Parkinson disease in Gaucher disease.
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ABSTRACT: Background
Gaucher disease (GD) is an inborn error of metabolism caused by mutations in the gene (GBA) coding for glucocerebrosidase (GCase), inherited in an autosomal recessive pattern. GD patients have up to 9% risk of developing PD.Case presentation
We report two patients with GD that developed PD at different disease stages.Conclusion
We reviewed the literature on the coexistence of PD and GD and speculate that the severity of symptoms may be related to the type of GBA mutation inherited.
SUBMITTER: Rodriguez-Porcel F
PROVIDER: S-EPMC5440911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHomozygous and compound heterozygous variants in glucocerebrosidase (GBA) can cause Gaucher disease (GD), whereas heterozygous variants increase the risk of developing Parkinson's disease (PD). GD patients display altered peripheral immune proteins. However, it is unknown if these are altered in GBA carriers with PD.ObjectivesTo determine whether plasma cytokines and immune biomarkers associated with GD are also altered in GBA carriers with or without PD.MethodsInflammatory cytokines and established GD biomarkers, ferritin, CD162, CCL18, and chitotriosidase (28 biomarkers) were measured in GBA pathogenic variant carriers with (n = 135) and without (n = 83) PD, and non-carriers with (n = 75) and without PD (n = 77).ResultsPD patients with biallelic pathogenic variants in GBA had elevated plasma levels of ferritin, CCL18, and MIP1α. These biomarkers were not elevated in heterozygous GBA carriers.ConclusionGD plasma biomarkers are not promising candidates for stratifying the risk for PD in carriers of heterozygous GBA pathogenic variants. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8248172 | biostudies-literature
Project description:Gaucher disease (GD) is an autosomal recessive disease caused by GBA mutations that is especially common in the Ashkenazi Jewish (AJ) population. The link between GBA mutations and Parkinson disease (PD), a later-onset neurodegenerative condition, is well established, and studies have shown that GBA carriers have an increased lifetime risk of developing PD. Carrier screening for GD is frequently offered to couples during or prior to pregnancy, especially to those of AJ descent. However, no studies have been performed to assess if prospective parents would want to learn about their risk of developing PD incidentally through carrier screening. It is also unknown if pre-test counseling on this topic would affect screening uptake. In order to answer these questions, a survey was administered to individuals who screened negative for GBA mutations. Of the 75 participants, 86.7% believed that patients should be informed about the increased risk of PD prior to having GD carrier screening, and 93.3% responded that this information would not have changed their decision to have carrier screening. These results indicate that healthcare providers should take into consideration patient preferences when determining how to counsel about GD carrier screening. Additionally, these results have implications for genetic counseling about other later-onset conditions that may be incidentally ascertained through carrier screening.
| S-EPMC5878114 | biostudies-literature
Project description:Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations.To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes.The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n?=?332) and Mount Sinai School of Medicine, New York, New York (n?=?95). GBA noncarrier non-PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n?=?77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation.The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n?=?427), among their parents who are obligate GBA mutation carriers (heterozygotes, n?=?694), and among noncarriers (parents of non-PD, non-GD control participants, n?=?154). The age-specific risk was compared among groups using the log-rank test.Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P?=?.003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P?=?.008, log-rank test) and in heterozygotes than noncarriers (P?=?.03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P?=?.07, log-rank test).Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset.
| S-EPMC4082726 | biostudies-literature
Project description:ObjectiveThis study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD).MethodsThe study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion.ResultsN-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects.ConclusionsThis is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.
| S-EPMC3934795 | biostudies-literature
Project description:The presynaptic protein α-synuclein (α-syn), particularly in its amyloid form, is widely recognized for its involvement in Parkinson disease (PD). Recent genetic studies reveal that mutations in the gene GBA are the most widespread genetic risk factor for parkinsonism identified to date. GBA encodes for glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage disorder, Gaucher disease (GD). In this work, we investigated the possibility of a physical linkage between α-syn and GCase, examining both wild type and the GD-related N370S mutant enzyme. Using fluorescence and nuclear magnetic resonance spectroscopy, we determined that α-syn and GCase interact selectively under lysosomal solution conditions (pH 5.5) and mapped the interaction site to the α-syn C-terminal residues, 118-137. This α-syn-GCase complex does not form at pH 7.4 and is stabilized by electrostatics, with dissociation constants ranging from 1.2 to 22 μm in the presence of 25 to 100 mm NaCl. Intriguingly, the N370S mutant form of GCase has a reduced affinity for α-syn, as does the inhibitor conduritol-β-epoxide-bound enzyme. Immunoprecipitation and immunofluorescence studies verified this interaction in human tissue and neuronal cell culture, respectively. Although our data do not preclude protein-protein interactions in other cellular milieux, we suggest that the α-syn-GCase association is favored in the lysosome, and that this noncovalent interaction provides the groundwork to explore molecular mechanisms linking PD with mutant GBA alleles.
| S-EPMC3151053 | biostudies-literature
Project description:Gaucher disease (GD) is an inherited lysosomal disorder, originating from deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Normally, GCase hydrolyzes glucocerebroside (GC) to glucose and ceramide; however, impaired activity of this enzyme leads to the accumulation of GC in macrophages, termed "Gaucher cells." Gaucher disease is associated with hepatosplenomegaly, cytopenias, skeletal complications and in some forms involves the central nervous system. Coagulation abnormalities are common among GD patients due to impaired production and chronic consumption of coagulation factors. Bleeding phenomena are variable (as are other symptoms of GD) and include mucosal and surgical hemorrhages. FOUR MAIN ETIOLOGICAL FACTORS ACCOUNT FOR THE HEMOSTATIC DEFECT IN GD: thrombocytopenia, abnormal platelet function, reduced production of coagulation factors, and activation of fibrinolysis. Thrombocytopenia relates not only to hypersplenism and decreased megakaryopoiesis by the infiltrated bone marrow but also to immune thrombocytopenia. Autoimmunity, especially the induction of platelet antibody production, might cause persistent thrombocytopenia. Enzyme replacement therapy reverses only part of the impaired coagulation system in Gaucher disease. Other therapeutic and supportive measures should be considered to prevent and/or treat bleeding in GD. Gaucher patients should be evaluated routinely for coagulation abnormalities especially prior to surgery and dental and obstetric procedures.
| S-EPMC4222428 | biostudies-other
Project description:We analyzed the transcriptome of the Frontal Cortex (FC) of Parkinson diseased (PD) individuals compared to age-matched controls.
2024-09-03 | GSE156928 | GEO
Project description:We aimed to profile the expression of the entire population of annotated lncRNAs (GENCODE 15) in the Frontal Cortex (FC) of Parkinson diseased (PD) individuals compared to age-matched controls.
2024-09-03 | GSE156926 | GEO
Project description:Gene expression data obtained from induced pluripotent stem cells derived from wild type fibroblasts (iPSc WT) and from Gaucher Disease type 2 fibroblasts (GD iPSc). Also, gene expression analysis from the initial fibroblasts was made (WT fibroblasts and GD- fibroblasts), as well as gene expression analysis from a human embryonic stem cell line (hES4). Two different iPSc cell lines derived from Gaucher Disease type 2 fibroblasts were analysed in order to be compared to iPSc derived from Wild Type fibroblasts (only one cell line) and human embryonic stem cells (only one cell line). The initial cells: two different wild type fibroblasts and one Gaucher disease type 2 fibroblasts were also analysed.
2012-12-07 | E-GEOD-41243 | biostudies-arrayexpress
Project description:Gene expression data obtained from induced pluripotent stem cells derived from wild type fibroblasts (iPSc WT) and from Gaucher Disease type 2 fibroblasts (GD iPSc). Also, gene expression analysis from the initial fibroblasts was made (WT fibroblasts and GD- fibroblasts), as well as gene expression analysis from a human embryonic stem cell line (hES4).
2012-12-07 | GSE41243 | GEO