Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2025 Mar 20;26(6):2825.
doi: 10.3390/ijms26062825.

Premutation Females with preFXTAS

Valentina Liani  1   2 , Carme Torrents  1   3 , Elisa Rolleri  1   4 , Nor Azyati Yusoff  1   5 , Narueporn Likhitweerawong  1   6 , Sydney Moore  1 , Flora Tassone  1   7 , Andrea Schneider  1   8 , Ellery Santos  1   8 , Hazel M B Biag  1   8 , James A Bourgeois  9 , Kathryn E Unruh  10 , Matthew W Mosconi  10 , Randi J Hagerman  1
Affiliations
Case Reports

Premutation Females with preFXTAS

Valentina Liani et al. Int J Mol Sci. .

Abstract

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder associated with the FMR1 gene premutation, characterized by the presence of 55 to 200 CGG triplet repeat expansions. Although the initial symptoms of FXTAS typically manifest in males around the age of 60 with motor symptoms and cognitive deficits, the presentation and progression in females differ. Women, in fact, exhibit a higher prevalence of neuropsychiatric symptoms, with an earlier onset compared to the motor symptoms observed in men. The following article reports on ten cases of women with a diagnosis of FMR1 gene premutation, originating from two medical centers. All the women in the study exhibited neuropsychiatric symptoms and subtle neurological signs as common features. Symptoms typically observed in the male population, such as tremors and cerebellar ataxia, were either absent or significantly reduced in the female cohort. Conversely, there was a higher prevalence of neuropsychiatric symptoms among the women. Neurocognitive impairment was only minimally evident, with mild executive dysfunction and memory complaints noted in a subset of cases. For this reason, we propose the terminology preFXTAS or prodromic FXTAS to define a clinical presentation in women characterized by early manifestations of FXTAS that do not entirely fulfill the established diagnostic criteria but exhibit MRI evidence of white matter alterations suggesting the initiation of the disease process. The study underscores the importance of establishing new diagnostic criteria for FXTAS and, at the same time, developing new biomarkers and interview checklists/assessment scales dedicated to females.

Keywords: FMR1 gene; FXTAS; neurological problems; neuropsychiatric problems; premutation.

PubMed Disclaimer

Conflict of interest statement

R.J.H. has received funding from Zynerba Pharmaceuticals and Tetra/Shionogi for clinical trials in those with fragile X syndrome. J.A.B. is funded by Abbott for research in deep brain stimulation for depressive disorders and receives royalties from various medical publishers. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Splenium sign ((a): Case 3, (b): Case 5), white matter disease ((c): Case 6) white matter disease in the genu and splenium of the corpus callosum and in periventricular area ((d): Case 7).
Figure 1
Figure 1
Splenium sign ((a): Case 3, (b): Case 5), white matter disease ((c): Case 6) white matter disease in the genu and splenium of the corpus callosum and in periventricular area ((d): Case 7).
See this image and copyright information in PMC

References

    1. Tassone F., Hagerman R.J., Taylor A.K., Gane L.W., Godfrey T.E., Hagerman P.J. Elevated levels of FMR1 mRNA in carrier males: A new mechanism of involvement in the fragile-X syndrome. Am. J. Hum. Genet. 2000;66:6–15. doi: 10.1086/302720. - DOI - PMC - PubMed
    1. Tassone F., Protic D., Allen E.G., Archibald A.D., Baud A., Brown T.W., Budimirovic D.B., Cohen J., Dufour B., Eiges R., et al. Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation. Cells. 2023;12:2330. doi: 10.3390/cells12182330. - DOI - PMC - PubMed
    1. Dufour B.D., Bartley T., McBride E., Allen E., McLennan Y.A., Hagerman R.J., Martínez-Cerdeño V. FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration. Ann. Neurol. 2024;95:558–575. doi: 10.1002/ana.26851. - DOI - PMC - PubMed
    1. Leehey M.A. Fragile X-associated tremor/ataxia syndrome: Clinical phenotype, diagnosis, and treatment. J. Investig. Med. 2009;57:830–836. doi: 10.2310/JIM.0b013e3181af59c4. - DOI - PMC - PubMed
    1. Jacquemont S., Hagerman R.J., Leehey M.A., Hall D.A., Levine R.A., Brunberg J.A., Zhang L., Jardini T., Gane L.W., Harris S.W., et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291:460–469. doi: 10.1001/jama.291.4.460. - DOI - PubMed

Publication types

Substances

Supplementary concepts