Fuchs, J. et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68, 916-922

Department of Psychiatry, Lund University, Lund, Skåne, Sweden
Neurology (Impact Factor: 8.29). 04/2007; 68(12):916-22. DOI: 10.1212/01.wnl.0000254458.17630.c5
Source: PubMed


The "Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjönes in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree.
Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([123]I)-beta-CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records.
The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of <0.9 Mb encompassing alpha-synuclein and multimerin 1 (SNCA-MMRN1), flanked by long interspersed repeat sequences (LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha-synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex.
Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA-MMRN11 multiplication, but whereas SNCA-MMRN1 duplication in the Swedish proband (Branch J) leads to late-onset autonomic dysfunction and parkinsonism, SNCA-MMRN1 triplication in the Swedish American family (Branch I) leads to early-onset Parkinson disease and dementia.

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Available from: Owen A Ross, Jan 17, 2014
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    • "To date, no GWAS or large-scale association studies have been published for MSA. Genomic multiplication of the SNCA locus has been observed to cause parkinsonism, dementia and autonomic dysfunction, characteristic of the MSA phenotype [17]. "
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    ABSTRACT: Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. α-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders.
    Parkinsonism & Related Disorders 09/2015; DOI:10.1016/j.parkreldis.2015.09.011 · 3.97 Impact Factor
    • "Interestingly, it is known that a Swedish family with SNCA duplication and a Swedish American family with triplication were descended from a common ancestor [15]. Genetic analysis of this large pedigree indicates a duplication event occurred at first through recombination, and subsequently triplication was generated by unequal crossing-over [15]. This result suggests a possible conversion to triplication could occur in the future generations of duplication families. "
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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; DOI:10.1016/j.parkreldis.2015.09.007 · 3.97 Impact Factor
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    • "Whole-locus multiplications seem to lead Abbreviations: AAV, adeno-associated virus; aSyn, alpha-synuclein; ANOVA, analysis of variance; BSA, bovine serum albumin; CBA, chicken β-actin; DA, dopamine; DAergic, dopaminergic; DAPI, 4,6-diamidino-2-phenylindole; DIV, day in vitro; DMEM, Dulbecco's modified Eagle's medium; GAP-43, growth associated protein 43; GDNF, Glial cell line-derived neurotrophic factor; MDN, midbrain dopaminergic neurons; PBS, phosphate-buffered saline; PFA, paraformaldehyde ; PD, Parkinson's disease; ROCK, rho kinase; RT, room temperature; SNpc, Substantia nigra, pars compacta; TH, tyrosine hydroxylase; WT, wildtype. to an earlier and more severe onset of disease depending on the gene copy number (Fuchs et al., 2007). The A53T variant has broadly varying phenotypes and is neuropathologically characterized by DAergic cell loss and a dense burden of aSyn neuritic pathology including axonal spheroids and rare Lewy bodies with fibrillar aSyn-immunoreactive aggregates (Duda et al., 2002). "
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    ABSTRACT: The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects.
    Frontiers in Aging Neuroscience 09/2014; 6:239. DOI:10.3389/fnagi.2014.00239 · 4.00 Impact Factor
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