Effect of GBA Mutations on Phenotype of Parkinson's Disease: A Study on Chinese Population and a Meta-Analysis

Yuan Zhang, Qi-Ying Sun, Yu-Wen Zhao, Li Shu, Ji-Feng Guo, Qian Xu, Xin-Xiang Yan, Bei-Sha Tang, Yuan Zhang, Qi-Ying Sun, Yu-Wen Zhao, Li Shu, Ji-Feng Guo, Qian Xu, Xin-Xiang Yan, Bei-Sha Tang

Abstract

GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = -3.10 [95% CI: -4.88, -1.32]), bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94]), having family history (OR = 1.50 [95% CI: 1.18, 1.91]), and dementia (OR = 3.21 [95% CI: 1.97, 5.24]) during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03]), the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: -0.06, 0.17]) and UPDRS-III (MD = 1.61 [95% CI: -0.65, 3.87]) and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84]) during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers.

Figures

Figure 1
Figure 1
Flowchart of included publications.
Figure 2
Figure 2
(a) Forest plot of family history in GBA + PD and GBA − PD. (b) Funnel plot of family history in GBA + PD and GBA − PD.
Figure 3
Figure 3
(a) Forest plot of age at onset in GBA + PD and GBA − PD. (b) Funnel plot of age at onset in GBA + PD and GBA − PD.
Figure 4
Figure 4
(a) Forest plot of bradykinesia as an initial symptom in GBA + PD and GBA − PD. (b) Forest plot of tremor as an initial symptom in GBA + PD and GBA − PD. (c) Funnel plot of bradykinesia as an initial symptom in GBA + PD and GBA − PD. (d) Funnel plot of tremor as an initial symptom in GBA + PD and GBA − PD.
Figure 5
Figure 5
(a) Forest plot of H-Y in GBA + PD and GBA − PD. (b) Forest plot of UPDRS-III in GBA + PD and GBA − PD. (c) Funnel plot of H-Y in GBA + PD and GBA − PD. (d) Funnel plot of UPDRS-III in GBA + PD and GBA − PD.
Figure 6
Figure 6
(a) Forest plot of dementia in GBA + PD and GBA − PD. (b) Funnel plot of dementia in GBA + PD and GBA − PD.
Figure 7
Figure 7
(a) Forest plot of dyskinesia in GBA + PD and GBA − PD. (b) Funnel plot of dyskinesia in GBA + PD and GBA − PD.

References

    1. Siebert M., Sidransky E., Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain. 2014;137(5):1304–1322. doi: 10.1093/brain/awu002.
    1. Aharon-Peretz J., Badarny S., Rosenbaum H., Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology. 2005;65(9):1460–1461. doi: 10.1212/01.wnl.0000176987.47875.28.
    1. Winder-Rhodes S. E., Evans J. R., Ban M., et al. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013;136(2):392–399. doi: 10.1093/brain/aws318.
    1. Hu F.-Y., Xi J., Guo J., et al. Association of the glucocerebrosidase N370S allele with Parkinson's disease in two separate Chinese Han populations of mainland China. European Journal of Neurology. 2010;17(12):1476–1478. doi: 10.1111/j.1468-1331.2010.03097.x.
    1. Hughes A. J., Daniel S. E., Kilford L., Lees A. J. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. Journal of Neurology Neurosurgery and Psychiatry. 1992;55(3):181–184. doi: 10.1136/jnnp.55.3.181.
    1. Wang C., Cai Y., Gu Z., et al. Clinical profiles of Parkinson's disease associated with common leucine-rich repeat kinase 2 and glucocerebrosidase genetic variants in Chinese individuals. Neurobiology of Aging. 2014;35(3):725.e1–725.e6. doi: 10.1016/j.neurobiolaging.2013.08.012.
    1. Pulkes T., Choubtum L., Chitphuk S., et al. Glucocerebrosidase mutations in Thai patients with Parkinson's disease. Parkinsonism & Related Disorders. 2014;20(9):986–991. doi: 10.1016/j.parkreldis.2014.06.007.
    1. Malec-Litwinowicz M., Rudzińska M., Szubiga M., Michalski M., Tomaszewski T., Szczudlik A. Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients. Neurologia i Neurochirurgia Polska. 2014;48(4):258–261. doi: 10.1016/j.pjnns.2014.07.005.
    1. Li Y., Sekine T., Funayama M., et al. Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. Neurobiology of Aging. 2014;35(4):935.e3–935.e8. doi: 10.1016/j.neurobiolaging.2013.09.019.
    1. Asselta R., Rimoldi V., Siri C., et al. Glucocerebrosidase mutations in primary parkinsonism. Parkinsonism and Related Disorders. 2014;20(11):1215–1220. doi: 10.1016/j.parkreldis.2014.09.003.
    1. Kumar K. R., Ramirez A., Göbel A., et al. Glucocerebrosidase mutations in a Serbian Parkinson's disease population. European Journal of Neurology. 2013;20(2):402–405. doi: 10.1111/j.1468-1331.2012.03817.x.
    1. Kresojević N., Mijajlović M., Perić S., et al. Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations. Parkinsonism and Related Disorders. 2013;19(4):431–435. doi: 10.1016/j.parkreldis.2012.12.006.
    1. Wang Y., Liu L., Xiong J., et al. Glucocerebrosidase L444P mutation confers genetic risk for Parkinson's disease in central China. Behavioral and Brain Functions. 2012;8, article 57 doi: 10.1186/1744-9081-8-57.
    1. Setó-Salvia N., Pagonabarraga J., Houlden H., et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. Movement Disorders. 2012;27(3):393–399. doi: 10.1002/mds.24045.
    1. Emelyanov A., Boukina T., Yakimovskii A., et al. Glucocerebrosidase gene mutations are associated with Parkinson's disease in Russia. Movement Disorders. 2012;27(1):158–159. doi: 10.1002/mds.23950.
    1. de Carvalho Guimarães B., Valente Pereira A. C., da Costa Rodrigues F., et al. Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson's disease in Brazilian patients. Parkinsonism and Related Disorders. 2012;18(5):688–689. doi: 10.1016/j.parkreldis.2011.11.028.
    1. Alcalay R. N., Caccappolo E., Mejia-Santana H., et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology. 2012;78(18):1434–1440. doi: 10.1212/wnl.0b013e318253d54b.
    1. Lesage S., Anheim M., Condroyer C., et al. Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. Human Molecular Genetics. 2011;20(1):202–210. doi: 10.1093/hmg/ddq454.
    1. Huang C.-L., Wu-Chou Y.-H., Lai S.-C., et al. Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson's disease in Taiwan. European Journal of Neurology. 2011;18(10):1227–1232. doi: 10.1111/j.1468-1331.2011.03362.x.
    1. Mao X.-Y., Burgunder J.-M., Zhang Z.-J., et al. Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China. Neuroscience Letters. 2010;469(2):256–259. doi: 10.1016/j.neulet.2009.12.007.
    1. Gan-Or Z., Bar-Shira A., Mirelman A., et al. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics. 2010;11(1):121–125. doi: 10.1007/s10048-009-0198-9.
    1. Socal M. P., Bock H., Michelin-Tirelli K., et al. Parkinson's disease and the heterozygous state for glucocerebrosidase mutations among Brazilians. Parkinsonism & Related Disorders. 2009;15(1):76–78. doi: 10.1016/j.parkreldis.2008.01.019.
    1. De Marco E. V., Annesi G., Tarantino P., et al. Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy. Movement Disorders. 2008;23(3):460–463. doi: 10.1002/mds.21892.
    1. Chen J., Li W., Zhang T., et al. Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population. PLoS ONE. 2014;9(12) doi: 10.1371/journal.pone.0115747.e115747
    1. Guo J. F., Li K., Yu R. L., et al. Polygenic determinants of Parkinson's disease in a Chinese population. Neurobiology of Aging. 2015;36(4):1765.e1–1765.e6.
    1. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology. 2010;25(9):603–605. doi: 10.1007/s10654-010-9491-z.
    1. Sidransky E., Nalls M. A., Aasly J. O., et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. The New England Journal of Medicine. 2009;361(17):1651–1661. doi: 10.1056/nejmoa0901281.
    1. Gan-Or Z., Giladi N., Orr-Urtreger A. Differential phenotype in Parkinson's disease patients with severe versus mild GBA mutations. Brain. 2009;132(10, article e125) doi: 10.1093/brain/awp161.
    1. Goker-Alpan O., Masdeu J. C., Kohn P. D., et al. The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow. Brain. 2012;135(8):2440–2448. doi: 10.1093/brain/aws174.
    1. Neumann J., Bras J., Deas E., et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain. 2009;132(7):1783–1794. doi: 10.1093/brain/awp044.

Source: PubMed

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