A patient clinically diagnosed as multiple system atrophy harboring LRRK2 p.G2019S.
Ontology highlight
ABSTRACT:
SUBMITTER: Ando S
PROVIDER: S-EPMC8288554 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveThe aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).MethodsOne series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association with MSA.ResultsIn the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio [OR] = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest single-variant association was again observed for p.M2397T (OR = 0.59, p = 0.0005).ConclusionsThese findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.
| S-EPMC4277668 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:The LRRK2 (PARK8; OMIM607060) substitution was recently identified as a causative mutation for Parkinson's disease (PD). The pathologic heterogeneity of LRRK2-positive patients suggests that mutation of the LRRK2 gene is associated with the pathogenesis of PD and Parkinson-plus disorders, such as multiple system atrophy (MSA). We previously reported that the G2019S LRRK2 mutation-which is the most common LRRK2 mutation-was not found in a sample of 453 Korean PD patients. In the present study, we extended the screening for the G2019S mutation to a larger group of PD and MSA patients. METHODS:We performed a genetic analysis of the G2019S mutation in 877 patients with PD and 199 patients with MSA using a standard PCR and restriction digestion method. RESULTS:None of the subjects carried the G2019S mutation. CONCLUSIONS:The results of the present study support that the G2019S mutation is extremely rare in PD and is unlikely to be associated with MSA in the Korean population.
| S-EPMC2686897 | biostudies-literature
Project description: Not available
| EMPIAR-11095 | biostudies-other
Project description:BackgroundCerebellum has an important role in sensorimotor control including speech. Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with Parkinsonism or cerebellar ataxia.Case reportWe report a case of MSA-cerebellum subtype associated with emergence of irreversible explosive speech following olanzapine therapy.ConclusionsFurther investigation into speech problems in MSA according to subtype and disease severity is needed, and side effects of olanzapine therapy should also be considered.
| S-EPMC6427994 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed ?-synucleinopathies, which also include Parkinson's disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal ?-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of ?-synuclein are oligodendroglial cells . This pathological hallmark, also called glial cytoplasmic inclusions (GCIs) , is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of ?-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson's syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies.
| S-EPMC4730554 | biostudies-literature
Project description:Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an ?-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant ?-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded ?-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.
| S-EPMC5870010 | biostudies-other
Project description:BACKGROUND:Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. OBJECTIVE:This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and ?-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect ?-synuclein uptake in a oligodendrocyte cell. METHODS:One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with ?-synuclein and recombinant human apolipoprotein E, with internalized ?-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. RESULTS:No significant association with risk of MSA or was observed for either Apolipoprotein E ?2 or ?4. ?-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ?4 significantly reduced ?-synuclein uptake in the oligodendrocytic cell line. CONCLUSIONS:Despite differential effects of apolipoprotein E isoforms on ?-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or ?-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.
| S-EPMC5889322 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.
| S-EPMC4276800 | biostudies-literature
Project description:Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of ?-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic ?-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of ?-synuclein in a prion-like manner, ?-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of ?-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit ?-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.
| S-EPMC4265580 | biostudies-other
Project description:Genome-wide methylation profiling of DNA extracted from the prefrontal cortex of post-mortem MSA patients (n=41) or normal, healthy controls (CTRLs; n=37). The Illumina Infinium MethylationEPIC BeadChip was used, investigating app. 850,000 CpG sites throughout the genome
2020-03-10 | GSE143157 | GEO