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Gaucher disease type 2

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
Dominick Amato, Mary Anne Patterson
BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms...
January 27, 2018: Journal of Medical Case Reports
R N Alcalay, P Wolf, O A Levy, U J Kang, C Waters, S Fahn, B Ford, S H Kuo, N Vanegas, H Shah, C Liong, S Narayan, M W Pauciulo, W C Nichols, Z Gan-Or, G A Rouleau, W K Chung, P Oliva, J Keutzer, K Marder, X K Zhang
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University...
January 21, 2018: Neurobiology of Disease
Suraj D Serai, Anjani P Naidu, T Andrew Burrow, Carlos E Prada, Stavra Xanthakos, Alexander J Towbin
Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease...
January 5, 2018: Molecular Genetics and Metabolism
Joel Charrow, Cristina Fraga, Xuefan Gu, Hiroyuki Ida, Nicola Longo, Elena Lukina, Alexandre Nonino, Sebastiaan J M Gaemers, Marie-Helene Jouvin, Jing Li, Yaoshi Wu, Yong Xue, M Judith Peterschmitt
Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (>90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing...
January 4, 2018: Molecular Genetics and Metabolism
Ida Vanessa D Schwartz, Özlem Göker-Alpan, Priya S Kishnani, Ari Zimran, Lydie Renault, Zoya Panahloo, Patrick Deegan
The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. Historically, there has been a limited understanding of type 3 GD (GD3) and its natural history in patients irrespective of their treatment status. Here, we describe the disease characteristics of patients with GD3 enrolled in GOS. As of October 2015, 1002 patients had been enrolled, 26 of whom were reported as GD3...
March 2018: Molecular Genetics and Metabolism Reports
Seung Pil Yun, Donghoon Kim, Sangjune Kim, SangMin Kim, Senthilkumar S Karuppagounder, Seung-Hwan Kwon, Saebom Lee, Tae-In Kam, Suhyun Lee, Sangwoo Ham, Jae Hong Park, Valina L Dawson, Ted M Dawson, Yunjong Lee, Han Seok Ko
BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin...
January 8, 2018: Molecular Neurodegeneration
Leelamma M Panicker, Manasa P Srikanth, Thiago Castro-Gomes, Diana Miller, Norma W Andrews, Ricardo A Feldman
Gaucher disease (GD) is caused by bi-allelic mutations in GBA1, the gene that encodes acid β-glucocerebrosidase (GCase). Individuals affected by GD have hematologic, visceral and bone abnormalities, and in severe cases there is also neurodegeneration. To shed light on the mechanisms by which mutant GBA1 causes bone disease, we examined the ability of human induced pluripotent stem cells (iPSC) derived from patients with types 1, 2 and 3 GD, to differentiate to osteoblasts and carry out bone deposition. Differentiation of GD iPSC to osteoblasts revealed that these cells had developmental defects and lysosomal abnormalities that interfered with bone matrix deposition...
January 2, 2018: Human Molecular Genetics
Beom Hee Lee, Ahmed Fathy Abdalla, Jin-Ho Choi, Amal El Beshlawy, Gu-Hwan Kim, Sun Hee Heo, Ahmed Megahed Hassan Megahed, Mona Abdel Latif Elsayed, Tarik El-Sayed Mohammad Barakat, Khaled Mohamed Abd El-Azim Eid, Mona Hassan El-Tagui, Mona Mohamed Hamdy Mahmoud, Ekram Fateen, June-Young Park, Han-Wook Yoo
BACKGROUND: Gaucher disease (GD) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. Enzyme replacement therapy (ERT) is recommended for clinical improvement. METHODS: The efficacy and safety of a new imiglucerase, Abcertin, were assessed in 7 Egyptian patients with treatment-naïve type 1 GD. Each patient was administered a biweekly 60 U/kg dose of Abcertin for 6 months. The primary endpoint was the change in hemoglobin concentration. The secondary endpoints were changes from baseline in platelet counts, spleen and liver volumes, biomarker levels, skeletal parameters, and bone mineral density...
November 2017: Medicine (Baltimore)
Ermias Hagege, Richard J Grey, Grisel Lopez, Tamanna Roshan Lal, Ellen Sidransky, Nahid Tayebi
Gaucher disease (GD) is a recessively inherited autosomal lysosomal storage disease, the most severe of which is type 2, an acute neuronopathic form. We report an affected infant who inherited one mutant allele, Arg257Gln (c.887G>A; p.Arg296Gln) from his father, while the second, Gly202Arg (c.721G>A; p.Gly241Arg) arose by either maternal germline mosaicism or as a de novo mutation. This is the first time mutation Gly202Arg has been reported to be inherited non-traditionally. This report is part of a growing literature suggesting that GD can be inherited via germline or de novo mutations, and emphasizes that it is critical for clinicians to consider such inheritance when making diagnostic decisions or providing genetic counseling...
December 2017: American Journal of Medical Genetics. Part A
Ari Zimran, Nadia Belmatoug, Bruno Bembi, Patrick Deegan, Deborah Elstein, Diego Fernandez-Sasso, Pilar Giraldo, Ozlem Goker-Alpan, Heather Lau, Elena Lukina, Zoya Panahloo, Ida Vanessa D Schwartz
The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy...
November 1, 2017: American Journal of Hematology
Usha R Somaraju, Krishna Tadepalli
BACKGROUND: Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice from enzyme replacement therapy, substrate reduction therapy and hemotopoietic stem cell transplantation (HSCT). HSCT is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. This is an update of a previously published Cochrane Review...
October 18, 2017: Cochrane Database of Systematic Reviews
Tamanna Roshan Lal, Ellen Sidransky
Gaucher disease, the most common lysosomal storage disorder, is due to a deficiency in the enzyme glucocerebrosidase. This leads to the accumulation of its normal substrate, glucocerebroside, in tissue macrophages, affecting the hematological, visceral, bone and neurologic systems. Gaucher disease is classified into three broad phenotypes based upon the presence or absence of neurological involvement: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Phenotypically, there is a wide spectrum of visceral and neurological manifestations...
March 2, 2017: Diseases (Basel)
Buge Yilmazer, Z Begum Yagci, Emre Bakar, Burcu Ozden, Kutlu Ulgen, Elif Ozkirimli
Beta-Glucocerebrosidase (GBA) is a lysosomal protein that is responsible for the hydrolysis of glycosylceramide into glucose and ceramide. Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease. Enzyme replacement therapies and substrate reduction methods that are used to treat Gaucher Disease fail when the disease is neuropathic because they fail to pass the blood brain barrier...
July 20, 2017: Journal of Molecular Graphics & Modelling
Barbara K Burton, Joel Charrow, George E Hoganson, Darrell Waggoner, Brad Tinkle, Stephen R Braddock, Michael Schneider, Dorothy K Grange, Claudia Nash, Heather Shryock, Rebecca Barnett, Rong Shao, Khaja Basheeruddin, George Dizikes
OBJECTIVES: To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. STUDY DESIGN: Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p...
November 2017: Journal of Pediatrics
Christine I Ha, Stephanie DeArmey, Heidi Cope, Mugdha Rairikar, Priya S Kishnani
The availability of three enzyme replacement therapy (ERT) drugs and two substrate reduction therapy (SRT) drugs to treat Gaucher disease provides an opportunity to tailor therapies to a patient's specific clinical concerns. However, there is a gap in the literature regarding individual drug effectiveness in treating particular symptoms and the potential benefits of combination treatment. This report details treatment of a patient with Gaucher disease type 1 whose main clinical concern was profound thrombocytopenia (around 20 × 10(9)/L, normal range: 150-450 × 10(9)/L) with several episodes of bleeding with minimal trauma and bruises...
September 2017: Molecular Genetics and Metabolism Reports
Josefine Blume, Stanislav Beniaminov, Cecilia Kämpe Björkvall, Maciej Machaczka, Per Svenningsson
BACKGROUND: Chronic neuronopathic Gaucher's disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3. OBJECTIVE: To characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique. METHODS: Horizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41...
2017: Frontiers in Neurology
Shiori Endo, Kunihiro Mizuta, Takashi Yamatodani, Hiroshi Nakanishi, Kumiko Hosokawa, Kiyoshi Misawa, Seiji Hosokawa, Hiroyuki Mineta
Gaucher disease is a lysosomal storage disorder that is caused by congenital defective function of the enzyme glucocerebrosidase. Glucocerebroside that is not hydrolyzed by glucocerebrosidase mainly accumulates in the reticular tissue. We describe a Japanese boy with Gaucher disease type 1 who developed bilateral profound sensorineural hearing loss within approximately 4years. We performed cochlear implantation initially on his right ear and again on his left ear 5 months later. The cochlear implants were successfully utilized with a speech discrimination score of 95% on a Japanese sentence recognition test...
June 22, 2017: Auris, Nasus, Larynx
Magy Abdelwahab, Michael Potegal, Elsa G Shapiro, Igor Nestrasil
OBJECTIVE: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. METHODS: Thirty-four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording...
June 2017: Neurology. Genetics
Yvonne Nitschke, Frank Rutsch
PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC...
August 2017: Current Osteoporosis Reports
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