There is growing evidence suggesting an association between Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, and parkinsonism. This includes clinical studies of Gaucher probands, neuropathologic evaluations, family studies and screening of tissues from subjects with Parkinson disease. Rare patients with Gaucher disease have been identified with early onset, treatment-refractory parkinsonism. In a series of seventeen such patients, a review of medical records demonstrated many shared clinical features, while sequencing of the glucocerebrosidase gene (GBA) revealed twelve different genotypes, including individuals with the common non-neuronopathic N370S mutation. Neuropathology from several of these cases demonstrated large, immunoreactive Lewy bodies in the substantia nigra and changes in brain regions specifically associated with Gaucher disease, including hippocampal layers CA2-CA4, a region of vulnerability also in diffuse Lewy body disease. Although parkinsonism is relatively common, deriving from multiple different causes, the shared clinical and neuropathologic findings in this subgroup suggested a related etiology. A family history of Parkinson disease noted in some of these subjects indicated that the incidence of parkinsonism may be more frequent in obligate heterozygotes for Gaucher disease. Family histories of families of patients with Gaucher disease alone identified several carrier relatives who developed parkinsonism, often associated with dementia. This prompted an examination of the glucocerebrosidase gene in probands with Parkinson disease. Complete gene sequencing of GBA was performed in brain samples from individuals who died carrying the clinical and/or pathologic diagnosis of Parkinson disease. Of note a significant number had alterations in GBA including glucocerebrosidase mutations and base changes considered to be polymorphisms. Most of the subjects with alterations were among the probands who died by age 75, corresponding to an earlier onset or greater severity of Parkinson manifestations. Most also had a confirmed pathologic diagnosis of diffuse Lewy body disease. Our studies indicate that an alteration in glucocerebrosidase, even in heterozygotes, may contribute to a vulnerability to aggressive parkinsonism. Should the current finding persist in other cohorts, mutations in glucocerebrosidase could be a frequent inherited risk factor associated with parkinsonism. Moreover, this project demonstrates how studies of a rare metabolic disorder, Gaucher disease, may provide a window into both the genetics and pathogenesis of a common complex disorder, Parkinson disease.
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