{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:25:39Z","timestamp":1791293139551,"version":"4.1.0"},"reference-count":45,"publisher":"BMJ","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Male carriers of the\n                      <jats:italic>FMR1<\/jats:italic>\n                      premutation are at risk of developing the fragile X\u2013associated tremor\/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score \u2a7d123 on the MDRS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p&lt;0.01 and p&lt;0.03 for logistic and survival model, respectively) role in cognitive impairment. The estimated penetrance of marked cognitive impairment in our sample (adjusted for the mean age 63.4 years and mean education level 9.7 years) for midsize\/large (70\u2013200 CGG) and small (55\u201369 CGG) premutation alleles was 33.3% (relative risk (RR) 6.5; p\u200a=\u200a0.01) and 5.9% (RR 1.15; p\u200a=\u200a0.9) respectively. Penetrance in the control group was 5.1%.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. In addition, it was observed that cognitive impairment may precede motor symptoms. These data provide guidance for genetic counselling although larger samples are required to refine these estimates.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg.2008.065953","type":"journal-article","created":{"date-parts":[[2009,6,19]],"date-time":"2009-06-19T20:18:14Z","timestamp":1245442694000},"page":"818-824","source":"Crossref","is-referenced-by-count":52,"title":["Penetrance of marked cognitive impairment in older male carriers of the\n                    <i>FMR1<\/i>\n                    gene premutation"],"prefix":"10.1136","volume":"46","author":[{"given":"M","family":"S\u00e9vin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Kutalik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Bergman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Vercelletto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Renou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Lamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F J","family":"Vingerhoets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Di Virgilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Boisseau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Bezieau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Pasquier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-M","family":"Rival","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J S","family":"Beckmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Damier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Jacquemont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2009,6,18]]},"reference":[{"key":"2025101713402939000_46.12.818.1","doi-asserted-by":"publisher","DOI":"10.1159\/000057963"},{"key":"2025101713402939000_46.12.818.2","doi-asserted-by":"publisher","DOI":"10.1086\/420700"},{"key":"2025101713402939000_46.12.818.3","doi-asserted-by":"publisher","DOI":"10.1086\/374321"},{"key":"2025101713402939000_46.12.818.4","doi-asserted-by":"publisher","DOI":"10.1086\/386296"},{"key":"2025101713402939000_46.12.818.5","doi-asserted-by":"publisher","DOI":"10.1038\/ncpneuro0373"},{"key":"2025101713402939000_46.12.818.6","first-page":"1757","article-title":"Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction.","volume":"23","author":"Brunberg","year":"2002","journal-title":"AJNR Am J Neuroradiol"},{"key":"2025101713402939000_46.12.818.7","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20542"},{"key":"2025101713402939000_46.12.818.8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.291.4.460"},{"key":"2025101713402939000_46.12.818.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropsychologia.2004.05.002"},{"key":"2025101713402939000_46.12.818.10","doi-asserted-by":"publisher","DOI":"10.1097\/01.wnn.0000213906.57148.01"},{"key":"2025101713402939000_46.12.818.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2006.05.016"},{"key":"2025101713402939000_46.12.818.12","doi-asserted-by":"publisher","DOI":"10.1176\/appi.neuropsych.18.2.171"},{"key":"2025101713402939000_46.12.818.13","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21359"},{"key":"2025101713402939000_46.12.818.14","doi-asserted-by":"crossref","unstructured":"Brega AG Goodrich G Bennett RE Hessl D Engle K Leehey MA Bounds LS Paulich MJ Hagerman RJ Hagerman PJ Cogswell JB Tassone F Reynolds A Kooken R Kenny M Grigsby J . 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