Yi-Chung Lee1, Chih-Ping Chung1, Ming-Hong Chang1, Shuu-Jiun Wang1, Yi-Chu Liao2. 1. From the Department of Neurology (Y.-C. Lee, C.-P.C., S.-J.W., Y.-C. Liao), Taipei Veterans General Hospital; Department of Neurology (Y.-C. Lee, C.-P.C., M.-H.C., S.-J.W., Y.-C. Liao) and Brain Research Center (Y.-C. Lee, S.-J.W., Y.-C. Liao), National Yang-Ming, University School of Medicine, Taipei; and Department of Neurology (M.-H.C.), Taichung Veterans General Hospital, Taiwan. 2. From the Department of Neurology (Y.-C. Lee, C.-P.C., S.-J.W., Y.-C. Liao), Taipei Veterans General Hospital; Department of Neurology (Y.-C. Lee, C.-P.C., M.-H.C., S.-J.W., Y.-C. Liao) and Brain Research Center (Y.-C. Lee, S.-J.W., Y.-C. Liao), National Yang-Ming, University School of Medicine, Taipei; and Department of Neurology (M.-H.C.), Taichung Veterans General Hospital, Taiwan. ycliao5@vghtpe.gov.tw.
Abstract
OBJECTIVE: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. METHODS: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. RESULTS: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 × 10-10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. CONCLUSION: The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.
OBJECTIVE: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. METHODS: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. RESULTS: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 × 10-10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. CONCLUSION: The NOTCH3p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.
Authors: Julie W Rutten; Remco J Hack; Marco Duering; Gido Gravesteijn; Johannes G Dauwerse; Maurice Overzier; Erik B van den Akker; Eline Slagboom; Henne Holstege; Kwangsik Nho; Andrew Saykin; Martin Dichgans; Rainer Malik; Saskia A J Lesnik Oberstein Journal: Neurology Date: 2020-07-30 Impact factor: 9.910