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Herein, we address the issue of diagnostic delay in Friedreich\u2019s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u200957, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR\u2009=\u20092\u20139) years and it improved significantly after the introduction of genetic testing (2(IQR\u2009=\u20091\u20135) years,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u20090.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u20090.001) as well as in b) patients with late-onset (3(IQR\u2009=\u20091\u20137) vs 2(IQR\u2009=\u20091\u20135) years compared to typical onset &lt;\u200925\u2009years of age,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u20090.03).\n                    <\/jats:p>\n                    <jats:p>\n                      Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r\u2009=\u2009\u2212\u20090,6;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u20090,0001), but not in patients with non-neurological presentation (r\u2009=\u2009\u2212\u20090,1;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00,4). Across 54 siblings\u2019 pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r\u2009=\u2009\u2212\u20090,14,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00,3).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-020-01475-9","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T21:02:47Z","timestamp":1596574967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Onset features and time to diagnosis in Friedreich\u2019s Ataxia"],"prefix":"10.1186","volume":"15","author":[{"given":"Elisabetta","family":"Indelicato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Nachbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Eigentler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Amprosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Matteucci Gothe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Giunti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Arpa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Durr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Sch\u00f6ls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"B\u00fcrk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Pandolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Didszdun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg B.","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1657-7368","authenticated-orcid":false,"given":"Sylvia","family":"Boesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the EFACTS (European Friedreich\u2019s Ataxia Consortium for Translational Studies)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,3]]},"reference":[{"issue":"Suppl 1","key":"1475_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/jnc.12215","volume":"126","author":"P Vankan","year":"2013","unstructured":"Vankan P. 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Written informed consent was given from each subject and legal guardian before inclusion in the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication of anonymized data was given by each participant or legal guardian at the time of inclusion in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"PG is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. CM reports grant from REATA Pharmaceuticals for phase 2 study in the treatment of Friedreich ataxia. TK discloses research funding in the last 12\u2009months from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for an investigator-initiated trial of nicotinamide in Friedreich ataxia, as well as (unrelated to this manuscript) research funding from the Bundesministerium f\u00fcr Bildung und Forschung (BMBF, Federal Ministry of Education and Research), and research funding, travel support and speaker\/consultancy honoraria from Santhera Pharmaceuticals, Retrophin Inc. and ApoPharma Inc.. LS discloses research funding unrelated to this study from CureVac AG (T\u00fcbingen, Germany). MP reports grants from the Friedreich Ataxia Research Alliance, grants from FNRS (Belgium), grants and personal fees from Biomarin, grants and personal fees from Voyager Therapeutics, personal fees from Apopharma, personal fees from Vertex, personal fees from Pfizer, and grants from Euroataxia outside the submitted work. JBS serves on scientific advisory boards for Lundbeck Inc., TEVA, Novartis, ForwardPharma, and Lilly, received funding for travel and speaker honoraria from GlaxoSmithKline, Merz Pharmaceuticals, Medical Tribune, Lundbeck Inc., Pfizer Inc., Boehringer, Bayer, serves as Editor-in-Chief of the Journal of Neurochemistry, and is Associate Editor for eNeuro. SB reports funding from E-Rare-3 \u201cClinical research for new therapeutic uses of already existing molecules (repurposing) in rares diseases\u201d (E_Rare-3JTC2016).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"198"}}