Patients Homozygous and Heterozygous for SNCA Duplication in a Family With Parkinsonism and Dementia

Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan.
Archives of neurology (Impact Factor: 7.42). 05/2008; 65(4):514-9. DOI: 10.1001/archneur.65.4.514
Source: PubMed


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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    • "One affected member of each of the two consanguineous families with SNCA duplications, one Japanese and one Pakistani, was homozygous for SNCA duplication and thus possessed four copies of SNCA, resembling the situation in SNCA triplication carriers [9] [10]. Symptoms manifested at 28 years in the Japanese patient with four SNCA copies, versus at 57 (mean, n ¼ 3, SD: 16, range 39e71) years in family members with three copies [9]. Similarly, the homozygous duplication carrier from Pakistan developed symptoms at the age of 31 years; whereas her mother, carrying SNCA duplication, remained clinically unaffected when examined at the age of 72 years [10]. "
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    ABSTRACT: The discovery in 1997 that mutations in the SNCA gene cause Parkinson's disease (PD) greatly advanced our understanding of this illness. There are pathogenic missense mutations and multiplication mutations in SNCA. Thus, not only a mutant protein, but also an increased dose of wild-type protein can produce autosomal dominant parkinsonism. We review the literature on SNCA duplications and focus on pathologically-confirmed cases. We also report a newly-identified American family with SNCA duplication whose proband was autopsied. We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia. Only a few cases have presented with typical features of PD. Our case presented with depression and RBD that preceded parkinsonism, and dysautonomia that led to an initial diagnosis of multiple system atrophy. Dementia and visual hallucinations followed. Our patient and the other reported cases with SNCA duplications had widespread cortical Lewy pathology. Neuronal loss in the hippocampal cornu ammonis 2/3 regions were seen in about half of the autopsied SNCA duplication cases. Similar pathology was also observed in SNCA missense mutation and triplication carriers.
    Parkinsonism & Related Disorders 09/2015; 22 Suppl 1. DOI:10.1016/j.parkreldis.2015.09.007 · 3.97 Impact Factor
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    • "Asymptomatic carriers and intrafamilial variability found in PD pedigrees with SNCA duplications suggested that in addition to copy number variations, other factors, such as another genetic variability of the SNCA gene, genetic modifiers, genetic background or environmental exposures, could influence the development of symptoms in subjects with SNCA duplications (Ahn et al., 2008; Elia et al., 2013; Nishioka et al., 2009, 2006). A direct relation between SNCA gene dosage and age at disease onset, the disease severity and progression was reported (Ahn et al., 2008; Chartier-Harlin et al., 2004; Ibáñez et al., 2009, 2004; Ikeuchi et al., 2008), and the phenotype of the SNCA duplication may also be influenced by the range of duplication region (Nishioka et al., 2006). "
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    ABSTRACT: Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
    Ageing research reviews 04/2014; 15(1). DOI:10.1016/j.arr.2014.04.002 · 4.94 Impact Factor
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    • "Proteins expressed in the amygdala and parahippocampal gyrus of the autopsied patient and three control subjects were extracted as previously described [10,11]. Briefly, we fractionated the samples by resolubilization in increasingly stringent buffers (Tris-buffered saline, 1% Triton X-100, 1% sarcosyl, 8 M urea) as previously described. "
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    ABSTRACT: Background Infantile neuroaxonal dystrophy (INAD) is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually show neurological symptoms with infant onset and die in childhood. Recently, it was reported that mutations in the PLA2G6 gene cause INAD, but neuropathological analysis of genetically confirmed individuals with neuroaxonal dystrophy has been limited. Results Here, we report a Japanese individual with neuroaxonal dystrophy associated with compound heterozygous mutations in the PLA2G6 gene. A novel splice-site mutation resulting in skipping and missense mutations (p.R538C) in exon 9 was identified in the patient. This patient initially presented with cerebellar ataxia at the age of 3 years, which was followed by symptoms of mental retardation, extrapyramidal signs, and epileptic seizure. The patient survived until 20 years of age. Neuropathological findings were characterized by numerous axonal spheroids, brain iron deposition, cerebellar neuronal loss, phosphorylated alpha-synuclein-positive Lewy bodies (LBs), and phosphorylated-tau-positive neurofibrillary tangles. In particular, LB pathology exhibited a unique distribution with extremely severe cortical involvement. Conclusions Our results support a genetic clinical view that compound heterozygous mutations with potential residual protein function are associated with a relatively mild phenotype. Moreover, the severe LB pathology suggests that dysfunction of the PLA2G6 gene primarily contributes to LB formation.
    05/2013; 1(1). DOI:10.1186/2051-5960-1-12
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