Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
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.
Ikeuchi
Takeshi
T
Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan. ikeuchi@bri.niigata-u.ac.jp
Kakita
Akiyoshi
A
Shiga
Atsushi
A
Kasuga
Kensaku
K
Kaneko
Hiryoyuki
H
Tan
Chun-Feng
CF
Idezuka
Jiro
J
Wakabayashi
Koichi
K
Onodera
Osamu
O
Iwatsubo
Takeshi
T
Nishizawa
Masatoyo
M
Takahashi
Hitoshi
H
Ishikawa
Atsushi
A
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*
C497604:SNCA protein, human; D051844:alpha-Synuclein