{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:01:52Z","timestamp":1761609712689,"version":"build-2065373602"},"reference-count":22,"publisher":"Georg Thieme Verlag KG","issue":"11","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arq Neuropsiquiatr"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The syndrome defined by cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS) has been previously described as a cause of late-onset ataxia. With the discovery of biallelic expansion in the replication factor C subunit 1 (RFC1) gene as its underlying genetic cause, this syndrome and the broader gene disease became more clinically heterogeneous and one of the most common genetic causes of ataxia in adults.<\/jats:p>\n                  <jats:p>To characterize the phenotypic spectrum of RFC1 expansion using a multidisciplinary approach combining neurological, otoneurological, and neuroimaging assessments.<\/jats:p>\n                  <jats:p>A retrospective cohort study comprising patients with a genetically confirmed diagnosis of biallelic RFC1 repeat expansions was conducted. Data related to neurological examination, video head impulse test (vHIT), caloric tests, posturography, electromyography\/nerve conduction studies and brain magnetic resonance imaging (MRI) were considered.<\/jats:p>\n                  <jats:p>We included 15 patients, of whom 10 (66.7%) presented with the complete clinical triad. At neurological examination, 13 patients showed signs of peripheral neuropathy. Cerebellar dysfunction was observed in 12, whereas postural instability was seen in 11. Electromyography\/nervous conduction studies revealed peripheral neuropathy in all of the cases, while bilateral vestibular dysfunction was confirmed in approximately half of them. The mean balance values from the posturography were lower in the majority (n\u2009=\u200914). In the imaging assessment (n\u2009=\u200911), 6 patients displayed significant vermian atrophy, predominantly in the anterior\/dorsal regions, while the other 5 patients showed moderate atrophy.<\/jats:p>\n                  <jats:p>This study underscores the clinical importance of comprehensive phenotyping and multimodal diagnostic approaches\u2014including neurological, otoneurological, electrophysiological, and imaging assessments\u2014in enhancing diagnostic precision, especially when neurological examination findings are inconclusive or in atypical\/incomplete clinical presentations.<\/jats:p>","DOI":"10.1055\/s-0045-1811723","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T23:56:20Z","timestamp":1761609380000},"page":"001-007","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive phenotyping of RFC1-related disorder: integrating electrophysiological, brain imaging, and otoneurological data in deep phenotyping"],"prefix":"10.1055","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-9323","authenticated-orcid":false,"given":"Andr\u00e9 Aires","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Neurologia, Porto, Portugal."},{"name":"Universidade do Porto, Faculdade de Medicina, Departamento de Neuroci\u00eancias Cl\u00ednicas e Sa\u00fade Mental, Porto, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7579-3733","authenticated-orcid":false,"given":"Pedro L.","family":"Alexandre","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Otorrinolaringologia, Porto, Portugal."},{"name":"Universidade do Porto, Faculdade de Medicina, Departamento de Cirurgia e Fisiologia, Unidade de Otorrinolaringologia, Porto, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7421-5459","authenticated-orcid":false,"given":"Sofia","family":"Vedor","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Neuroradiologia, Porto, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2865-0888","authenticated-orcid":false,"given":"Rita","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Neuroradiologia, Porto, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1132-3983","authenticated-orcid":false,"given":"Pedro","family":"Marques","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Otorrinolaringologia, Porto, Portugal."},{"name":"Universidade do Porto, Faculdade de Medicina, Departamento de Cirurgia e Fisiologia, Unidade de Otorrinolaringologia, Porto, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3312-4283","authenticated-orcid":false,"given":"Lu\u00eds","family":"Braz","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, Servi\u00e7o de Neurologia, Porto, Portugal."},{"name":"Universidade do Porto, Faculdade de Medicina, Departamento de Neuroci\u00eancias Cl\u00ednicas e Sa\u00fade Mental, Porto, Portugal."}]}],"member":"194","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"issue":"11","key":"ref1","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.11477\/mf.1416202222","article-title":"RFC1 CANVAS\/Spectrum Disorder: Historical Details and Clinical Diversity","volume":"74","author":"K Yoshida","year":"2022","journal-title":"Brain Nerve"},{"issue":"01","key":"ref2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1136\/practneurol-2020-002822","article-title":"Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects","volume":"22","author":"A Cortese","year":"2022","journal-title":"Pract Neurol"},{"issue":"05","key":"ref3","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s12311-020-01192-w","article-title":"Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)","volume":"20","author":"M Dupr\u00e9","year":"2021","journal-title":"Cerebellum"},{"volume-title":"RFC1 CANVAS \/ Spectrum Disorder. 2020","author":"A Cortese","key":"ref4"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1111\/j.1749-6632.2011.06158.x","article-title":"Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis","volume":"1233","author":"D J Szmulewicz","year":"2011","journal-title":"Ann N Y Acad Sci"},{"issue":"04","key":"ref6","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1038\/s41588-019-0372-4","article-title":"Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia","volume":"51","author":"A Cortese","year":"2019","journal-title":"Nat Genet"},{"issue":"02","key":"ref7","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1093\/brain\/awz418","article-title":"Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion","volume":"143","author":"A Cortese","year":"2020","journal-title":"Brain"},{"issue":"05","key":"ref8","doi-asserted-by":"publisher","first-page":"e200190","DOI":"10.1212\/cpj.0000000000200190","article-title":"Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome","volume":"13","author":"M J Malaquias","year":"2023","journal-title":"Neurol Clin Pract"},{"issue":"05","key":"ref9","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1111\/ene.15717","article-title":"Association of biallelic RFC1 expansion with early-onset Parkinson's disease","volume":"30","author":"P Ylikotila","year":"2023","journal-title":"Eur J Neurol"},{"issue":"05","key":"ref10","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1093\/brain\/awab072","article-title":"RFC1 expansions are a common cause of idiopathic sensory neuropathy","volume":"144","author":"R Curr\u00f2","year":"2021","journal-title":"Brain"},{"issue":"03","key":"ref11","doi-asserted-by":"publisher","first-page":"e440","DOI":"10.1212\/nxg.0000000000000440","article-title":"Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort","volume":"6","author":"D A Syriani","year":"2020","journal-title":"Neurol Genet"},{"key":"ref12","first-page":"664","volume-title":"Electromyography and Neuromuscular Disorders E-Book: Clinical-Electrophysiologic Correlations (Expert Consult - Online)","author":"D C Preston","year":"2012"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1093\/med\/9780199738687.001.0001","volume-title":"Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice","author":"J Kimura","year":"2013"},{"issue":"01","key":"ref14","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/mus.24943","article-title":"Sensory neuronopathies","volume":"53","author":"K G Gwathmey","year":"2016","journal-title":"Muscle Nerve"},{"issue":"04","key":"ref15","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3233\/ves-170619","article-title":"Bilateral vestibulopathy: Diagnostic criteria Consensus document of the Classification Committee of the B\u00e1r\u00e1ny Society","volume":"27","author":"M Strupp","year":"2017","journal-title":"J Vestib Res"},{"issue":"01","key":"ref16","doi-asserted-by":"publisher","first-page":"130","DOI":"10.5152\/iao.2018.4335","article-title":"Instability in Patients with CANVAS: Can Computerized Dynamic Posturography Help in Diagnosis?","volume":"14","author":"A MM de la Roca-Morales","year":"2018","journal-title":"J Int Adv Otol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"120565","DOI":"10.1016\/j.jns.2023.120565","article-title":"RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit","volume":"446","author":"D S\u00e1nchez-Tejerina","year":"2023","journal-title":"J Neurol Sci"},{"issue":"02","key":"ref18","doi-asserted-by":"publisher","first-page":"304","DOI":"10.5152\/iao.2019.7068","article-title":"Is Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS) a Vestibular Ganglionopathy?","volume":"15","author":"D A Yacovino","year":"2019","journal-title":"J Int Adv Otol"},{"issue":"09","key":"ref19","doi-asserted-by":"publisher","first-page":"e1369","DOI":"10.1212\/wnl.0000000000011528","article-title":"Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease","volume":"96","author":"A Trasch\u00fctz","year":"2021","journal-title":"Neurology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"465","DOI":"10.3233\/ves-140536","article-title":"CANVAS an update: clinical presentation, investigation and management","volume":"24","author":"D J Szmulewicz","year":"2014","journal-title":"J Vestib Res"},{"issue":"05","key":"ref21","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1093\/brain\/awad436","article-title":"Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease","volume":"147","author":"R Curr\u00f2","year":"2024","journal-title":"Brain"},{"issue":"05","key":"ref22","doi-asserted-by":"publisher","first-page":"e543","DOI":"10.1212\/wnl.0000000000201486","article-title":"Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome","volume":"100","author":"R Ronco","year":"2023","journal-title":"Neurology"}],"container-title":["Arquivos de Neuro-Psiquiatria"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/s-0045-1811723.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T23:56:21Z","timestamp":1761609381000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/s-0045-1811723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":22,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,7,28]]},"published-print":{"date-parts":[[2025,11]]}},"alternative-id":["s00451811723"],"URL":"https:\/\/doi.org\/10.1055\/s-0045-1811723","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0004-282X","1678-4227"],"issn-type":[{"type":"print","value":"0004-282X"},{"type":"electronic","value":"1678-4227"}],"subject":[],"published":{"date-parts":[[2025,10,27]]}}}