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dc.contributor.authorLoesch, Danuta Z
dc.contributor.authorTassone, Flora
dc.contributor.authorAtkinson, Anna
dc.contributor.authorStimpson, Paige
dc.contributor.authorTrost, Nicholas
dc.contributor.authorPountney, Dean L
dc.contributor.authorStorey, Elsdon
dc.date.accessioned2021-02-14T23:05:33Z
dc.date.available2021-02-14T23:05:33Z
dc.date.issued2020
dc.identifier.issn2296-889Xen_US
dc.identifier.doi10.3389/fmolb.2020.577246en_US
dc.identifier.urihttp://hdl.handle.net/10072/402091
dc.description.abstractExpansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called "Fragile X-Associated Tremor Ataxia Syndrome" (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40-50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.en_US
dc.description.peerreviewedYesen_US
dc.languageengen_US
dc.publisherFrontiers Media SAen_US
dc.relation.ispartofpagefrom577246en_US
dc.relation.ispartofjournalFront Mol Bioscien_US
dc.relation.ispartofvolume7en_US
dc.subject.fieldofresearchClinical Sciencesen_US
dc.subject.fieldofresearchcode1103en_US
dc.subject.keywordsCGG repeaten_US
dc.subject.keywordsFMR1 premutationen_US
dc.subject.keywordsfemale carriersen_US
dc.subject.keywordsgender differencesen_US
dc.subject.keywordsmotor scoresen_US
dc.titleDifferential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement.en_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationLoesch, DZ; Tassone, F; Atkinson, A; Stimpson, P; Trost, N; Pountney, DL; Storey, E, Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement., Front Mol Biosci, 2020, 7, pp. 577246en_US
dcterms.dateAccepted2020-12-09
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-02-14T22:49:06Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 2021 Loesch, Tassone, Atkinson, Stimpson, Trost, Pountney and Storey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
gro.hasfulltextFull Text
gro.griffith.authorPountney, Dean L.


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