Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
ABSTRACT 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.
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.
Four-generation family study.
Academic research. Patients We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.
We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.
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.
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.
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ABSTRACT: Although classic Parkinson disease is the disorder most commonly associated with the clinical feature of parkinsonism, there is in fact a broader spectrum of disease represented by a collection of phenotypically similar neurodegenerative conditions that mimic many of its core features. These atypical parkinsonian disorders most commonly include progressive supranuclear palsy and corticobasal degeneration, disorders both associated with frontotemporal dementia, as well as multiple system atrophy and dementia with Lewy bodies. Although the clinical distinction of these disorders still remains a challenge to physicians, recent advances in genetics are poised to tease apart the differences. Insights into the molecular etiologies underlying these conditions will improve diagnosis, yield a better understanding of the underlying disease pathology, and ultimately lend stimulation to the development of potential treatments. At the same time, the wide range of phenotypes observed from mutations in a single gene warrants broad testing facilitated by advances in DNA sequencing. These expanding genomic approaches, ranging from the use of next-generation sequencing to identify causative or risk-associated gene variations to the study of epigenetic modification linking human genetics to environmental factors, are poised to lead the field into a new age of discovery.Seminars in Neurology 04/2014; 34(2):217-224. DOI:10.1055/s-0034-1381738 · 1.78 Impact Factor
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