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Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
Arch Neurol. 2008 Apr; 65(4):514-9.AN

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.

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 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+Show Affiliations

Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan. ikeuchi@bri.niigata-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18413475

Citation

Ikeuchi, Takeshi, et al. "Patients Homozygous and Heterozygous for SNCA Duplication in a Family With Parkinsonism and Dementia." Archives of Neurology, vol. 65, no. 4, 2008, pp. 514-9.
Ikeuchi T, Kakita A, Shiga A, et al. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch Neurol. 2008;65(4):514-9.
Ikeuchi, T., Kakita, A., Shiga, A., Kasuga, K., Kaneko, H., Tan, C. F., Idezuka, J., Wakabayashi, K., Onodera, O., Iwatsubo, T., Nishizawa, M., Takahashi, H., & Ishikawa, A. (2008). Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Archives of Neurology, 65(4), 514-9. https://doi.org/10.1001/archneur.65.4.514
Ikeuchi T, et al. Patients Homozygous and Heterozygous for SNCA Duplication in a Family With Parkinsonism and Dementia. Arch Neurol. 2008;65(4):514-9. PubMed PMID: 18413475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. AU - Ikeuchi,Takeshi, AU - Kakita,Akiyoshi, AU - Shiga,Atsushi, AU - Kasuga,Kensaku, AU - Kaneko,Hiryoyuki, AU - Tan,Chun-Feng, AU - Idezuka,Jiro, AU - Wakabayashi,Koichi, AU - Onodera,Osamu, AU - Iwatsubo,Takeshi, AU - Nishizawa,Masatoyo, AU - Takahashi,Hitoshi, AU - Ishikawa,Atsushi, PY - 2008/4/17/pubmed PY - 2008/5/22/medline PY - 2008/4/17/entrez SP - 514 EP - 9 JF - Archives of neurology JO - Arch Neurol VL - 65 IS - 4 N2 - 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. 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 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. SN - 1538-3687 UR - https://www.unboundmedicine.com/medline/citation/18413475/Patients_homozygous_and_heterozygous_for_SNCA_duplication_in_a_family_with_parkinsonism_and_dementia_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/archneur.65.4.514 DB - PRIME DP - Unbound Medicine ER -