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Takeshi Ikeuchi, MD, PhD; Akiyoshi Kakita, MD; Atsushi Shiga, MS; Kensaku Kasuga, MD; Hiryoyuki Kaneko, MS; Chun-Feng Tan, MD; Jiro Idezuka, MD; Koichi Wakabayashi, MD; Osamu Onodera, MD; Takeshi Iwatsubo, MD; Masatoyo Nishizawa, MD; Hitoshi Takahashi, MD; Atsushi Ishikawa, MD

Arch Neurol. 2008;65(4):514-519.

Background  Multiplication of the -synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies.

Objective  To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.

Design  Four-generation family study.

Setting  Academic research.

Patients  We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.

Main Outcome Measures  We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.

Results  Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated -synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.

Conclusions  Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated -synuclein in the brains of patients.

Author Affiliations: Departments of Molecular Neuroscience (Drs Ikeuchi, Kasuga, and Onodera and Messrs Shiga and Kaneko), Pathology Neuroscience (Dr Kakita), Pathology (Drs Tan and Takahashi), and Neurology (Messrs Shiga and Kaneko and Drs Kasuga and Nishizawa), Brain Research Institute, Niigata University, Department of Neurology, Ojiya-Sakura Hospital (Dr Idezuka), and Department of Neurology, Nishi-Ojiya National Hospital, and Department of Neurology, Brain Disease Center, Agano Hospital (Dr Ishikawa), Niigata; Japan Department of Neuropathology, Hirosaki University School of Medicine, Hirosaki (Dr Wakabayashi); and Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo (Dr Iwatsubo); Japan.