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Caleb Pitcairn, Willayat Yousuf Wani, Joseph R Mazzulli
The finding that mutations in the Gaucher's Disease (GD) gene GBA1 are a strong risk factor for Parkinson's Disease (PD) has allowed for unique insights into pathophysiology centered on disruption of the autophagic-lysosomal pathway. Protein aggregations in the form of Lewy bodies and the effects of canonical PD mutations that converge on the lysosomal degradation system suggest that neurodegeneration in PD is mediated by dysregulation of protein homeostasis. The well-characterized clinical and pathological relationship between PD and the lysosomal storage disorder GD emphasizes the importance of dysregulated protein metabolism in neurodegeneration, and one intriguing piece of this relationship is a shared phenotype of autophagic-lysosomal dysfunction in both diseases...
March 14, 2018: Neurobiology of Disease
Anna Tylki-Szymańska, Paulina Szymańska-Rożek, Piotr Hasiński, Agnieszka Ługowska
Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate...
February 27, 2018: Molecular Genetics and Metabolism
Michael R Freund, Petachia Reissman, Ari Zimran, Joseph Alberton
OBJECTIVE: The objective of this article was to demonstrate that Gaucher disease (GD) patients with refractory hypersplenism and massive splenomegaly may successfully undergo hand-assisted laparoscopic splenectomy (HALS). METHODS: This was a retrospective audit conducted at the Gaucher clinic at a national referral center over a 10-year period. PATIENT POPULATION: This study included 8 GD patients who underwent hand-assisted or conventional laparoscopic splenectomy for massive or complicated splenomegaly between the years 2007 and 2017...
March 7, 2018: Surgical Laparoscopy, Endoscopy & Percutaneous Techniques
Rohini Sidhu, Christina R Mikulka, Hideji Fujiwara, Mark S Sands, Jean E Schaffer, Daniel S Ory, Xuntian Jiang
Deficiencies of galactosylceramidase and glucocerebrosidase result in the accumulation of galactosylsphingosine (GalSph) and glucosylsphingosine (GluSph) in Krabbe and Gaucher diseases, respectively. GalSph and GluSph are useful biomarkers for both diagnosis and monitoring of treatment effects. We have developed and validated a sensitive, accurate, high throughput assay for simultaneous determination of the concentration of GalSph and GluSph in mouse serum. GalSph and GluSph and their deuterated internal standards were extracted by protein precipitation in quantitative recoveries, baseline separated by hydrophilic interaction chromatography, and detected by positive-ion electrospray mass spectrometry in multiple reaction monitoring mode...
March 8, 2018: Biomedical Chromatography: BMC
Ratna Dua Puri, Seema Kapoor, Priya S Kishnani, Ashwin Dalal, Neerja Gupta, Mamta Muranjan, Shubha R Phadke, Anupam Sachdeva, Ishwar C Verma, Pramod K Mistry
JUSTIFICATION: Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients. PROCESS: Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics...
February 15, 2018: Indian Pediatrics
Andrea Lazzati, Sandrine Katsahian, David Maladry, Emma Gerard, Sonia Gaucher
BACKGROUND: Bariatric patients are often candidates for plastic surgery. However, the rate of postbariatric procedures is not known. OBJECTIVES: The aim of this study was to analyze the rate of plastic surgery, and factors related to surgery, in bariatric patients. SETTING: University hospital, France. METHODS: This was a cohort study based on administrative data. All adult patients who received bariatric surgery in France between 2007 and 2013 were included to estimate the rate of plastic surgery and related predictive factors...
January 12, 2018: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
Yuan Wu, Hong Xia, Jinzhong Yuan, Hongbo Xu, Xiong Deng, Jun Liu, Hao Zhang, Hao Deng
Introduction: Fabry Disease (FD), the second most common lysosomal storage disorder after Gaucher disease, is characterized by variable clinical manifestations, including angiokeratoma, corneal dystrophy, recurrent episodes of extremity pain, renal impairment, cardiac complications and cerebrovascular manifestations. It is caused by mutations in the α-galactosidase A gene (gene symbol GLA) on chromosome Xq22, which leads to deficiency of lysosomal α-galactosidase A (α-Gal A), and subsequent accumulation of glycosphingolipids in various tissues and organs...
January 2018: Current Genomics
Mustafa Resorlu, Nilufer Aylanc, Ozan Karatag, Canan Akgun Toprak
Gaucher's disease is characterized by glucocerebroside accumulation in the cells of the reticuloendothelial system. There are three subtypes. The most common is type 1, known as the non-neuropathic form. Pancytopenia, hepatosplenomegaly and bone lesions occur as a result of glucocerebroside accumulation in the liver, lung, spleen and bone marrow in these patients. Findings associated with liver, spleen or bone involvement may be seen at radiological analysis. Improvement in extraskeletal system findings is seen with enzyme replacement therapy...
December 2017: Revista da Associação Médica Brasileira
Michael S Marshall, Benas Jakubauskas, Wil Bogue, Monika Stoskute, Zane Hauck, Emily Rue, Matthew Nichols, Lisa L DiAntonio, Richard B van Breemen, Jeffrey H Kordower, Carlos A Saavedra-Matiz, Ernesto R Bongarzone
α-Synuclein aggregation has been linked to Gaucher's disease (GD) and Krabbe's disease (KD), lysosomal conditions affecting glycosphingolipid metabolism. α-Synuclein pathology has been directly attributed to the dysregulation of glycosphingolipids in both conditions, specifically to increased galactosylsphingosine (psychosine) content in the context of KD. Furthermore, the gene (GALC) coding for the psychosine degrading enzyme galactosylceramidase (GALC), has recently been identified as a risk loci for Parkinson's disease...
2018: PloS One
Manoj K Pandey, Gregory A Grabowski, Jörg Köhl
The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism...
February 22, 2018: Seminars in Immunology
Sergei M Danilov, Victoria E Tikhomirova, Roman Metzger, Irina A Naperova, Tatiana M Bukina, Ozlem Goker-Alpan, Nahid Tayebi, Nurshat M Gayfullin, David E Schwartz, Larisa M Samokhodskaya, Olga A Kost, Ellen Sidransky
BACKGROUND: Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin-converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. METHODS: ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes...
February 17, 2018: Molecular Genetics and Metabolism
Bénédicte Sudrié-Arnaud, Florent Marguet, Sophie Patrier, Jelena Martinovic, Ferielle Louillet, Françoise Broux, Françoise Charbonnier, Hélène Dranguet, Sophie Coutant, Myriam Vezain, Raphaël Lanos, Abdellah Tebani, Maria Fuller, Foudil Lamari, Pascal Chambon, Anne-Claire Brehin, Laetitia Trestard, Isabelle Tournier, Stéphane Marret, Eric Verspyck, Annie Laquerrière, Soumeya Bekri
PURPOSES: Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming...
February 21, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Jonathan Gaucher, Emilie Montellier, Paolo Sassone-Corsi
The cell cycle and the circadian clock operate as biological oscillators whose timed functions are tightly regulated. Accumulating evidence illustrates the presence of molecular links between these two oscillators. This mutual interplay utilizes various coupling mechanisms, such as the use of common regulators. The connection between these two cyclic systems has unique interest in the context of aberrant cell proliferation since both of these oscillators are frequently misregulated in cancer cells. Further studies will provide deeper understanding of the detailed molecular connections between the cell cycle and the circadian clock and may also serve as a basis for the design of innovative therapeutic strategies...
February 19, 2018: Trends in Cell Biology
Ari Zimran, Michael Wajnrajch, Betina Hernandez, Gregory M Pastores
Taliglucerase alfa is an enzyme replacement therapy (ERT) approved for treatment of adult and paediatric patients with Type 1 Gaucher disease (GD) in several countries and the first plant cell-expressed recombinant therapeutic protein approved by the US Food and Drug Administration for humans. Here, we review the findings across six key taliglucerase alfa clinical studies. A total of 33 treatment-naïve adult patients were randomized to taliglucerase alfa 30 U/kg or 60 U/kg in a 9-month, multicentre, randomized, double-blind, parallel-group, dose-comparison pivotal study, after which eligible patients continued into two consecutive extension studies; 17 treatment-naïve adult patients completed 5 total years of treatment with taliglucerase alfa...
February 23, 2018: Orphanet Journal of Rare Diseases
Magdalena Cerón-Rodríguez, Edgar Barajas-Colón, Lyuva Ramírez-Devars, Claudia Gutiérrez-Camacho, Juan L Salgado-Loza
BACKGROUND: Gaucher disease type 1 (GD1, OMIM# 230800), is a condition with high impact in patient's quality of life (QoL). We report the improvement in QoL of children with GD1 measured by Lansky play-performance scale (LS) after enzymatic replacement therapy (ERT) and to describe our experience in the treatment of children with GD1. METHODS: Five children with diagnosis of GD1 received imiglucerase 60 mg/kg every two weeks. LS, hepatomegaly, splenomegaly, hemoglobin, platelets, and growth rate were measured every 6 months after beginning ERT for 30 months...
January 2018: Molecular Genetics & Genomic Medicine
Nouf Althonaian, Abdulrahman Alsultan, Eva Morava, Majid Alfadhel
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Clinically, it is characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. It can be classified as primary if it is due to a genetic defect, or secondary if it is due to a different etiology such as severe infection, immune deficiency syndrome, rheumatological disorder, malignancy, and inborn errors of metabolism such as galactosemia, multiple sulfatase deficiency, lysinuric protein intolerance, Gaucher disease, Niemann-Pick disease, Wolman disease, propionic acidemia, methylmalonic acidemia, biotinidase deficiency, cobalamin C defect, galactosialidosis, Pearson syndrome, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency...
February 15, 2018: JIMD Reports
XuanLi Liu, Pauline Heitz, Michel Roux, Daniel Keller, Tristan Bourcier, Arnaud Sauer, Gilles Prévost, David Gaucher
Experimental models have established Panton-Valentine leukocidin (PVL) as a potential critical virulence factor during Staphylococcus aureus endophthalmitis. In the present study, we aimed to identify retinal cell targets for PVL and to analyze early retinal changes during infection. After the intravitreous injection of PVL, adult rabbits were euthanized at different time points (30 min, 1, 2, 4 and 8 h). PVL location in the retina, expression of its binding receptor C5a receptor (C5aR), and changes in Müller and microglial cells were analyzed using immunohistochemistry, Western blotting and RT-qPCR...
February 13, 2018: Scientific Reports
Martine Regenboog, Laura van Dussen, Joanne Verheij, Neal J Weinreb, David Santosa, Stephan Vom Dahl, Dieter Häussinger, Meike N Müller, Ali Canbay, Miriam Rigoldi, Alberto Piperno, Tama Dinur, Ari Zimran, Pramod K Mistry, Karima Yousfi Salah, Nadia Belmatoug, David J Kuter, Carla E M Hollak
Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied...
February 8, 2018: Journal of Inherited Metabolic Disease
Elena Gras-Colomer, María-Amparo Martínez-Gómez, Mónica Climente-Martí, Miguel Fernandez-Zarzoso, Mercedes Almela-Tejedo, Vicente Giner-Galvañ, Jose-Antonio Marcos-Rodríguez, Alicia Rodríguez-Fernández, Miguel-Ángel Torralba-Cabeza, Matilde Merino-Sanjuan
The quantification of enzyme activity in the patient treated with enzyme replacement therapy (ERT) has been suggested as a tool for dosage individualisation, so we conducted a study to evaluate the relationship between glucocerebrosidase activity and clinical response in patients with Gaucher disease type I (GD1) to ERT. The study included patients diagnosed with GD1, who were being treated with ERT, and healthy individuals. Markers based on glucocerebrosidase activity measurement in patients' leukocytes were studied: enzyme activity at 15 min...
February 8, 2018: Basic & Clinical Pharmacology & Toxicology
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
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