{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T13:18:30Z","timestamp":1793366310287,"version":"4.5.0"},"reference-count":14,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21ek0109486, JP21ek0109549, JP21cm0106503 and JP21ek0109493 (N. Matsumoto)"],"award-info":[{"award-number":["JP21ek0109486, JP21ek0109549, JP21cm0106503 and JP21ek0109493 (N. Matsumoto)"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS KAKENHI","award":["JP19H03621 (N. Miyake), JP20K07907 (S. Miyatake), JP21K07298 (H. Doi), JP21K07869 (E. Koshimizu), JP20K16932 (K. Hamanaka), JP20K17936 (A. Fujita), JP21K15907 (Y. Uchiyama), JP20K17428 (N. Tsuchida) and JP20K08164 (T. Mizuguchi)"],"award-info":[{"award-number":["JP19H03621 (N. Miyake), JP20K07907 (S. Miyatake), JP21K07298 (H. Doi), JP21K07869 (E. Koshimizu), JP20K16932 (K. Hamanaka), JP20K17936 (A. Fujita), JP21K15907 (Y. Uchiyama), JP20K17428 (N. Tsuchida) and JP20K08164 (T. Mizuguchi)"]}]},{"name":"Takeda Science Foundation (H. Doi, N. Miyake, T. Mizuguchi and N. Matsumoto) and a Grant for Strategic Research Promotion from Yokohama City University","award":["F. Tanaka: #SK2804"],"award-info":[{"award-number":["F. Tanaka: #SK2804"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied.<\/jats:p>\n                  <jats:p>To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION.<\/jats:p>\n                  <jats:p>We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp\/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp\/(AAGGG)exp] (ACAGG\/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp\/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11\/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG\/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort.<\/jats:p>\n                  <jats:p>Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.<\/jats:p>","DOI":"10.1093\/brain\/awab363","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T08:48:19Z","timestamp":1633078099000},"page":"1139-1150","source":"Crossref","is-referenced-by-count":36,"title":["Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7587-5168","authenticated-orcid":false,"given":"Satoko","family":"Miyatake","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"},{"name":"Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Koshimizu","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-2523","authenticated-orcid":false,"given":"Hiroshi","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8381-4274","authenticated-orcid":false,"given":"Mitsunori","family":"Yamada","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Miyaji","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohisa","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tsuyuzaki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Asama Nanroku Komoro Medical Center, Komoro, Nagano 384-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minori","family":"Kodaira","sequence":"additional","affiliation":[{"name":"Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Onoue","sequence":"additional","affiliation":[{"name":"Department of Neurology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama 343-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Taguri","sequence":"additional","affiliation":[{"name":"Department of Data Science, Yokohama City University School of Data Science, Yokohama, Kanagawa 236-0027, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Imamura","sequence":"additional","affiliation":[{"name":"Fisheries Technology Institute, Japan Fisheries Research and Education Agency, 2-12-4 Fukuura, Kanazawa, Yokohama, Kanagawa, 236-8648, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"},{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Hamanaka","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takabumi","family":"Miyama","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuko","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kurita","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa 245-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Okubo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitaru","family":"Kishida","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Koyano","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa 236-0037, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa 245-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoya","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Higashida","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Yoshikura","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gifu University Graduate School of Medicine, Gifu 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"},{"name":"Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Miyake","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Shimohata","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gifu University Graduate School of Medicine, Gifu 501-1194, 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