Partial Trisomy 4q Associated With Young-Onset Dopa-Responsive Parkinsonism

Garraux, Gaëtan; Caberg, Jean-Hubert; Vanbellinghen, Jean-François; Jamar, Mauricette; Moonen, Gustave; Dive, Dominique

doi:10.1001/archneurol.2011.802

Cited by 17 publications

(20 citation statements)

References 18 publications

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“…Secondly, we also hypothesised that, above a certain duplication length threshold, the individual will exhibit a more complex phenotype with features unusual for SNCA multiplications. Consequently, two individuals with such complex presentations, one described by Garraux et al (2012) 11 and the case reported herein carrying duplications larger than 5Mb were excluded from this analysis. Published individuals were also excluded if any of the following were true: a) there was no information on the length of the duplication, b) there was insufficient clinical information, c) clinical presentation was clearly inconsistent with parkinsonism, d) they were affected relatives of probands with SNCA duplications but their carrier status wasn’t assessed (efigure 1).…”

Section: Methodsmentioning

confidence: 99%

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism

Kara¹,

Kiely

Proukakis³

et al. 2014

JAMA Neurol

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IMPORTANCE α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown.OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTSWe report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURESWe assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTSWe identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively.CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

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Section: Methodsmentioning

confidence: 99%

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism

Kara¹,

Kiely

Proukakis³

et al. 2014

JAMA Neurol

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“…Genetic analyses have revealed widely variable sizes of the duplicated genomic region, ranging from 0.2 to 41.2 Mb and containing anywhere from 2 to 150 genes [11–13]. Combined with haplotype analyses, this data indicates there is no common ancestor but duplications have arisen independently in most of the families reported [12].…”

Section: Review Of Snca Duplication Casesmentioning

confidence: 99%

“…There are reports of two patients whose parents were healthy and were not carriers of SNCA duplication. Thus these two patients had a de novo mutation [13, 14]. There is no clear correlation between the size of the duplication and resulting clinical phenotypes, implying that other genetic and environmental factors may contribute.…”

Section: Review Of Snca Duplication Casesmentioning

confidence: 99%

Autosomal dominant Parkinson's disease caused by SNCA duplications

Konno

Ross

Puschmann

et al. 2016

Parkinsonism & Related Disorders

174

133

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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.

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“…The largest multiplication detected so far is about 41.2 Mb, containing 150 genes and defined a partial trisomy 4q [55]. The smallest one sizes about 0.2 Mb and was found in a Japanese family [43].…”

Section: Sncamentioning

confidence: 96%

“…Their clinical course was similar to typical sporadic PD without severe progression or cognitive decline. Other cases of sporadic PD carrying de novo SNCA duplication were later revealed by different detection assays [55][56][57][58][59].…”

Section: Sncamentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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Partial Trisomy 4q Associated With Young-Onset Dopa-Responsive Parkinsonism

Abstract: To describe a patient who developed a youngonset, dopa-responsive parkinsonism linked to a de novo heterozygous interstitial duplication 4q.

Cited by 17 publications

References 18 publications

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism

A 6.4 Mb Duplication of the α-Synuclein Locus Causing Frontotemporal Dementia and Parkinsonism

Autosomal dominant Parkinson's disease caused by SNCA duplications

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

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