Keyword: Stroke, CADASIL, NOTCH3, prevalence.

prevalence

Prevalence and Clinical Characteristics of Stroke Patients with R544C Notch3 Mutation in Taiwan