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


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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    • "In the past decade it has been shown that carrying one or two mutations in the -glucocerebrosidase gene (GBA) that cause Gaucher disease (GD), as based initially on clinical evidence [12], is a risk factor for PD [13] [14]. Gaucher disease is a rare autosomal single-gene disorder with a predilection among Ashkenazi Jews for its non-neuronopathic form [in conjunction usually with an N370S mutation] that is characterized by lipid storage in the cells of the monocyte-macrophage system such as the bone marrow , spleen, and liver [15]. "
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    ABSTRACT: Background: Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the β-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. Objective: The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. Methods: The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. Results: Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. Conclusions: These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients.
    Journal of Parkinson's Disease 09/2015; 5(3):525-531. DOI:10.3233/JPD-150585 · 1.91 Impact Factor
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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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