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Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations

Authors

  • Coro Paisán-Ruiz PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Rocio Guevara BSc,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Monica Federoff MS,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Hasmet Hanagasi MD,

    1. Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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  • Fardaz Sina MD,

    1. Iran University of Medical Sciences, Hazrat Rasool Hospital, Tehran, Iran
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  • Elahe Elahi PhD,

    1. Department of Biotechnology, University of Tehran, Tehran, Iran
    2. School of Biology, University College of Science, University of Tehran, Tehran, Iran
    3. Center of Excellence in Biomathematics, School of Mathematics, Statistics and Computer Science, College of Science, University of Tehran, Tehran, Iran
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  • Susanne A. Schneider MD,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom
    2. Schilling Section of Clinical and Molecular Neurogenetics, Department of Neurology, University Luebeck, Germany
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  • Petra Schwingenschuh MD,

    1. Schilling Section of Clinical and Molecular Neurogenetics, Department of Neurology, University Luebeck, Germany
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  • Nin Bajaj MD,

    1. Department of Neurology, Queens Medical Center, University of Nottingham, Nottingham, United Kingdom
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  • Murat Emre MD,

    1. Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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  • Andrew B. Singleton PhD,

    1. Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Mary Land, USA
    2. Public Health Sciences and Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
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  • John Hardy PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Kailash P. Bhatia MD,

    Corresponding author
    1. Schilling Section of Clinical and Molecular Neurogenetics, Department of Neurology, University Luebeck, Germany
    • Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom, WCIN 3BG
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  • Sebastian Brandner PhD,

    1. Division of Neuropathology, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
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  • Andrew J. Lees MD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Henry Houlden MD

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Potential conflict of interest: Nothing to report.

Abstract

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. © 2010 Movement Disorder Society.

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