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https://www.readbyqxmd.com/read/28231462/the-complicated-relationship-between-gaucher-disease-and-parkinsonism-insights-from-a-rare-disease
#1
REVIEW
Elma Aflaki, Wendy Westbroek, Ellen Sidransky
The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric α-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases...
February 22, 2017: Neuron
https://www.readbyqxmd.com/read/28226774/modeling-non-clinical-and-clinical-drug-tests-in-gaucher-disease
#2
Clyde F Phelix, Allen K Bourdon, Greg Villareal, Richard G LeBaron, Clyde F Phelix, Allen K Bourdon, Greg Villareal, Richard G LeBaron, Richard G LeBaron, Clyde F Phelix, Allen K Bourdon, Greg Villareal
There is need for modeling biological systems to accelerate drug pipelines for treating metabolic diseases. The eliglustat treatment for Gaucher disease is approved by the FDA with a companion genomic test. The Transcriptome-To-Metabolome™ biosimulation technology was used to model, in silico, a standard non-clinical eliglustat test with an in vitro canine kidney cell system over-expressing a human gene; and a clinical test using human fibroblasts from control and Gaucher disease subjects. Protein homology modeling and docking studies were included to gather affinity parameters for the kinetic metabolic model...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28225753/complement-drives-glucosylceramide-accumulation-and-tissue-inflammation-in-gaucher-disease
#3
Manoj K Pandey, Thomas A Burrow, Reena Rani, Lisa J Martin, David Witte, Kenneth D Setchell, Mary A Mckay, Albert F Magnusen, Wujuan Zhang, Benjamin Liou, Jörg Köhl, Gregory A Grabowski
Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease...
February 22, 2017: Nature
https://www.readbyqxmd.com/read/28224082/clinical-characteristics-of-adult-patients-with-inborn-errors-of-metabolism-in-spain-a-review-of-500-cases-from-university-hospitals
#4
J Pérez-López, L Ceberio-Hualde, J S García-Morillo, J M Grau-Junyent, A Hermida Ameijeiras, M López-Rodríguez, J C Milisenda, M Moltó Abad, M Morales-Conejo, J J Nava Mateos
Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification...
March 2017: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/28223512/glucosylceramide-synthase-inhibition-alleviates-aberrations-in-synucleinopathy-models
#5
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba(D409V/D409V) and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28219443/a-new-framework-for-evaluating-the-health-impacts-of-treatment-for-gaucher-disease-type-1
#6
Michael L Ganz, Sean Stern, Alex Ward, Luba Nalysnyk, Martin Selzer, Alaa Hamed, Neal Weinreb
BACKGROUND: The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3...
February 20, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28218669/a-review-of-gaucher-disease-pathophysiology-clinical-presentation-and-treatments
#7
REVIEW
Jérôme Stirnemann, Nadia Belmatoug, Fabrice Camou, Christine Serratrice, Roseline Froissart, Catherine Caillaud, Thierry Levade, Leonardo Astudillo, Jacques Serratrice, Anaïs Brassier, Christian Rose, Thierry Billette de Villemeur, Marc G Berger
Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells...
February 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28207759/investigations-on-therapeutic-glucocerebrosidases-through-paired-detection-with-fluorescent-activity-based-probes
#8
Wouter W Kallemeijn, Saskia Scheij, Sascha Hoogendoorn, Martin D Witte, Daniela Herrera Moro Chao, Cindy P A A van Roomen, Roelof Ottenhoff, Herman S Overkleeft, Rolf G Boot, Johannes M F G Aerts
Deficiency of glucocerebrosidase (GBA) causes Gaucher disease (GD). In the common non-neuronopathic GD type I variant, glucosylceramide accumulates primarily in the lysosomes of visceral macrophages. Supplementing storage cells with lacking enzyme is accomplished via chronic intravenous administration of recombinant GBA containing mannose-terminated N-linked glycans, mediating the selective uptake by macrophages expressing mannose-binding lectin(s). Two recombinant GBA preparations with distinct N-linked glycans are registered in Europe for treatment of type I GD: imiglucerase (Genzyme), contains predominantly Man(3) glycans, and velaglucerase (Shire PLC) Man(9) glycans...
2017: PloS One
https://www.readbyqxmd.com/read/28194070/intriguing-morphology-of-igg-lambda-secreting-myeloma-cells
#9
Sreejesh Sreedharanunni, Narender Kumar, Neelam Varma
Myeloma cells are known to show varied morphology and various types of nuclear or cytoplasmic inclusions. There are a few reports of myeloma with presence of pseudo-Gaucher type histiocytes; however myeloma cells itself resembling storage histiocytes is distinctly uncommon. We report images of plasma cells resembling storage cells from a case of IgG/lambda plasma cell myeloma. Hematopathologist must be aware of such varied morphology of plasma cells especially while dealing with extra medullary plasmacytomas...
March 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28190666/design-of-a-framework-for-the-deployment-of-collaborative-independent-rare-disease-centric-registries-gaucher-disease-registry-model
#10
Matthew I Bellgard, Kathryn R Napier, Alan H Bittles, Jeffrey Szer, Sue Fletcher, Nikolajs Zeps, Adam A Hunter, Jack Goldblatt
Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases...
January 27, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28187999/intraobserver-and-interobserver-variability-of-the-bone-marrow-burden-bmb-score-for-the-assessment-of-disease-severity-in-gaucher-disease-possible-impact-of-reporting-experience
#11
Jeffrey K C Lai, Patricia L Robertson, Christine Goh, Jeff Szer
AIM: To evaluate the intraobserver and interobserver agreement for bone marrow burden (BMB) scores for individual examinations and for the change in BMB score over time in the same patient. METHODS: A total of 119 sets of MR images of the lumbar spine and femora from 60 patients with Gaucher disease were included. Each set of MR images was scored using the BMB score independently by two experienced MSK radiologists. One radiologist performed a second read four weeks later...
November 14, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28185830/children-with-type-1-gaucher-disease-changing-profiles-in-the-21st-century
#12
Deborah Elstein, Gheona Altarescu, Aya Abrahamov, Ari Zimran
Gaucher disease (GD) has phenotypic variability. Increased GD awareness especially among at-risk Ashkenazi Jews (AJ) and availability of non-invasive diagnosis induced trend to prenatal screening. We retrospectively assessed pediatric (<16years) Israeli AJ GD patients to ascertain demographics and phenotype at presentation and over-time because many were identified by large-scale screening. 55/67 patients born since 01/01/2000 are AJ with non-neuronopathic GD: 28 (50.9%) are N370S/N370S; 24 (43.6%) are N370S/other; 3 (3...
December 19, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28173573/letter-outpatient-cervical-and-lumbar-spine-surgery-is-feasible-and-safe-a-consecutive-single-center-series-of-1449-patients
#13
Sonia Gaucher, Samir Bouam, David Maladry, Jean-Pierre Bethoux, Henri-Jean Philippe
No abstract text is available yet for this article.
February 1, 2017: Neurosurgery
https://www.readbyqxmd.com/read/28171725/fluorinated-chaperone-%C3%AE-cyclodextrin-formulations-for-%C3%AE-glucocerebrosidase-activity-enhancement-in-neuronopathic-gaucher-disease
#14
M Isabel Garcia-Moreno, Mario de la Mata, Elena Matilde Sánchez-Fernández, Juan M Benito, Antonio J Díaz-Quintana, Santos Fustero, Eiji Nanba, Katsumi Higaki, José A Sánchez Alcázar, José Manuel García Fernández, Carmen Ortiz Mellet
Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts...
February 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28167660/eliglustat-maintains-long-term-clinical-stability-in-patients-with-gaucher-disease-type-1-stabilized-on-enzyme-therapy
#15
Timothy M Cox, Guillermo Drelichman, Renata Cravo, Manisha Balwani, Thomas Andrew Burrow, Ana Maria Martins, Elena Lukina, Barry Rosenbloom, Ozlem Goker-Alpan, Nora Watman, Amal El-Beshlawy, Priya S Kishnani, Maria Lucia Pedroso, Sebastiaan J M Gaemers, Regina Tayag, M Judith Peterschmitt
In the phase 3 trial of eliglustat in patients with Gaucher disease type 1 already stabilized with enzyme therapy (ENCORE), at one year, eliglustat was non-inferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available...
February 6, 2017: Blood
https://www.readbyqxmd.com/read/28166796/coenzyme-q10-partially-restores-pathological-alterations-in-a-macrophage-model-of-gaucher-disease
#16
Mario de la Mata, David Cotán, Manuel Oropesa-Ávila, Marina Villanueva-Paz, Isabel de Lavera, Mónica Álvarez-Córdoba, Raquel Luzón-Hidalgo, Juan M Suárez-Rivero, Gustavo Tiscornia, José A Sánchez-Alcázar
BACKGROUND: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease...
February 6, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28144704/gaucher-disease-in-the-liver-on-hepatocyte-specific-contrast-agent-enhanced-mr-imaging
#17
Rama S Ayyala, Lisa A Teot, Jeanette M Perez Rossello
Gaucher disease is a hereditary lipid storage disorder that affects the enzyme beta glucocerebrosidase, causing accumulation of glucocerebroside in macrophages of the reticuloendothelial system. Accumulation can occur in the liver and spleen, manifesting as hepatosplenomegaly, as well as within the bone marrow. Hepatic involvement is usually diffuse but can occasionally manifest as focal liver lesions. We present a case of a 2-year-old boy with Gaucher disease and an infiltrating liver lesion detected on imaging, which was pathologically shown to be focal changes related to the disease...
February 1, 2017: Pediatric Radiology
https://www.readbyqxmd.com/read/28141506/antiviral-activity-of-acid-beta-glucosidase-1-on-enterovirus-71-a-causative-agent-of-hand-foot-mouth-disease
#18
Keiko Nakata, Satoshi Takeda, Atsushi Tanaka, Jimmy Kwang, Jun Komano
Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease (HFMD). EV71 causes fever, rash, diarrhea, and, in some cases, acute encephalopathy/encephalitis, which can be fatal. No specific treatment is currently available for EV71 infection. Here, we conducted a cDNA library screen and identified acid β-glucosidase 1 (GBA1; also known as β-glucocerebrosidase) as an EV71 resistance factor. The anti-EV71 function of GBA1 was verified by gene transduction and knockdown experiments. Cerezyme, a molecular drug used to treat Gaucher's disease having recombinant human GBA1 as the active ingredient, protected against EV71 infection...
January 27, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28131618/taliglucerase-alfa-in-gaucher-disease-description-of-a-brazilian-experience
#19
R Cravo, V Rotman, P M N Oliveira, H G T Defendi, D A Conceição, J R Xavier, R Chertkoff, T G Noronha, M L S Maia
We evaluated retrospectively, efficacy and safety of taliglucerase alfa for Gaucher disease in a Brazilian population. Thirteen patients were included for efficacy analysis only one of them naïve to enzyme replacement therapy. All the parameters evaluated remained stable throughout treatment (mean duration 3,5years). Only three patients (out of 35) had to discontinue treatment due to a serious adverse event. In conclusion, treatment with taliglucerase alfa was found to be safe and efficient.
January 16, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28126847/lipids-regulate-the-hydrolysis-of-membrane-bound-glucosylceramide-by-lysosomal-%C3%AE-glucocerebrosidase-gba1
#20
Misbaudeen Abdul-Hammed, Bernadette Breiden, Günter Schwarzmann, Konrad Sandhoff
Glucosylceramide is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B and C. The regulatory roles of lipids on the hydrolysis of membrane bound glucosylceramide by glucocerebrosidase GBA1 was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of Sap C. However, anionic lipids stimulate glucosylceramide hydrolysis at low pH by up to 1000 fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH...
January 26, 2017: Journal of Lipid Research
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