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Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a “premutation” (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS.

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Acknowledgments

We sincerely thank our premutation carrier and control participants. The authors thank Maura E. Walsh, Tracy Waliczek, and Lili Zhou for assistance with the data collection. We also thank the Rush University Medical Center (RUMC) Generations Program and RUMC Alzheimer’s Research Program for assistance with control subject recruitment. This work was supported by the following: Rush University Cohn Fellowship award (JAO), Rush Translational Science Consortium (DAH), and FRAXA Foundation grant (EBK).

Conflict of Interest

Joan A. O’Keefe reports no disclosures or conflicts of interests related to this manuscript.

Erin Robertson-Dick reports no disclosures or conflicts of interests related to this manuscript.

Deborah A. Hall receives research support from the NIH (R01 NS082416, R01NS074343, R01NS083054), Pfizer, the Anti-Aging Foundation, and the Shapiro Foundation; she reports no conflicts of interests related to this manuscript.

Elizabeth Berry-Kravis has received funding from Novartis, Roche, Neuren, and Alcobra Pharmaceuticals to consult on trial design and conduct clinical trials in FXS and from Asuragen Inc. to develop testing standards for FMR1 testing, as well as research support from NICHD, NINDS, NIMH, and the Merck Foundation. She reports no conflicts of interests related to this manuscript.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina Street, Office 505B, Chicago, IL, 60612, USA

    Joan A. O’Keefe & Erin E. Robertson-Dick

  2. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    Deborah A. Hall & Elizabeth Berry-Kravis

  3. Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA

    Elizabeth Berry-Kravis

  4. Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA

    Elizabeth Berry-Kravis

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  1. Joan A. O’Keefe
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  4. Elizabeth Berry-Kravis
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Correspondence to Joan A. O’Keefe.

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O’Keefe, J.A., Robertson-Dick, E.E., Hall, D.A. et al. Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome. Cerebellum 15, 475–482 (2016). https://doi.org/10.1007/s12311-015-0714-4

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  • DOI: https://doi.org/10.1007/s12311-015-0714-4

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