Parkinsonism among Gaucher disease carriers

Section on Molecular Neurogenetics, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3708, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 01/2005; 41(12):937-40. DOI: 10.1136/jmg.2004.024455
Source: PubMed

ABSTRACT An association between Gaucher disease and Parkinson disease has been demonstrated by the concurrence of Gaucher disease and parkinsonism in rare patients and the identification of glucocerebrosidase mutations in probands with sporadic Parkinson disease. Using a different and complementary approach, we describe 10 unrelated families of subjects with Gaucher disease where obligate or confirmed carriers of glucocerebrosidase mutations developed parkinsonism. These observations indicate that mutant glucocerebrosidase, even in heterozygotes, may be a risk factor for the development of parkinsonism. Understanding the relationship between altered glucocerebrosidase and the development of parkinsonian manifestations will provide insights into the genetics, pathogenesis, and treatment of Parkinson disease.

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Available from: Ozlem Goker-Alpan, Sep 28, 2015
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    • "A study of GBA in 57 brain bank samples from subjects with pathologically confirmed PD demonstrated that 12 % carried a mutation, which was significantly higher than the mutation frequency even in the at-risk Ashkenazi Jewish population (Lwin et al. 2004). Family studies revealed that among relatives of Gaucher probands, there was an increased number of individuals affected with parkinsonism (Goker-Alpan et al. 2004). Importantly, several additional genetic studies in large patient cohorts demonstrated that patients with parkinsonism have an increased incidence of GBA mutations. "
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    ABSTRACT: Gaucher disease is associated with Parkinson's disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases α-synuclein (α-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects α-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between α-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on α-syn and GCase, and it provides some new thoughts that may be helpful for understanding the α-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism.
    Cellular and Molecular Neurobiology 03/2015; 35(6). DOI:10.1007/s10571-015-0176-8 · 2.51 Impact Factor
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    • "GBA was first recognized in PD when it was observed that a subset of Gaucher’s disease patients suffered from parkinsonian symptoms and that about 25% of them had a first or second degree relative with PD. Family members affected with PD were found to be heterozygous carriers of the GBA mutations [26]. To assess the importance of the GBA mutations in PD, several PD series have since then been screened; carriers represent 10.7% to 31.3% of Ashkenazi Jewish (AJ) patients and 2.3% to 9.4% of patients of other ethnicity [27]. "
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    ABSTRACT: Parkinson's disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson's disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson's disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.
    Current Genomics 02/2014; 15(1):2-10. DOI:10.2174/1389202914666131210212745 · 2.34 Impact Factor
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    • "In this respect, parkinsonism is occasionally a feature of Gaucher's disease, a recessive disorder caused by mutations in the gene glucocerebrosidase (GBA) encoding the lysosomal enzyme glucocerebrosidase (Neudorfer et al., 1996; Tayebi et al., 2003; Goker-Alpan et al., 2004; Capablo et al., 2008). At post-mortem, patients with Gaucher's disease and parkinsonism have been found to have several of the neuropathological features of Parkinson's disease, including alpha-synuclein positive Lewy bodies in the cortex and brainstem (Wong et al., 2004). "
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    ABSTRACT: Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinson's disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson's disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson's disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.
    Brain 02/2013; 136(Pt 2):392-9. DOI:10.1093/brain/aws318 · 9.20 Impact Factor
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