Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course§

Authors

  • Núria Setó-Salvia BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Àrea de Prehistoria, Universitat Rovira i Virgili, Tarragona, Spain
    3. Institut Català de Paleoecologia Humana i Evolució Social (IPHES), Tarragona, Spain
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  • Javier Pagonabarraga MD, PhD,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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  • Henry Houlden MD, PhD,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College London (UCL), Queen Square, London, United Kingdom
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  • Berta Pascual-Sedano MD, PhD,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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  • Oriol Dols-Icardo BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Arianna Tucci MD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London (UCL), Queen Square, London, United Kingdom
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  • Coro Paisán-Ruiz PhD,

    1. Departments of Neurology, Psychiatry, Genetics and Genomics Sciences, and The Friedman Brain Institute, Mount Sinai School of Medicne. New York, New York, USA
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  • Antonia Campolongo BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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  • Sofía Antón-Aguirre BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Inés Martín BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Laia Muñoz BS,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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  • Enric Bufill MD, PhD,

    1. Neurology Service. Hospital General de Vic., Barcelona, Spain
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  • Lluïsa Vilageliu PhD,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, CIBERER, Barcelona, Spain
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  • Daniel Grinberg PhD,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, CIBERER, Barcelona, Spain
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  • Mónica Cozar BS,

    1. Departament de Genètica, Universitat de Barcelona, IBUB, CIBERER, Barcelona, Spain
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  • Rafael Blesa MD, PhD,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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  • Alberto Lleó MD, PhD,

    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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  • John Hardy PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London (UCL), Queen Square, London, United Kingdom
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  • Jaime Kulisevsky MD, PhD,

    Corresponding author
    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    • Neurology Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, Spain
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  • Jordi Clarimón PhD

    Corresponding author
    1. Neurology Department. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
    • Neurology Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, Spain
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  • Funding agencies: This work was supported by a research grant from CIBERNED and by the Fondo de Investigaciones Sanitarias (PI09/00098 and PI07/1150). Also, this work has been developed in the framework of the Spanish MICINN (CGL2009-12703-C03-02, SAF2010-17589, and SAF2011-25431), and the Catalan AGAUR (2009SGR-188 and 2009SGR-971).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • §

    Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia. © 2011 Movement Disorder Society

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