Department of Enzymology and Cellular Function, Institute of Child Health, Athens, Greece.
Mol Genet Metab. 2011 Sep-Oct;104(1-2):149-52. doi: 10.1016/j.ymgme.2011.06.015. Epub 2011 Jun 24.
An increasing number of clinical, neuropathological and experimental evidence linking Gaucher disease and a spectrum of synucleinopathies, including Parkinson's disease (PD) has emerged over the last decade. In particular, several studies, despite individual differences, have shown that mutations in the β-glucocerebrosidase gene (GBA) are a risk factor for PD. Recently a study from Northern Greece has shown a significant overrepresentation of such mutations only in patients with early onset PD. In the present study 8 different GBA mutations covering 87% of the mutations identified in Gaucher disease patients diagnosed in Greece were investigated in two ethnic Greek cohorts of patients with sporadic Parkinson's disease. Cohort A included patients residing and originating from Thessaly, Central Greece (n=100) and cohort B included patients residing and/or originating from the greater area of Athens (n=105). Age-gender-ethnicity matched healthy individuals from the same areas were included as controls (n=206). In patients of cohort A 11 carriers of GBA mutations were identified (5/11:N370S, 2/11:L444P, 2/11: D409H;H255Q, 1/11:H255Q, 1/11D409H) as opposed to 3 in the controls (n=105) (1/3:N370S, 1/3:H255Q, 1/3:Y108C) (p=0.021, OR 4.2, 95% CI=1.14-15.54). In patients of cohort B 10 carriers of GBA mutations were identified (4/10:L444P, 4/10:D409H;H255Q, 1/10:N370S, 1/10:IVS10-1G→A) as opposed to 4 in controls (n=101) (3/4:N370S, 1/4:L444P). However the difference was not statistically significant (p=0.113, OR 2.5, 95% CI=0.77-8.42). In both cohorts, patients with PD harboring a GBA mutation had an earlier onset of symptoms than non-carriers (p=0.034, p=0.004). The overall difference in the number of carriers identified in PD patients and controls was statistically significant (p=0.006; OR 3.24; 95% CI=1.35-7.81). The association was reinforced in the early onset PD patients (EOPD; n=28, p=0.000, OR 11.37; 95% CI=3.73-34.6). In conclusion GBA mutations were identified with increased frequency in both geographical cohorts of patients with sporadic PD studied compared to control individuals, with the difference being statistically significant only in cohort A. An impressive association with EOPD was found and one third of the EOPD patients examined harbored a GBA mutation. Qualitative differences regarding the type of mutations and/or their relative frequencies were observed between cohorts A and B of PD patients. Genetic and/or environmental factors may account for the observed differences.
越来越多的临床、神经病理学和实验证据表明，戈谢病与包括帕金森病（PD）在内的一系列突触核蛋白病之间存在关联。特别是，尽管存在个体差异，几项研究表明β-葡糖脑苷脂酶基因（GBA）的突变是 PD 的一个风险因素。最近，来自希腊北部的一项研究表明，这种突变仅在早发性 PD 患者中显著过度表达。在本研究中，研究人员在两个希腊裔帕金森病患者队列中研究了覆盖希腊戈谢病患者中鉴定出的 87%突变的 8 种不同 GBA 突变。队列 A 包括居住和原籍在希腊中部色萨利地区的患者（n=100），队列 B 包括居住和/或原籍在雅典大都市区的患者（n=105）。来自同一地区的年龄、性别和种族相匹配的健康个体作为对照（n=206）。在队列 A 的 11 名患者中发现了 11 名 GBA 突变携带者（5/11：N370S，2/11：L444P，2/11：D409H；H255Q，1/11：H255Q，1/11：D409H），而对照组中只有 3 名（n=105）（1/3：N370S，1/3：H255Q，1/3：Y108C）（p=0.021，OR 4.2，95%CI=1.14-15.54）。在队列 B 的 10 名患者中发现了 10 名 GBA 突变携带者（4/10：L444P，4/10：D409H；H255Q，1/10：N370S，1/10：IVS10-1G→A），而对照组中只有 4 名（n=101）（3/4：N370S，1/4：L444P）。然而，这一差异没有统计学意义（p=0.113，OR 2.5，95%CI=0.77-8.42）。在两个队列中，携带 GBA 突变的 PD 患者的症状发作时间早于非携带者（p=0.034，p=0.004）。PD 患者和对照组中突变携带者的数量差异具有统计学意义（p=0.006；OR 3.24；95%CI=1.35-7.81）。这种关联在早发性 PD 患者（EOPD；n=28，p=0.000，OR 11.37；95%CI=3.73-34.6）中得到了加强。总之，与对照组相比，研究中两个散发性 PD 患者队列中 GBA 突变的发生率均增加，仅在队列 A 中差异具有统计学意义。研究还发现与 EOPD 存在显著关联，检查的三分之一 EOPD 患者携带 GBA 突变。在 PD 患者的 A 组和 B 组之间观察到突变类型和/或其相对频率的定性差异。遗传和/或环境因素可能是导致观察到的差异的原因。
