Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease
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DOI：
10.1093/brain/awp044
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发表时间：
2009-07-01
期刊：
影响因子：
14.5
通讯作者：
Wood, Nicholas W.
中科院分区：
文献类型：
--
作者：
Neumann, Juliane;Bras, Jose;Wood, Nicholas W.
葡萄糖脑苷脂酶基因（GBA）的突变与戈谢病（最常见的溶酶体贮积症）有关。帕金森综合征是戈谢病的一个既定特征，在几个不同种族的散发性帕金森病患者中报告了GBA突变频率增加。在这项研究中，我们评估了受帕金森病影响的英国患者中GBA突变的频率。我们使用了790名患者和257名对照的DNA，年龄和种族相匹配，以筛选GBA基因内的突变。对所有确定的GBA突变携带者的临床数据进行了审查和分析。此外，在所有脑组织可用的情况下，进行神经病理学评价，并与无GBA突变的散发性帕金森病进行比较。与对照组（3/257 = 1.17%）相比，英国患者中GBA突变的频率（33/790 = 4.18%）显著更高（P = 0.01;比值比= 3.7; 95%置信区间= 1.12-12.14）。14个不同的GBA突变被鉴定，包括三个以前未描述的突变，K7 E，D443 N和G193 E。病理学检查显示，所有17例GBA突变携带者均存在广泛和丰富的α-突触核蛋白病理学改变，Braak分期为5-6期，并具有McKeith边缘系统或弥漫性新皮质Lewy体型病理学改变。与帕金森病对照组相比，GBA突变组中弥漫性新皮质Lewy体型病理学倾向于更频繁发生。临床特征包括早期发病，45%（14/31）的患者出现幻觉，48%（15/31）的患者出现认知功能下降或痴呆症状。这项研究表明，在英国受试者中发现GBA突变的频率高于任何其他已知的帕金森病基因。这是迄今为止对非犹太患者样本进行的最大规模的研究，具有详细的基因型/表型/病理分析，这加强了GBA突变代表帕金森病发展的重要风险因素的假设，并表明迄今为止，这是该疾病最常见的遗传因素。
Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.