Mosaicism of alpha-synuclein gene rearrangements: Report of two unrelated cases of early-onset parkinsonism

Perandones, Claudia; Giugni, Juan C.; Calvo, Daniela S.; Raina, Gabriela; López, Laura de Jorge; Volpini, Vı́ctor; Zabetian, Cyrus P.; Mata, Ignacio; Caputo, Mariela; Corach, Daniel; Radrizzani, Martı́n; Micheli, Federico

doi:10.1016/j.parkreldis.2013.11.014

Cited by 14 publications

(19 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One very large mosaic duplication involving SNCA was reported in PBL of a 69-year old case, which appears likely pathogenic, but again no brain tissue was available [105]. An interesting study claimed high level mosaicism for SNCA gains in ectodermal cells from the oral mucosa in two early onset cases based on FISH [106], but another assay (multiple ligation probe amplification, MLPA) was negative, even in the case with apparent 75% mosaicism, and no brain was available.…”

Section: Evidence For a Role Of Somatic Mutations In Neurodegenerationmentioning

confidence: 99%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.

show abstract

Section: Evidence For a Role Of Somatic Mutations In Neurodegenerationmentioning

confidence: 99%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

show abstract

“…In this regard, Perandones et al [60] have reported two interesting cases. In these patients, the exon dosage test conducted on peripheral blood revealed no alterations, while FISH analysis conducted on interphase cells from the buccal cavity (oral mucosa cells) revealed a good percentage of cells with SNCA triplication or duplication.…”

Section: Sncamentioning

confidence: 94%

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

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 86%

“…Mutations in PINK1, PARK2, and DJ were not found and were excluded as causes for the patient's symptoms. Further description of the ancestral origin, genetic tests and immunohistochemical findings of this patient can be found in Perandones et al [8].As he rapidly showed disabling motor fluctuations and severe peak-dose dyskinesias refractory to pharmacological strategies, the patient was proposed for DBS. The target chosen was the globus pallidus internus (GPi) based on the dyskinesias that affected his quality of life and the fact that he already presented mild cognitive impairment as demonstrated in the preoperative neuropsychological examination.…”

mentioning

confidence: 90%

Successful GPi stimulation in genetic Parkinson’s disease caused by mosaicism of alpha-synuclein gene duplication: first description

et al. 2014

Self Cite

View full text Add to dashboard Cite

DBS is an established therapy for advanced PD [1] and has been reported to be efficacious in a few patients with monogenic parkinsonisms such as LRRK2, Parkin, and PINK1 [2][3][4][5][6]. By contrast, knowledge about the outcome of DBS in patients with SNCA mutations is scarce, since only one case has been reported to date [7].We now report the case of a 26-year-old male with Parkinson's disease due to mosaicism of alpha-synuclein duplication, who has successfully undergone GPi-DBS.The patient, who has no family history of PD, developed PD at the age of 18. He initially presented dystonic posturing and tremor in his left foot. Within a few months, this had progressed to micrographia, bradykinesia and resting tremor in his upper left limb. He subsequently developed mild autonomic failure, and mild cognitive decline, as well as behavior disorders (rage episodes, panic attacks, and hallucinations). He initially showed good response to dopamine agonists, but after a short period levodopa was needed to obtain satisfactory motor control. He also developed impulse control disorders secondary to treatment with dopamine agonists, resulting in punding behaviors (e.g., disassembling guitars, computers and his car).FISH was conducted using rhodamine-labeled SNCA probes at 4q22.1 (BAC RP11-614o7, 151 kb) and 4q21.3 [BAC-RP11-711j3, 192 kb (control)]. Results indicated few or no rearrangements (i.e., B4 FISH probe signals in [20 % of interphase cells scored) [6] in peripheral leucocytes from the patient, but 43 % of oral mucosa cells showed duplication of SNCA gene. No exon dosage rearrangements were detected in SNCA or other relevant PD genes using MLPA technique. Mutations in PINK1, PARK2, and DJ were not found and were excluded as causes for the patient's symptoms. Further description of the ancestral origin, genetic tests and immunohistochemical findings of this patient can be found in Perandones et al. [8].As he rapidly showed disabling motor fluctuations and severe peak-dose dyskinesias refractory to pharmacological strategies, the patient was proposed for DBS. The target chosen was the globus pallidus internus (GPi) based on the dyskinesias that affected his quality of life and the fact that he already presented mild cognitive impairment as demonstrated in the preoperative neuropsychological examination. A quadripolar brain electrode (model 3387, Medtronic) was implanted stereotactically with microregistration technique in each GPi and fixed with the Stimloc system. Magnetic resonance imaging was performed in stereotactic conditions; the images were processed with WinNeus Ò program to identify coordinates for both GPi. The electrodes were connected to a pulse generator (Activa RC; Medtronic).

show abstract

Mosaicism of alpha-synuclein gene rearrangements: Report of two unrelated cases of early-onset parkinsonism

Cited by 14 publications

References 9 publications

Review: Somatic mutations in neurodegeneration

Review: Somatic mutations in neurodegeneration

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

Successful GPi stimulation in genetic Parkinson’s disease caused by mosaicism of alpha-synuclein gene duplication: first description

Contact Info

Product

Resources

About