{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:21Z","timestamp":1787028621501,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Although larger trinucleotide expansions give rise to a neurodevelopmental disorder called fragile X syndrome, fragile X-associated tremor\/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a \u201cpremutation\u201d (55\u2013200 CGG repeats) in the FMR1 gene. FXTAS is one of the more common single-gene forms of late-onset ataxia and tremor that may have a more complex development in women, with atypical presentations. After a brief presentation of the atypical case of an Italian woman with FXTAS, who had several paroxysmal episodes suggestive of acute cerebellar and\/or brainstem dysfunction, this article will revise the phenotype of FXTAS in women. Especially in females, FXTAS has a broad spectrum of symptoms, ranging from relatively severe diseases in mid-adulthood to mild cases beginning in later life. Female FXTAS and male FXTAS have a different symptomatic spectrum, and studies on the fragile X premutation should be conducted separately on women or men. Hopefully, a better understanding of the molecular processes involved in the polymorphic features of FXTAS will lead to more specific and effective therapies for this complex disorder.<\/jats:p>","DOI":"10.3390\/jcm11041002","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T22:44:47Z","timestamp":1644965087000},"page":"1002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS): A Gender Perspective"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4847-7812","authenticated-orcid":false,"given":"Daniele","family":"Orsucci","sequence":"first","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Lorenzetti","sequence":"additional","affiliation":[{"name":"Unit of Internal Medicine, Santa Croce Hospital, 55032 Castelnuovo Garfagnana, Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulvia","family":"Baldinotti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, University Hospital of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4019-4412","authenticated-orcid":false,"given":"Andrea","family":"Rossi","sequence":"additional","affiliation":[{"name":"Medical Affairs and Scientific Communications, 1260 Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Vitolo","sequence":"additional","affiliation":[{"name":"Unit of Internal Medicine, Santa Croce Hospital, 55032 Castelnuovo Garfagnana, Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio Luigi","family":"Gheri","sequence":"additional","affiliation":[{"name":"Unit of Internal Medicine, Santa Croce Hospital, 55032 Castelnuovo Garfagnana, Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Unit of Neurology, NOA Hospital, 54100 Massa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Tintori","sequence":"additional","affiliation":[{"name":"Unit of Internal Medicine, Santa Croce Hospital, 55032 Castelnuovo Garfagnana, Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Vista","sequence":"additional","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, Via Lippi-Francesconi, 55100 Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"ref_1","first-page":"107","article-title":"Fragile X-associated tremor\/ataxia syndrome\u2014An older face of the fragile X gene","volume":"3","author":"Hagerman","year":"2007","journal-title":"Nat. Clin. Pr. Cardiovasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3389\/fped.2020.00266","article-title":"Fragile X Premutation Associated Conditions (FXPAC)","volume":"8","author":"Johnson","year":"2020","journal-title":"Front. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/ana.24800","article-title":"Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor\/ataxia syndrome","volume":"80","author":"Krans","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cabal-Herrera, A.M., Tassanakijpanich, N., Salcedo-Arellano, M.J., and Hagerman, R.J. (2020). Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124391"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Salcedo-Arellano, M.J., Cabal-Herrera, A.M., Tassanakijpanich, N., McLennan, Y.A., and Hagerman, R.J. (2020). Ataxia as the Major Manifestation of Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS): Case Series. Biomedicines, 8.","DOI":"10.3390\/biomedicines8050136"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/mdc3.12944","article-title":"A Case of Generalized Chorea Presenting as an Early Feature of Fragile-X Associated Tremor\/Ataxia Syndrome","volume":"7","author":"Islam","year":"2020","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1212\/WNL.0000000000001612","article-title":"White matter disease and cognitive impairment in FMR1 premutation carriers","volume":"84","author":"Filley","year":"2015","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1086\/374321","article-title":"Fragile X premutation tremor\/ataxia syndrome: Molecular, clinical, and neuroimaging correlates","volume":"72","author":"Jacquemont","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/S1474-4422(13)70125-X","article-title":"Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor\/ataxia syndrome","volume":"12","author":"Hagerman","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"212576","DOI":"10.7573\/dic.212576","article-title":"Therapy of episodic ataxias: Case report and review of the literature","volume":"8","author":"Orsucci","year":"2019","journal-title":"Drugs Context"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8","DOI":"10.21037\/atm.2019.11.31","article-title":"Complicated paroxysmal kinesigenic dyskinesia associated with SACS mutations","volume":"8","author":"Lu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ijdevneu.2014.07.002","article-title":"EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome","volume":"38","author":"Heard","year":"2014","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1086\/420700","article-title":"Fragile-X\u2013Associated Tremor\/Ataxia Syndrome (FXTAS) in Females with the FMR1 Premutation","volume":"74","author":"Hagerman","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/mdc3.13045","article-title":"Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X-associated Tremor\/Ataxia Syndrome","volume":"7","author":"Bang","year":"2020","journal-title":"Mov. Disord. Clin. Pr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102332","DOI":"10.1016\/j.nicl.2020.102332","article-title":"Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers","volume":"27","author":"McKinney","year":"2020","journal-title":"NeuroImage Clin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/s41431-019-0554-7","article-title":"Methylated premutation of the FMR1 gene in three sisters: Correlating CGG expansion and epigenetic inactivation","volume":"28","author":"Tabolacci","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/cge.12646","article-title":"Neurological and endocrine phenotypes of fragile X carrier women","volume":"89","author":"Hall","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/mdc3.13084","article-title":"Women with Fragile X\u2013associated Tremor\/Ataxia Syndrome","volume":"7","author":"Schneider","year":"2020","journal-title":"Mov. Disord. Clin. Pr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/molehr\/gaaa057","article-title":"The molecular mechanisms that underlie fragile X-associated premature ovarian insufficiency: Is it RNA or protein based?","volume":"26","author":"Rosario","year":"2020","journal-title":"Mol. Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1002\/mds.28559","article-title":"Cerebral Microbleeds in Fragile X\u2013Associated Tremor\/Ataxia Syndrome","volume":"36","author":"Wang","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16676","DOI":"10.1096\/fj.202001880R","article-title":"Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS)","volume":"34","author":"Zafarullah","year":"2020","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Abbasi, D.A., Nguyen, T.T.A., Hall, D.A., Robertson-Dick, E., Berry-Kravis, E., and Cologna, S.M. (2021). Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor\/Ataxia Syndrome. Cerebellum.","DOI":"10.1007\/s12311-021-01262-7"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"578640","DOI":"10.3389\/fmolb.2020.578640","article-title":"Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked FMR1 Gene","volume":"7","author":"Napoli","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"165918","DOI":"10.1016\/j.bbadis.2020.165918","article-title":"The emerging molecular mechanisms for mitochondrial dysfunctions in FXTAS","volume":"1866","author":"Gohel","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00439-019-02104-7","article-title":"Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene","volume":"139","author":"NNobile","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.mito.2020.03.004","article-title":"Role of mitochondrial DNA variants in the development of fragile X-associated tremor\/ataxia syndrome","volume":"52","author":"Santos","year":"2020","journal-title":"Mitochondrion"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12565","DOI":"10.1111\/gbb.12565","article-title":"Fragile X-associated tremor\/ataxia syndrome: Regional decrease of mitochondrial DNA copy number relates to clinical manifestations","volume":"18","author":"Podlesniy","year":"2019","journal-title":"Genes Brain Behav."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, J., Napoli, E., Kim, K., McLennan, Y.A., Hagerman, R.J., and Giulivi, C. (2021). Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179171"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105427","DOI":"10.1016\/j.nbd.2021.105427","article-title":"Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome","volume":"157","author":"Napoli","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.1007\/s12035-018-1330-3","article-title":"Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor\/Ataxia Syndrome: A Pilot Study","volume":"56","author":"Napoli","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s13311-017-0555-6","article-title":"Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor\/Ataxia Syndrome","volume":"14","author":"Wang","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/WCO.0000000000000954","article-title":"Fragile X-associated tremor\/ataxia syndrome: Pathophysiology and management","volume":"34","author":"Hagerman","year":"2021","journal-title":"Curr. Opin. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1007\/s10072-021-05310-2","article-title":"Thrombocytopenia and agranulocytosis in a FXTAS choreic patient treated with tetrabenazine","volume":"42","author":"Lapostolle","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1093\/hmg\/ddab143","article-title":"Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation","volume":"30","author":"Haify","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41467-021-21021-w","article-title":"Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats","volume":"12","author":"Derbis","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Higuchi, Y., Ando, M., Yoshimura, A., Hakotani, S., Koba, Y., Sakiyama, Y., Hiramatsu, Y., Tashiro, Y., Maki, Y., and Hashiguchi, A. (2021). Prevalence of Fragile X-Associated Tremor\/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan. Cerebellum.","DOI":"10.1007\/s12311-021-01323-x"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Almansour, A., Ishiura, H., Mitsui, J., Matsukawa, T., Matsukawa, M.K., Shimizu, H., Sugiyama, A., Toda, T., and Tsuji, S. (2021). Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population. Cerebellum.","DOI":"10.1007\/s12311-021-01329-5"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Martin, E.M., Zhu, Y., Kraan, C.M., Kumar, K.R., Godler, D.E., and Field, M. (2021). Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor\/ataxia syndrome (FXTAS). J. Med. Genet., 107758.","DOI":"10.1136\/jmedgenet-2021-107758"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104740","DOI":"10.1016\/j.nbd.2020.104740","article-title":"Fragile X syndrome and associated disorders: Clinical aspects and pathology","volume":"136","author":"Dufour","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40673-021-00138-0","article-title":"Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways","volume":"8","author":"Storey","year":"2021","journal-title":"Cerebellum Ataxia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1002\/mds.28683","article-title":"Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community-Based Cohort","volume":"36","author":"Mailick","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s11689-022-09415-3","article-title":"Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation","volume":"14","author":"Klusek","year":"2022","journal-title":"J. Neurodev. Disord."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"577246","DOI":"10.3389\/fmolb.2020.577246","article-title":"Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement","volume":"7","author":"Loesch","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/mdc3.13234","article-title":"Dystonia in a Female Fragile X Premutation Carrier","volume":"8","author":"Latorre","year":"2021","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"752973","DOI":"10.3389\/fnins.2021.752973","article-title":"Allopregnanolone Improves Locomotor Activity and Arousal in the Aged CGG Knock-in Mouse Model of Fragile X-Associated Tremor\/Ataxia Syndrome","volume":"5","author":"Schwartzer","year":"2021","journal-title":"Front Neurosci."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/4\/1002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:19:49Z","timestamp":1760134789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/4\/1002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,15]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jcm11041002"],"URL":"https:\/\/doi.org\/10.3390\/jcm11041002","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,15]]}}}