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May 2009

The Expanding Role of Genetics in the Lewy Body Diseases: The Glucocerebrosidase Gene

Arch Neurol. 2009;66(5):555-556. doi:10.1001/archneurol.2009.61

In this month's Archives, 2 articles describe the association of mutations in the glucocerebrosidase gene (GBA) with Parkinson disease (PD) and dementia with Lewy bodies (DLB).1,2 These studies add to the growing literature linking mutations in GBA to diseases characterized clinically by parkinsonism and pathologically by the presence of Lewy body–related pathology (LRP) (including classic Lewy bodies and abnormal α-synuclein inclusions and neurites). Historically, the link between GBA and LRP-associated diseases began with case reports noting clinical parkinsonism in Ashkenazi Jewish patients with Gaucher disease (GD).3,4 Subsequent examination of larger samples of patients with GD found a high frequency of parkinsonism and the presence of LRP in some of these patients.5 The next question was whether there was an increased frequency of GBA mutations in PD, particularly in samples that were not Ashkenazi Jewish. Subsequent studies of multiple PD samples did, in fact, find a higher than expected frequency of GBA mutations.6-10However, until this point the study samples were either small, often with limited control samples, or only evaluated the most frequently observed GBA mutations (ie, did not sequence the entire gene). Likely owing to these methodological limitations, the reported frequency of GBA mutations in PD samples has been quite variable.

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