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  • Review Article
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Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

Nature Reviews Neurology volume 12, pages 403–412 (2016)Cite this article

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Key Points

  • Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition in carriers of premutations in the FMR1 gene; only 40–75% of males and 16–20% of females with premutations develop FXTAS

  • Premutation carriers can experience neurodevelopmental and reproductive problems earlier in life, as well as other symptoms that may require treatment, including hypertension, hypothyroidism, primary ovarian insufficiency, migraines, insomnia, sleep apnoea, depression and anxiety

  • Presentation of FXTAS is variable and can include tremor, cerebellar ataxia, neuropathy and/or cognitive decline; radiological features include brain atrophy and white matter disease in specific brain regions

  • The clinical manifestations of FXTAS require expression of the abnormal FMR1 mRNA, but the mechanistic link between the mRNA and disease manifestations is unclear

  • Proposed molecular mechanisms of FXTAS pathogenesis, including sequestration of proteins by the excess FMR1 mRNA, production of toxic FMRPolyG protein, and chronic activation of the DNA damage repair process

  • Advances in understanding the pathogenesis of FXTAS could enable development of targeted therapies that are more effective than current management

Abstract

Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55–200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150–300 females, and 1 in 400–850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

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Figure 1: Proposed mechanisms for the pathogenesis of FXTAS.

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Article 11 November 2021

Thomas Welton, Francisco Cardoso, … Eng-King Tan

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Acknowledgements

This work was supported by NICHD grant # R01 HD036071, MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125), and NICHD grant # R01 HD040661.

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  1. MIND Institute and Department of Pediatrics, University of California, Davis, Medical Center, 2825 50th Street, Sacramento, 95817, California, USA

    Randi J. Hagerman

  2. Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, 95616, California, USA

    Paul Hagerman

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Correspondence to Randi J. Hagerman.

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Competing interests

R.H. has received funding from Alcobra, Neuren, Novartis, Roche and Seaside Therapeutics to carry out treatment studies in fragile X syndrome, autism and Down syndrome. R.H. has also consulted with Novartis, Roche/Genentech and Zynerba regarding treatment studies in fragile X syndrome. P.H. is an uncompensated collaborator with Pacific Biosciences and Roche regarding new FMR1 sequencing strategies; he holds patents for FMR1 genotyping and protein tests.

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Hagerman, R., Hagerman, P. Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management. Nat Rev Neurol 12, 403–412 (2016). https://doi.org/10.1038/nrneurol.2016.82

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