Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

作者：Juliane Neumann, José Brás, Emma Deas, Sean S. O’Sullivan, Laura Parkkinen, Robin Lachmann, Abi Li, Janice L. Holton, Rita Guerreiro, Reema Paudel, Badmavady Segarane, Andrew Singleton, Andrew J. Lees, John Hardy, Henry Houlden, Tamás Révész, Nicholas Wood · 发表于：Brain · 年份：2009 · DOI：10.1093/brain/awp044 · 被引用次数：710 · 研究领域：Lysosomal Storage Disorders Research、Parkinson's Disease Mechanisms and Treatments、Cellular transport and secretion

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 muta...