Effect of<i>GBA</i>Mutations on Phenotype of Parkinson’s Disease: A Study on Chinese Population and a<i>Meta-Analysis</i>

Zhang, Yuan; Sun, Qiying; Zhao, Yuwen; Li, Shu; Guo, Jifeng; Xu, Qian; Yan, Xinxiang; Tang, Beisha

doi:10.1155/2015/916971

Cited by 28 publications

(48 citation statements)

References 30 publications

(20 reference statements)

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“…GBA1 heterozygotes have an earlier age at onset compared with noncarriers of 3‐6 years for PD and 5‐7 years for DLB, respectively. Mean age at onset in heterozygous PD carriers is about 50‐55 years . Among GBA1 carriers who develop PD, homozygotes have a 6‐ to 11‐year earlier onset than heterozygotes .…”

Section: Clinical and Neuroimaging Features Of Gba‐related Synucleinomentioning

confidence: 99%

“…52,53 Nonetheless, as the 2 prospective studies to date were performed among family members of GD cases, 52,53 the actual penetrance of GBA1 mutations in the general population remains to be established conclusively. A positive familial history can be identified in 21.5%-31% of PD carriers of GBA1 mutations, 6,47,49,54 suggesting that more than two-thirds of PD carriers of GBA1 mutations are sporadic. The agespecific risk for PD among homozygotes is not significantly different from heterozygotes, being 4.7% by age 60 years and 9.1% by age 80 years.…”

Section: Clinical and Neuroimaging Features Of Gba-related Synucleinomentioning

confidence: 99%

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Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

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Section: Clinical and Neuroimaging Features Of Gba‐related Synucleinomentioning

confidence: 99%

Section: Clinical and Neuroimaging Features Of Gba-related Synucleinomentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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“…No difference was observed in tremor and dyskinesia between GBA and idiopathic cases in one series [49], although a large European series reported that levodopa induced dyskinesia was more severe in PD with GBA mutations than with controls [48]. Severity of the GBA mutation in terms of its effect on enzyme activity, is associated with earlier age of onset [48,50].…”

Section: Motor Featuresmentioning

confidence: 84%

“…Studies of the presenting motor features in GBA associated PD demonstrated that bradykinesia is a more common initial symptom compared with idiopathic cases and that age of onset in GBA carriers (heterozygotes) and homozygotes is earlier [47][48][49]. No difference was observed in tremor and dyskinesia between GBA and idiopathic cases in one series [49], although a large European series reported that levodopa induced dyskinesia was more severe in PD with GBA mutations than with controls [48].…”

Section: Motor Featuresmentioning

confidence: 92%

“…Several studies assessed the difference in cognitive performance between PD patients with and without GBA mutations [10,55,58,[61][62][63][65][66][67][68][69][70]; according to a recent meta-analysis, the risk of cognitive impairment is estimated to be 3 times higher for patients with GBA mutations [49]. However, significant differences in cognitive function between PD patients with and without GBA mutations were not confirmed in some studies [13,62,71,72].…”

Section: Non Motor Featuresmentioning

confidence: 99%

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Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

104

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta‐analyses

Creese

Bell

Johar

et al. 2017

American J of Med Genetics Pt B

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Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.

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Effect ofGBAMutations on Phenotype of Parkinson’s Disease: A Study on Chinese Population and aMeta-Analysis

Cited by 28 publications

References 30 publications

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase Mutations in Parkinson Disease

Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta‐analyses

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