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GBA

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) cause Gaucher’s disease, an autosomal recessive lysosomal storage disorder. The observation that patients with Gaucher’s disease develop parkinsonism [61] in association with deposition of Lewy bodies in the brainstem and cortex [62] led to the hypothesis that GBA mutations may also contribute to the development of idiopathic PD. Over the past decade, this association has been firmly established: GBA mutations are significantly overrepresented even in seemingly sporadic PD, and are the most common single genetic cause of PD identified to date [63]. The mechanism underlying this association remains unclear; however, neuropathological studies have demonstrated that glucocerebrosidase co-localizes with Lewy bodies in mutation carriers, supporting the theory that mutant glucocerebrosidase may contribute to increased aggregation of a-synuclein [64]. On this basis, GBA mutations would also be expected to predispose to dementia in PD, and clinical comparisons have shown that this is indeed the case.

A recent cross-sectional study of 225 PD cases reported that dementia affected 50% of GBA mutation carriers (n = 22) versus 24% of non-carriers (n = 203), corresponding to an odds ratio for dementia of 5.8 (95% CI 1.98-17.2) after adjustment for age, disease duration, and gender [65]. This is in line with a prevalence of cognitive decline or dementia of 48% among GBA mutation carriers (n = 33) in a larger study of 790 pathologically confirmed PD cases. Neuropathological examination revealed more pronounced Lewy body pathology in the GBA mutation carriers than in the non-carriers, spreading into limbic and diffuse neocortical regions [66]. Another study which employed detailed cross-sectional neuropsychological assessment in early onset PD cases reported a higher frequency of memory and visuospatial impairments in those carrying a GBA mutation (n = 26) compared with non-carriers (n = 39) [67].

Our own work [68] has evaluated the influence of GBA mutations on cognitive phenotype in an unselected incident cohort (n = 121). Interestingly, at diagnosis GBA mutation carriers were clinically indistinguishable from non-carriers, with only a minor trend towards lower MMSE scores. However, over a 10-year follow-up period, GBA mutation carriers (n = 4) had an increased risk of developing dementia compared with non-carriers, after adjustment for MAPT genotype (HR 4.6; 95% CI 1.3-15.9). Furthermore, patients carrying more common GBA polymorphisms (n = 11), which have not consistently been associated with risk for PD, had a greater propensity than non-carriers to develop dementia (HR 3.3; 95% CI 1.1-10.0), suggesting that these variants may contribute to the heterogeneity of cognitive impairment in PD. Although GBA mutations are relatively rare and might only make a modest contribution to the overall burden of dementia in PD, they may provide important insights into the converging pathological mechanisms that contribute to this aspect of the disease.

 
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