Ikuko Mizuta1, Akiko Watanabe-Hosomi1, Takashi Koizumi1, Mao Mukai1, Ai Hamano1, Yasuhiro Tomii1, Masaki Kondo1, Masanori Nakagawa2, Hidekazu Tomimoto3, Teruyuki Hirano4, Makoto Uchino5, Osamu Onodera6, Toshiki Mizuno7. 1. Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 2. North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan. 3. Department of Neurology, Mie University Graduate School of Medicine, Mie, Japan. 4. Department of Stroke and Cerebrovascular Medicine, Kyorin University, Tokyo, Japan. 5. Department of Neurology, Jonan Hospital, Kumamoto, Japan. 6. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. 7. Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: mizuno@koto.kpu-m.ac.jp.
Abstract
PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.
PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young strokepatients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.
Authors: P J Dunn; N R Harvey; N Maksemous; R A Smith; H G Sutherland; L M Haupt; L R Griffiths Journal: Mol Neurobiol Date: 2022-06-14 Impact factor: 5.682