Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease

Authors

  • Kenya Nishioka MD,

    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    Search for more papers by this author
  • Shin Hayashi MD,

    1. Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
    Search for more papers by this author
  • Matthew J. Farrer PhD,

    1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL
    Search for more papers by this author
  • Andrew B. Singleton PhD,

    1. Laboratory of Neurogenetics, National Institute on Aging, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Genetic Diseases Research Branch, National Institute of Health, Bethesda, MD
    Search for more papers by this author
  • Hiroyo Yoshino BS,

    1. Research Institute for Disease of Old Ages, Juntendo University School of Medicine
    Search for more papers by this author
  • Hisamasa Imai MD,

    1. Deparment of Neurology, Tokyo Rinkai Hospital, Tokyo
    Search for more papers by this author
  • Toshiaki Kitami MD,

    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    Search for more papers by this author
  • Kenichi Sato MD,

    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    Search for more papers by this author
  • Ryu Kuroda MD,

    1. Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka
    Search for more papers by this author
  • Hiroyuki Tomiyama MD,

    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    2. Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka
    Search for more papers by this author
  • Koichi Mizoguchi MD,

    1. Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka
    Search for more papers by this author
  • Miho Murata MD,

    1. Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira
    2. CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan
    Search for more papers by this author
  • Tatsushi Toda MD,

    1. CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan
    2. Division of Functional Genomics, Osaka University Graduate School of Medicine, Suita, Japan
    Search for more papers by this author
  • Issei Imoto MD, PhD,

    1. Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
    Search for more papers by this author
  • Johji Inazawa MD, PhD,

    1. Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
    Search for more papers by this author
  • Yoshikuni Mizuno MD,

    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    2. Research Institute for Disease of Old Ages, Juntendo University School of Medicine
    Search for more papers by this author
  • Nobutaka Hattori MD, PhD

    Corresponding author
    1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    2. Research Institute for Disease of Old Ages, Juntendo University School of Medicine
    3. CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan
    • Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan
    Search for more papers by this author

Abstract

Objective

Recently, genomic multiplications of α-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD).

Methods

We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by flurorescence in situ hybridization (FISH) and comparative genomic hybridization array.

Results

Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCA duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCA multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected.

Interpretation

These two newly identified Japanese patients with SNCA duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated. Ann Neurol 2006

Ancillary