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      A Meta-Analysis of GBA-Related Clinical Symptoms in Parkinson's Disease

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          Abstract

          Background

          GBA gene had been proved to be a crucial gene to the risk of PD. Numerous studies had discussed about the unique clinical characteristics of PD patients with GBA carriers ( GBA + PD). However, there was lack of updated comprehensive analysis on the topic. In order to clarify the association between GBA variants and the clinical phenotypes of PD, we conducted this comprehensive meta-analysis.

          Method

          Medline, Embase, and Cochrane were used to perform the searching. Strict selection criteria were followed in screening for new published articles or data. Revman 5.3 software was applied to perform the total statistical analysis, and funnel plots in the software were used to assess the publication biases.

          Results

          A total of 26 articles including 931 GBA + PD and 14861 GBA noncarriers of PD ( GBA − PD) were involved in the final meta-analysis, and 14 of them were either newly added publications or related data newly analyzed compared with the version published in 2015. Then, a series of symptoms containing depression, orthostatic hypotension, motor fluctuation, wearing-off, and freezing were newly analyzed due to more articles eligible. Besides, clinical features like family history, AAO, UPDRS-III, H-Y, and dementia previously analyzed were updated with new data added. Significant statistical differences were found in wearing-off, family history, AAO, UPDRS-III, and dementia (OR: 1.14, 1.65; MD: −3.61, 2.17; OR: 2.44; p: 0.03, <0.00001, <0.00001, 0.003, and <0.00001). Depression was slightly associated with GBA + PD (OR: 1.47; p: 0.04). Clinical symptoms such as H-Y, orthostatic hypotension, motor fluctuation, and freezing did not feature GBA + PD.

          Conclusion

          Our results demonstrated that there were unique clinical features in GBA + PD which can help the management of the whole duration of PD patients.

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          Most cited references26

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          Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression.

          Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-β (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-β/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits.
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            Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease.

            Pathogenic variants in the glucocerebrosidase gene (GBA) encoding the enzyme deficient in Gaucher's disease (GD) are associated with Parkinson's disease (PD). To investigate the sequence variants, their association with PD and the related phenotypes in a large cohort of European, mostly French, patients and controls, we sequenced all exons of GBA in 786 PD patients from 525 unrelated multiplex families, 605 patients with apparently sporadic PD and 391 ethnically matched controls. GBA mutations were significantly more frequent (odds ratio=6.98, 95% confidence interval 2.54-19.21; P=0.00002) in the PD patients (76/1130=6.7%) than in controls (4/391=1.0%) and in patients with family histories of PD (8.4%) than in isolated cases (5.3%). Twenty-eight different mutations were identified in patient and control groups, including seven novel variants. N370S and L444P accounted for 70% of all mutant alleles in the patient group. PD patients with GBA mutations more frequently had bradykinesia as the presenting symptom and levodopa-induced dyskinesias. The phenotype was similar in patients with one, two or complex GBA mutations, although the two patients with c.1263del+RecTL and N370S/RecΔ55 mutations had signs of GD. Segregation analyses in 21 multiplex families showed that 17% of the affected relatives did not carry GBA mutations found in the given family, indicating heterogeneity of the aetiology, but 46% of the unaffected relatives were GBA mutation carriers. These genotype and clinical analyses on the largest homogeneous sample of European patients studied to date confirmed that GBA mutations are the most common genetic risk factor for PD, particularly in familial forms.
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              Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

              Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.
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                Author and article information

                Contributors
                Journal
                Parkinsons Dis
                Parkinsons Dis
                PD
                Parkinson's Disease
                Hindawi
                2090-8083
                2042-0080
                2018
                27 September 2018
                : 2018
                : 3136415
                Affiliations
                1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
                2National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410078, China
                3Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China
                4Parkinson's Disease Center of Beijing Institute for Brain Disorders, Beijing 100069, China
                5Collaborative Innovation Center for Brain Science, Shanghai 200032, China
                6Collaborative Innovation Center for Genetics and Development, Shanghai 200438, China
                7Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
                8Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
                Author notes

                Academic Editor: Jan Aasly

                Author information
                http://orcid.org/0000-0003-0577-7129
                http://orcid.org/0000-0003-4609-4666
                http://orcid.org/0000-0002-3658-3928
                http://orcid.org/0000-0003-2120-1576
                http://orcid.org/0000-0002-2031-8345
                Article
                10.1155/2018/3136415
                6180987
                30363648
                f3dc38fb-8dca-4905-8ddf-78355bf1e202
                Copyright © 2018 Yuan Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 April 2018
                : 4 August 2018
                : 14 August 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81430023
                Award ID: 81401059
                Funded by: National Key Plan for Scientific Research and Development of China
                Award ID: 2016YFC1306000
                Award ID: 2017YFC0909100
                Funded by: Hunan Provincial Innovation Foundation For Postgraduate
                Award ID: CX2017B066
                Categories
                Review Article

                Neurology
                Neurology

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