Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease§

Authors

  • Laura L. Kilarski PhD,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Justin P. Pearson MRCP,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Victoria Newsway BSc,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Elisa Majounie PhD,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • M. Duleeka W. Knipe BSc, MPH,

    1. Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Anjum Misbahuddin PhD MRCP,

    1. Department of Neurology, Barking, Havering & Redbridge University Hospitals NHS Trust, United Kingdom
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  • Patrick F. Chinnery PhD, FRCP,

    1. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom
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  • David J. Burn MD, FRCP,

    1. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom
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  • Carl E. Clarke MD, FRCP,

    1. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. Sandwell and West Birmingham Hospitals NHS Trust, United Kingdom
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  • Marie-Helene Marion MD,

    1. Department of Neurology, St George's Hospital, London, United Kingdom
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  • Alistair J. Lewthwaite MRCP,

    1. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom
    3. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • David J. Nicholl PhD, FRCP,

    1. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. Sandwell and West Birmingham Hospitals NHS Trust, United Kingdom
    3. City Hospital, Birmingham, United Kingdom
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  • Nicholas W. Wood PhD, FRCP,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • Karen E. Morrison DPhil, FRCP,

    1. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom
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  • Caroline H. Williams-Gray PhD, MRCP,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Hospital, Hills Road, Cambridge, United Kingdom
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  • Jonathan R. Evans PhD, MRCP,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Hospital, Hills Road, Cambridge, United Kingdom
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  • Stephen J. Sawcer PhD FRCP,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Hospital, Hills Road, Cambridge, United Kingdom
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  • Roger A. Barker PhD, MRCP,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Hospital, Hills Road, Cambridge, United Kingdom
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  • Mirdhu M. Wickremaratchi PhD, MRCP,

    1. Department of Neurology, Worthing Hospital, Worthing, United Kingdom
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  • Yoav Ben-Shlomo PhD, FFPH,

    1. School of Social and Community Medicine, Bristol University, Bristol, United Kingdom
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  • Nigel M. Williams PhD,

    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Huw R. Morris PhD, FRCP

    Corresponding author
    1. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
    • Neurology (C4), University Hospital of Wales, Cardiff CF14 4XN, United Kingdom
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  • Funding agencies: This work was supported by the Medical Research Council UK (G0700943), Parkinson's UK (Grant 8047), the Cambridge NIHR Biomedical Research Centre, the Midlands Neuroscience Teaching and Research Fund, the Sandwell and West Birmingham Hospitals NHS Trust, the Ipsen Fund, the Wellcome Trust, and a Patrick Berthoud Clinical Research Fellowship and Raymond and Beverly Sackler studentship.

  • 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

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity. © 2012 Movement Disorder Society.

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