{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:40:00Z","timestamp":1759970400107,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SID-BIRD 2023 Fund","award":["DI_G_BIRD23_01"],"award-info":[{"award-number":["DI_G_BIRD23_01"]}]},{"name":"FRAXA Foundation","award":["DI_G_BIRD23_01"],"award-info":[{"award-number":["DI_G_BIRD23_01"]}]},{"name":"PRIN","award":["DI_G_BIRD23_01"],"award-info":[{"award-number":["DI_G_BIRD23_01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder that causes a range of developmental problems including cognitive and behavioral impairment and learning disabilities. FXS is caused by full mutations (FM) of the FMR1 gene expansions to over 200 repeats, with hypermethylation of the cytosine\u2013guanine\u2013guanine (CGG) tandem repeated region in its promoter, resulting in transcriptional silencing and loss of gene function. Female carriers of FM are typically less impaired than males. The Activation Ratio (AR), the fraction of the normal allele carried on the active X chromosome, is thought to play a crucial modifying role in defining phenotype severity. Here, we compare the cognitive, neuropsychological, adaptive, and behavioral profile of two FXS girls (10 and 11 years old) with seemingly identical FMR1 genotypic profile of FM but distinctive AR levels (70% vs. 30%). A multi-method protocol, combining molecular pathophysiology and phenotypical measures, parent reports, lab-based tasks, gait analyses, and eye-tracking was employed. Results showed that lower AR corresponds to worse performances in most (cognitive, neuropsychological, adaptive, behavioral, social, mathematical skills), but not all the considered areas (i.e., time perception and gait analysis). These observations underscore the importance of AR as a phenotypic modifying parameter in females affected with FXS.<\/jats:p>","DOI":"10.3390\/ijms26020771","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T12:32:52Z","timestamp":1737376372000},"page":"771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurobehavioral Outcomes Relate to Activation Ratio in Female Carriers of Fragile X Syndrome Full Mutation: Two Pediatric Case Studies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1094-2363","authenticated-orcid":false,"given":"Elisa","family":"Di Giorgio","sequence":"first","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-7372","authenticated-orcid":false,"given":"Silvia","family":"Benavides-Varela","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"},{"name":"Padova Neuroscience Center, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9896-1648","authenticated-orcid":false,"given":"Annamaria","family":"Porru","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Caviola","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-4491","authenticated-orcid":false,"given":"Marco","family":"Lunghi","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"},{"name":"Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-6267","authenticated-orcid":false,"given":"Paola","family":"Rigo","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"},{"name":"Padova Neuroscience Center, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1212-4591","authenticated-orcid":false,"given":"Giovanna","family":"Mioni","sequence":"additional","affiliation":[{"name":"Department of General Psychology, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2913-8770","authenticated-orcid":false,"given":"Giulia","family":"Calignano","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Annunziata","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2570-7128","authenticated-orcid":false,"given":"Eloisa","family":"Valenza","sequence":"additional","affiliation":[{"name":"Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy"},{"name":"Padova Neuroscience Center, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Liani","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2549-2147","authenticated-orcid":false,"given":"Federica","family":"Beghetti","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4723-0546","authenticated-orcid":false,"given":"Fabiola","family":"Spolaor","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"},{"name":"Department of Information Engineering, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Bettella","sequence":"additional","affiliation":[{"name":"Neurodevelopment Molecular Genetics Laboratory, Department of Women\u2019s and Children\u2019s Health, University of Padova, 35127 Padova, Italy"},{"name":"Istituto di Ricerca Pediatrica, Foundation-Citt\u00e0 della Speranza, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7169-7111","authenticated-orcid":false,"given":"Roberta","family":"Polli","sequence":"additional","affiliation":[{"name":"Neurodevelopment Molecular Genetics Laboratory, Department of Women\u2019s and Children\u2019s Health, University of Padova, 35127 Padova, Italy"},{"name":"Istituto di Ricerca Pediatrica, Foundation-Citt\u00e0 della Speranza, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2624-5415","authenticated-orcid":false,"given":"Zimi","family":"Sawacha","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6788-0653","authenticated-orcid":false,"given":"Alessandra","family":"Murgia","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"},{"name":"Neurodevelopment Molecular Genetics Laboratory, Department of Women\u2019s and Children\u2019s Health, University of Padova, 35127 Padova, Italy"},{"name":"Istituto di Ricerca Pediatrica, Foundation-Citt\u00e0 della Speranza, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17065","DOI":"10.1038\/nrdp.2017.65","article-title":"Fragile X syndrome","volume":"3","author":"Hagerman","year":"2017","journal-title":"Nat. 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