A novel X-linked four-repeat tauopathy with Parkinsonism and spasticity

Authors

  • Parvoneh Poorkaj PhD,

    Corresponding author
    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
    2. Department of Medicine, University of Washington, Seattle, Washington, USA
    • Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, 1959 NE Pacific Street, Seattle, WA 98195

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  • Wendy H. Raskind MD, PhD,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
    2. Department of Medicine, University of Washington, Seattle, Washington, USA
    3. VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • James B. Leverenz MD,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
    2. VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
    3. Department of Neurology, University of Washington, Seattle, Washington, USA
    4. Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • Mark Matsushita BS,

    1. Department of Medicine, University of Washington, Seattle, Washington, USA
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  • Cyrus P. Zabetian MS, MD,

    1. Department of Neurology, University of Washington, Seattle, Washington, USA
    2. Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
    3. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • Ali Samii MD,

    1. Department of Neurology, University of Washington, Seattle, Washington, USA
    2. Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • Sophia Kim BS,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
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  • Nayiry Gazi BS,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
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  • John G. Nutt MD,

    1. Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA
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  • John Wolff BS,

    1. Department of Medicine, University of Washington, Seattle, Washington, USA
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  • Dora Yearout BS,

    1. Department of Neurology, University of Washington, Seattle, Washington, USA
    2. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • J. Lynne Greenup,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
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  • Ellen J. Steinbart MA, RN,

    1. Department of Neurology, University of Washington, Seattle, Washington, USA
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  • Thomas D. Bird MD

    1. Department of Medicine, University of Washington, Seattle, Washington, USA
    2. Department of Neurology, University of Washington, Seattle, Washington, USA
    3. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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  • Potential conflict of interest: Nothing to report.

Abstract

The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society

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