{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:42:35Z","timestamp":1790206955502,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T00:00:00Z","timestamp":1548720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/SAU\u2010GMG\/100240\/2008"],"award-info":[{"award-number":["PTDC\/SAU\u2010GMG\/100240\/2008"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/101352\/2014"],"award-info":[{"award-number":["SFRH\/BD\/101352\/2014"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/91160\/2012"],"award-info":[{"award-number":["SFRH\/BD\/91160\/2012"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Transthyretin (TTR)\u2010related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in <jats:italic>TTR<\/jats:italic>. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR\u2010FAP Val30Met families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed 329 Portuguese patients from 123 families. Repeat length (at <jats:italic>ATXN1<\/jats:italic>, <jats:italic>ATXN2<\/jats:italic>, <jats:italic>ATXN3<\/jats:italic>, <jats:italic>ATXN7<\/jats:italic>, <jats:italic>TBP, ATN1<\/jats:italic>, <jats:italic>HTT<\/jats:italic>, <jats:italic>JPH3<\/jats:italic>, <jats:italic>AR<\/jats:italic>, and <jats:italic>DMPK<\/jats:italic>) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family\u2010centered approach, and generalized estimating equations were used to account for AO correlation between family members.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>For <jats:italic>ATXN2<\/jats:italic>, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR\u2010FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = \u22128.81 to \u22122.19, <jats:italic>p<\/jats:italic> = 0.001). No association was found for the remaining repeat loci.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Length of normal repeats at <jats:italic>ATXN2<\/jats:italic> may modify AO in TTR\u2010FAP Val30Met and may function as a risk factor. This can be due to the role of <jats:italic>ATXN2<\/jats:italic> in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow\u2010up of presymptomatic carriers. <jats:bold>ANN NEUROL 2019;85:251\u2013258.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25409","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T22:56:52Z","timestamp":1546988212000},"page":"251-258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Large normal alleles of <i>ATXN2<\/i> decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients"],"prefix":"10.1002","volume":"85","author":[{"given":"Diana","family":"Santos","sequence":"first","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto"},{"name":"UnIGENe, IBMC, Institute for Molecular and Cell Biology Universidade do Porto"},{"name":"ICBAS, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Coelho","sequence":"additional","affiliation":[{"name":"UCA, Unidade Corino de Andrade Centro Hospitalar do Porto (CHP)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Alves\u2010Ferreira","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto"},{"name":"UnIGENe, IBMC, Institute for Molecular and Cell Biology Universidade do Porto"},{"name":"ICBAS, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto"},{"name":"UnIGENe, IBMC, Institute for Molecular and Cell Biology Universidade do Porto"},{"name":"ICBAS, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"ICBAS, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto"},{"name":"ISPUP, Instituto de Sa\u00fade P\u00fablica Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Alonso","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade Universidade do Porto"},{"name":"UnIGENe, IBMC, Institute for Molecular and Cell Biology Universidade do Porto"},{"name":"ICBAS, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar Universidade do Porto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda","family":"Sousa","sequence":"additional","affiliation":[{"name":"i3S, Instituto de Investiga\u00e7\u00e3o e 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