{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T04:37:22Z","timestamp":1777783042974,"version":"3.51.4"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2023,5]]},"abstract":"\n Background:<\/jats:title>\n \n Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in\n NOTCH2NLC<\/jats:italic>\n , has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that\n NOTCH2NLC<\/jats:italic>\n GGC expansion may contribute to cSVD.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without\n NOTCH3<\/jats:italic>\n ,\n HTRA1<\/jats:italic>\n , and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for\n NOTCH2NLC<\/jats:italic>\n GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without\n NOTCH2NLC<\/jats:italic>\n GGC repeat expansion.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion (\n P<\/jats:italic>\n =0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59\u201369) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging\u2014the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n NOTCH2NLC<\/jats:italic>\n GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/strokeaha.122.041848","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T05:01:29Z","timestamp":1679374889000},"page":"1236-1245","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["NOTCH2NLC<\/i>\n GGC Repeat Expansion in Patients With Vascular Leukoencephalopathy"],"prefix":"10.1161","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9644-2086","authenticated-orcid":true,"given":"Yi-Chu","family":"Liao","sequence":"first","affiliation":[{"name":"Departments of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), Taipei Veterans General Hospital, Taiwan."},{"name":"Department of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."},{"name":"Brain Research Center (Y.-C. Liao, Y.-C. Lee), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-9877","authenticated-orcid":true,"given":"Cheng-Yu","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei, Taiwan (C.-Y.W.)."},{"name":"Department of Neurology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan (C.-Y.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fu-Pang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine (F.-P.C.), Taipei Veterans General Hospital, Taiwan."},{"name":"Institute of Clinical Medicine (F.-P.C.), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-5051","authenticated-orcid":true,"given":"Ying-Tsen","family":"Chou","sequence":"additional","affiliation":[{"name":"Departments of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), Taipei Veterans General Hospital, Taiwan."},{"name":"Department of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6026-1697","authenticated-orcid":true,"given":"Shao-Lun","family":"Hsu","sequence":"additional","affiliation":[{"name":"Departments of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), Taipei Veterans General Hospital, Taiwan."},{"name":"Department of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9419-9070","authenticated-orcid":true,"given":"Chih-Ping","family":"Chung","sequence":"additional","affiliation":[{"name":"Departments of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), Taipei Veterans General Hospital, Taiwan."},{"name":"Department of Neurology (Y.-C. Liao, Y.-T.C., S.-L.H., C.-P.C., Y.-C. Lee), National Yang Ming Chao Tung University School of Medicine, Taipei, Taiwan."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Mizuguchi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan (T.M., N.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-6500","authenticated-orcid":true,"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan (T.M., N.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9097-3962","authenticated-orcid":true,"given":"Shaw-Fang","family":"Yet","sequence":"additional","affiliation":[{"name":"Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (S.-F.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-164X","authenticated-orcid":true,"given":"Yi-Chung","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Neurology (Y.-C. 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