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Here, we hypothesized that biallelic <jats:italic>RFC1<\/jats:italic> expansions may also represent a recurrent cause of DBN syndrome.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We genotyped the <jats:italic>RFC1<\/jats:italic> repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an <jats:italic>FGF14<\/jats:italic> GAA expansion, and 36 patients with presumed secondary DBN.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Biallelic <jats:italic>RFC1<\/jats:italic> AAGGG expansions were identified in 15\/65 patients with idiopathic DBN (23%). None of the 102 GAA-<jats:italic>FGF14<\/jats:italic>-positive patients, but 2\/36 (6%) of patients with presumed secondary DBN carried biallelic <jats:italic>RFC1<\/jats:italic> expansions. The DBN syndrome in <jats:italic>RFC1<\/jats:italic>-positive patients was characterized by additional cerebellar impairment in 100% (15\/15), bilateral vestibulopathy (BVP) in 100% (15\/15), and polyneuropathy in 80% (12\/15) of cases. Compared to GAA-<jats:italic>FGF14<\/jats:italic>-positive and genetically unexplained patients, <jats:italic>RFC1<\/jats:italic>-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in <jats:italic>RFC1<\/jats:italic>-positive patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>Biallelic <jats:italic>RFC1<\/jats:italic> expansions are a common monogenic cause of DBN syndrome.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-024-12229-z","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T15:03:29Z","timestamp":1708527809000},"page":"2886-2892","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile"],"prefix":"10.1007","volume":"271","author":[{"given":"David","family":"Pellerin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Heindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Trasch\u00fctz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Rujescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette M.","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Brais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Dufke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Riess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Haack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Strupp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-7273","authenticated-orcid":false,"given":"Matthis","family":"Synofzik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"issue":"6","key":"12229_CR1","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1097\/icu.0000000000000802","volume":"32","author":"TM Tran","year":"2021","unstructured":"Tran TM, Lee MS, McClelland CM (2021) Downbeat nystagmus: a clinical review of diagnosis and management. 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FH reports no disclosures. AT reports no disclosures. DR has received grant\/research support from Janssen and Lundbeck; he has served as a consultant or on advisory boards for AC Immune, Janssen, Roche and Rovi and he has served on speakers\u00b4 bureaus of Janssen and Pharmgenetix. He also received honoraria from Gerot Lannacher, Janssen and Pharmgenetix, and travel support from Angelini and Janssen, all unrelated to the present manuscript. AMH reports no disclosures. BB reports no disclosures. HH reports no disclosures. CD reports no disclosures.OR reports no disclosures. TH reports no disclosures. MSt is Joint Chief Editor of the Journal of Neurology, Editor in Chief of Frontiers of Neuro-otology and Section Editor of F1000. He has received speakers honoraria from Abbott, Auris Medical, Biogen, Eisai, Gr\u00fcnenthal, GSK, Henning Pharma, Interacoustics, J&J, MSD, NeuroUpdate, Otometrics, Pierre-Fabre, TEVA, UCB, and Viatris. He receives support for clinical studies from Decibel, U.S.A., Cure within Reach, U.S.A. and Heel, Germany. He distributes M-glasses and Positional vertigo App. He acts as a consultant for Abbott, AurisMedical, Bulbitec, Heel, IntraBio, Sensorion and Vertify. He is an investor and share-holder of IntraBio. All are unrelated to the present manuscript. MSy has received consultancy honoraria from Janssen, Ionis, Orphazyme, Servier, Reata, Biohaven, Zevra, Lilly, GenOrph, and AviadoBio, all unrelated to the present manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This study was approved by the ethics committee of the LMU Munich and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent from all the participants was obtained.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}