Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

http://brain.oxfordjournals.org/cgi/content/short/132/7/1783?rss=1

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

Juliane Neumann^1,2, Jose Bras^3,4,*, Emma Deas^1,*, Sean S. O’Sullivan¹, Laura Parkkinen¹, Robin H. Lachmann¹, Abi Li¹, Janice Holton¹, Rita Guerreiro^3,4, Reema Paudel¹, Badmavady Segarane¹, Andrew Singleton³, Andrew Lees¹, John Hardy¹, Henry Houlden¹, Tamas Revesz¹ and Nicholas W. Wood¹

1 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, and Reta Lila Weston Institute, Institute of Neurology, London, UK 2 International Graduate Program Medical Neurosciences, Charité University Hospital, Berlin, Germany 3 Molecular Genetics Unit, Laboratory of Neurogeneticso, National Institutes on Aging, National Institutes of Health, Bethesda, Maryland, USA 4 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

Correspondence to: Nicholas W. Wood, Institute of Neurology, Queen Square House, Queen Square, WC1N 3BG London, UK E-mail: n.wood@ion.ucl.ac.uk

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 -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.

 Key Words: Parkinson’s disease; GBA; Gaucher’s disease; neuropathology

 Abbreviations: AC, amygdaloid complex; BFB, basal forebrain; DMV, dorsal motor nucleus of vagus; GBA, glucocerebrosidase; HRC, human random control; LC, locus ceruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra