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Among patients with a family history of PD, 8.4% carried GBA mutations, compared with 5.3% of sporadic PD patients. Comparing the carriage rates with those of other PD-related genes, the authors concluded that GBA may be the commonest genetic risk factor for PD, especially familial PD, in their cohort of European patients. These results robustly reinforce the work of other authors in defining GBA as a potential genetic risk factor for PD.","journal-title":"Hum Mol Genet"},{"key":"368_CR8","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1212\/WNL.0b013e318253d54b","volume":"78","author":"RN Alcalay","year":"2012","unstructured":"\u2022 Alcalay RN, Caccappolo E, Mejia-Santana H, et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology. 2012;78:1434\u201340. In this study, the investigators sought to define the cognitive profile of GBA-associated PD, building on prior findings of increased risk of cognitive impairment in GBA carriers compared with noncarriers. They used the widely available and easily administered Mini Mental State Examination, as well as a more comprehensive neuropsychological battery. They found that although GBA carriers did not differ from noncarriers in terms of demographics, olfactory function, and motor severity, they had worse performance on multiple cognitive tasks, including the Mini Mental State Examination, and memory and visuospatial tasks. Most prominently, they had significant difficulty in the nonverbal memory domain. 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The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow. Brain. 2012;135:2440\u20138.","journal-title":"Brain"},{"key":"368_CR58","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1007\/s10545-012-9527-5","volume":"36","author":"MJ Barrett","year":"2013","unstructured":"Barrett MJ, Giraldo P, Capablo JL, et al. Greater risk of parkinsonism associated with non-N370S GBA1 mutations. J Inherit Metab Dis. 2013;36:575\u201380.","journal-title":"J Inherit Metab Dis"},{"key":"368_CR59","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.molmed.2011.05.003","volume":"17","author":"W Westbroek","year":"2011","unstructured":"\u2022 Westbroek W, Gustafson AM, Sidransky E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med. 2011;17:485\u201393. In this review, the authors explore multiple proposed mechanisms of PD pathogenesis, and the extent to which evidence implicates GBA mutations in each of them. Specifically, they evaluate \u03b1-synuclein aggregation, lysosomal pathways, cellular autophagy, mitochondrial dysfunction, dysfunctional ERAD of proteins, altered lipid metabolism, and the prion-protein hypothesis. They do not find a role for mitochondrial dysfunction or the prion-protein hypothesis in GBA-associated PD, but for the others they discuss evidence either clearly linking GBA mutations to the respective mechanism or persuasively connecting them to known pathophysiological pathways.","journal-title":"Trends Mol Med"},{"key":"368_CR60","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2011.06.001","volume":"146","author":"JR Mazzulli","year":"2011","unstructured":"\u2022\u2022 Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146:37\u201352. This pivotal work used induced pluripotent stem cells to expand the model for the relationship between enzyme and \u03b1-syncluclein aggregation in GBA-associated PD, and suggests a model whereby there may be a role for \u00df-glucocerebrosidase modification in the treatment of IPD as well.","journal-title":"Cell"},{"key":"368_CR61","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/ana.23614","volume":"72","author":"ME Gegg","year":"2012","unstructured":"\u2022 Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol. 2012;72:455\u201363. The authors demonstrate that \u00df-glucocerebrosidase activity is decreased in substantia nigra of brains with GBA mutations, but it is also diminished in those with IPD without GBA mutations, paving the way for possible application of therapies that modulate \u00df-glucocerebrosidase to IPD as well.","journal-title":"Ann Neurol"},{"key":"368_CR62","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1002\/mds.21399","volume":"22","author":"C Balducci","year":"2007","unstructured":"Balducci C, Pierguidi L, Persichetti E, et al. Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease. Mov Disord. 2007;22:1481\u20134.","journal-title":"Mov Disord"},{"key":"368_CR63","doi-asserted-by":"publisher","first-page":"28080","DOI":"10.1074\/jbc.M111.237859","volume":"286","author":"TL Yap","year":"2011","unstructured":"Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem. 2011;286:28080\u20138.","journal-title":"J Biol Chem"},{"key":"368_CR64","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1002\/ana.22400","volume":"69","author":"V Cullen","year":"2011","unstructured":"\u2022 Cullen V, Sardi SP, Ng J, et al. Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol. 2011;69:940\u201353. Together with that of Mazzulli et al. [60], this study expands our understanding of the relationship between \u00df-glucocerebrosidase and \u03b1-synuclein processing.","journal-title":"Ann Neurol"},{"key":"368_CR65","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s00401-010-0741-7","volume":"120","author":"O Goker-Alpan","year":"2010","unstructured":"Goker-Alpan O, Stubblefield BK, Giasson BI, et al. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol. 2010;120:641\u20139.","journal-title":"Acta Neuropathol"},{"key":"368_CR66","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1093\/hmg\/ddq292","volume":"19","author":"I Ron","year":"2010","unstructured":"Ron I, Rapaport D, Horowitz M. Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease. Hum Mol Genet. 2010;19:3771\u201381.","journal-title":"Hum Mol Genet"},{"key":"368_CR67","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1212\/WNL.0b013e31825dd369","volume":"79","author":"K Brockmann","year":"2012","unstructured":"Brockmann K, Hilker R, Pilatus U, et al. GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure. Neurology. 2012;79:213\u201320.","journal-title":"Neurology"},{"key":"368_CR68","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1002\/mds.23984","volume":"27","author":"SP Schmid","year":"2012","unstructured":"Schmid SP, Schleicher ED, Cegan A, et al. Cerebrospinal fluid fatty acids in glucocerebrosidase-associated Parkinson's disease. Mov Disord. 2012;27:288\u201392.","journal-title":"Mov Disord"},{"key":"368_CR69","first-page":"293","volume":"43","author":"M Sobstyl","year":"2009","unstructured":"Sobstyl M, Zabek M, Koziara H, et al. A patient with parkinsonism related to Gaucher's disease type I successfully treated by unilateral pallidotomy - a 3-year follow-up. Neurol Neurochir Pol. 2009;43:293\u20137.","journal-title":"Neurol Neurochir Pol"},{"key":"368_CR70","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.parkreldis.2006.07.010","volume":"13","author":"DA Hughes","year":"2007","unstructured":"Hughes DA, Ginsberg L, Baker R, et al. Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: a case report of 24 months' oral substrate reduction therapy with miglustat. Parkinsonism Relat Disord. 2007;13:365\u20138.","journal-title":"Parkinsonism Relat Disord"},{"key":"368_CR71","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.parkreldis.2007.01.002","volume":"14","author":"O Goker-Alpan","year":"2008","unstructured":"Goker-Alpan O, Sidransky E. Treating patients with Gaucher disease and parkinsonism: misrepresentation in a title. Parkinsonism Relat Disord. 2008;14:81\u20132. author reply 83.","journal-title":"Parkinsonism Relat Disord"},{"key":"368_CR72","doi-asserted-by":"publisher","first-page":"3537","DOI":"10.1073\/pnas.1220464110","volume":"110","author":"SP Sardi","year":"2013","unstructured":"Sardi SP, Clarke J, Viel C, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci USA. 2013;110:3537\u201342.","journal-title":"Proc Natl Acad Sci USA"},{"key":"368_CR73","doi-asserted-by":"publisher","first-page":"3214","DOI":"10.1073\/pnas.1300822110","volume":"110","author":"AH Schapira","year":"2013","unstructured":"Schapira AH, Gegg ME. Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease. Proc Natl Acad Sci USA. 2013;110:3214\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"368_CR74","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1212\/WNL.0b013e318245f476","volume":"78","author":"M Anheim","year":"2012","unstructured":"\u2022 Anheim M, Elbaz A, Lesage S, et al. Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology. 2012;78:417\u201320. Although earlier epidemiological studies established GBA carriage as a risk factor for PD, the risk of developing PD for an individual carrier has remained relatively undefined; thus, genetic counseling for family members of GBA carriers with PD has remained challenging. In this study, the authors reviewed the pedigrees of 525 probands with familial PD, and screened a large number of family members, including those with and those without PD, for GBA mutations. Using this data, and using a model that assumes GBA is an autosomal dominant PD gene with incomplete penetrance, the authors calculated an age-related penetrance of PD in GBA carriers of 7.6% at age 50 years, 13.7% at age 60 years, 21.4% at age 70 years, and 29.7% at age 80 years. Although some concerns have been raised about the study\u2019s methodology and assumptions (see [75]), this study provides an important starting point for gathering information that will guide genetic testing and counseling in families with PD related to GBA mutations.","journal-title":"Neurology"},{"key":"368_CR75","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1212\/01.wnl.0000416261.29035.4c","volume":"79","author":"E Sidransky","year":"2012","unstructured":"Sidransky E, Hart PS. Penetrance of PD in glucocerebrosidase gene mutation carriers. 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