title: Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
abstract: BACKGROUND
  Multiplication of the alpha-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.
  
  
  METHODS
  Four-generation family study.
  
  
  METHODS
  Academic research. Patients We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.
  
  
  METHODS
  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 alpha-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 alpha-synuclein in the brains of patients.
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan. ikeuchi@bri.niigata-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kasuga
authors.forename: Hiryoyuki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Tan
authors.forename: Jiro
authors.initials: J
authors.lastname: Idezuka
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishikawa
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D020961:Lewy Body Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein