Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation

Authors

  • Aikaterina Angeli MD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Niccolo E. Mencacci MD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
    2. Department of Neurology and Laboratory of Neuroscience, “Dino Ferrari” Centre, Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, Milan, Italy
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  • Raquel Duran MD,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
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  • Iciar Aviles-Olmos MD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Zinovia Kefalopoulou MD, PhD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Joseph Candelario BSc,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Sarah Rusbridge BSc,

    1. Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Jennifer Foley PhD,

    1. Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Priyanka Pradhan PhD,

    1. Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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  • Marjan Jahanshahi PhD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Ludvic Zrinzo MD, PhD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Marwan Hariz MD, PhD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Nicholas W. Wood PhD, FRCP,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
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  • John Hardy PhD, FRS, FMedSci,

    1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
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  • Patricia Limousin MD, PhD,

    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Tom Foltynie MRCP, MD

    Corresponding author
    1. Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
    • Correspondence to: Dr. Thomas Foltynie, Box 146, National Hospital for Neurology & Neurosurgery, Queen Square, London, WC1N 3BG United Kingdom; t.foltynie@ucl.ac.uk

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  • Funding agencies: This work was supported by Parkinson's UK (grant number K-0901 awarded to T.F.), the National Institute for Health Research (NIHR) UCL/UCLH Biomedical Research Centres funding Scheme and The Wellcome Trust/Medical Research Council (MRC) funded UK Parkinson's disease consortium.

  • 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

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

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