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parkin mutation analysis in clinic patients with early-onset Parkinson's disease

Authors

  • P. Poorkaj,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    2. Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington
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  • J. G. Nutt,

    1. Department of Neurology, Oregon Health & Science University, Portland, Oregon
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  • D. James,

    1. Department of Neurology, Oregon Health & Science University, Portland, Oregon
    2. Division of Genetic Disorders, Wadsworth Center, Albany, New York
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  • S. Gancher,

    1. Kaiser Permanante, Portland, Oregon
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  • T. D. Bird,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    2. Department of Neurology, University of Washington, Seattle, Washington
    3. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington
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  • E. Steinbart,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    2. Department of Neurology, University of Washington, Seattle, Washington
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  • G. D. Schellenberg,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    2. Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington
    3. Departments of Neurology, and Pharmacology, University of Washington, Seattle, Washington
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  • Haydeh Payami

    Corresponding author
    1. Department of Neurology, Oregon Health & Science University, Portland, Oregon
    2. Division of Genetic Disorders, Wadsworth Center, Albany, New York
    • Genomics Institute, New York State Department of Health Wadsworth Center, 120 New Scotland Ave., Albany, NY 12208.
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Abstract

parkin mutations are the most common identified cause of Parkinson's disease (PD). It has been suggested that patients with young-onset PD be screened for parkin mutations as a part of their clinical work-up. The aim of this study was to assess parkin mutation frequency in a clinical setting, correlate genotype with phenotype, and evaluate the current justification for clinical parkin testing. Patients were selected from a movement disorder clinic based on diagnosis of PD and onset age ≤40 years. parkin was genotyped by sequence and dosage analysis for all 12 exons. Key relatives and controls were screened for identified mutations. Mutations were found in 7/39 patients. Two patients were compound heterozygous; five were heterozygous. Mutations included deletions in exons 2, 3, and 8, duplications in exons 2–4, and 9, and P437L substitution. Seventy-eight percent of mutations were deletions/multiplications. A novel substitution (R402W) was found in one patient and in one control. None of the point mutations found in patients were detected in 96 controls. parkin phenotypes were consistent with idiopathic PD. In conclusion, parkin mutations are common in the clinic setting: 10% of PD patients had early-onset and 18% of them had parkin mutations. However, if parkin is recessive, only 5% of early-onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% CI 0.04–0.19). parkin cases can present as typical idiopathic PD, distinguishable only by molecular testing. Seventy percent of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic. parkin-based diagnosis and counseling require a better understanding of the mode of inheritance, penetrance, and carrier frequencies. © 2004 Wiley-Liss, Inc.

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