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Muacevic A, Adler JR. Targeted Screening for Gaucher Disease in High Suspicion Patients and Clinical Profile of Screen Positives in a Large Pediatric Multispecialty Hospital. Cureus 2022; 14:e29868. [PMID: 36348851 PMCID: PMC9630059 DOI: 10.7759/cureus.29868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2022] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES The proposed screening study was aimed at determining the prevalence of Gaucher disease in a selected high-risk population of patients and describing the clinical profile of diagnosed patients. METHODOLOGY It was a prospective observational study from January 2020 to September 2022 (two years and eight months) in the genetic clinic of the pediatric department. A total of 22 patients were suspected to be having Gaucher disease based on clinical findings of hepatosplenomegaly with bicytopenia or isolated thrombocytopenia. In these patients, chronic liver disease, portal hypertension, and other hematological conditions were ruled out. Three patients with Gaucher disease applied for enzyme replacement therapy (ERT) support under India Charitable Access Program and one patient received therapy for two months. Clinical findings were compared before and after ERT. Clinical findings were noted in all patients. RESULTS Among the 22 patients, nine (40.9%) patients were confirmed to be suffering from Gaucher disease with six based on enzyme assay on dry blood spot and three based on DNA mutation analysis. One patient among the screen positives received ERT for two months and was noted to have an improvement in hemoglobin and platelet count, a reduction in liver size, and better general well-being. CONCLUSION High-suspicion targeted screening of Gaucher disease in patients with splenomegaly and thrombocytopenia based on a dry blood spot enzyme assay is high yielding, effective strategy in identifying Gaucher disease patients. Clinical features were variable in severity, though a common mutation was found in the majority of patients.
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Parini R, Deodato F. Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int J Mol Sci 2020; 21:E2975. [PMID: 32340185 PMCID: PMC7215308 DOI: 10.3390/ijms21082975] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/13/2020] [Accepted: 04/21/2020] [Indexed: 12/21/2022] Open
Abstract
The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for mucopolysaccharidoses (MPSs) I, II, IVA, VI and VII, gained in phase III clinical trials and in observational post-approval studies. Post-marketing data are sometimes conflicting or controversial, possibly depending on disease severity, differently involved organs, age at starting treatment, and development of anti-drug antibodies (ADAs). There is general agreement that ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea and bronchi, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. All patients develop ADAs but their role in ERT tolerance and effectiveness has not been well defined yet. Lack of reliable biomarkers contributes to the uncertainties about effectiveness. The data obtained from affected siblings strongly indicates the need of neonatal screening for treatable MPSs. Currently, other treatments are under evaluation and will surely help improve the prognosis of MPS patients.
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Affiliation(s)
- Rossella Parini
- UOS Malattie Metaboliche Rare, Clinica Pediatrica dell’Università Milano Bicocca, Fondazione MBBM, ATS Monza e Brianza, 20900 Monza, Italy
| | - Federica Deodato
- Division of Metabolic Disease, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
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Vujosevic S, Medenica S, Vujicic V, Dapcevic M, Bakic N, Yang R, Liu J, Mistry PK. Gaucher disease in Montenegro - genotype/phenotype correlations: Five cases report. World J Clin Cases 2019; 7:1475-1482. [PMID: 31363476 PMCID: PMC6656677 DOI: 10.12998/wjcc.v7.i12.1475] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/01/2019] [Accepted: 05/11/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD.
CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient).
CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.
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Affiliation(s)
- Snezana Vujosevic
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Sanja Medenica
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Vesko Vujicic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Milena Dapcevic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Nikola Bakic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Ruhua Yang
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Jun Liu
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Pramod K Mistry
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
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Donida B, Jacques CED, Mescka CP, Rodrigues DGB, Marchetti DP, Ribas G, Giugliani R, Vargas CR. Oxidative damage and redox in Lysosomal Storage Disorders: Biochemical markers. Clin Chim Acta 2017; 466:46-53. [DOI: 10.1016/j.cca.2017.01.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 01/04/2017] [Accepted: 01/07/2017] [Indexed: 02/03/2023]
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Cravo R, Rotman V, Oliveira PMN, Defendi HGT, Conceição DA, Xavier JR, Chertkoff R, Noronha TG, Maia MLS. Taliglucerase alfa in Gaucher disease: Description of a Brazilian experience. Blood Cells Mol Dis 2017; 68:160-162. [PMID: 28131618 DOI: 10.1016/j.bcmd.2017.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/29/2016] [Accepted: 01/12/2017] [Indexed: 11/18/2022]
Abstract
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.
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Affiliation(s)
- R Cravo
- Hemorio Hospital, Rio de Janeiro, Brazil.
| | - V Rotman
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | - P M N Oliveira
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | - H G T Defendi
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | - D A Conceição
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | - J R Xavier
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | | | - T G Noronha
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
| | - M L S Maia
- BIO-Manguinhos/Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
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Drelichman G, Fernández Escobar N, Basack N, Aversa L, Larroude MS, Aguilar G, Szlago M, Schenone A, Fynn A, Cuello MF, Aznar M, Fernández R, Ruiz A, Reichel P, Guelbert N, Robledo H, Watman N, Bolesina M, Elena G, Veber SE, Pujal G, Galván G, Chain JJ, Arizo A, Bietti J, Bar D, Dragosky M, Marquez M, Feldman L, Muller K, Zirone S, Buchovsky G, Lanza V, Sanabria A, Fernández I, Jaureguiberry R, Contte M, Barbieri María A, Maro A, Zárate G, Fernández G, Rapetti MC, Donato H, Degano A, Kantor G, Albina R, Álvarez Bollea M, Brun M, Bacciedoni V, Del Río F, Soberón B, Boido N, Schweri M, Borchichi S, Welsh V, Corrales M, Cedola A, Carvani A, Diez B, Richard L, Baduel C, Nuñez G, Colimodio R, Barazzutti L, Medici H, Meschengieser S, Damiani G, Nucifora M, Girardi B, Gómez S, Papucci M, Verón D, Quiroga L, Carro G, De Ambrosio P, Ferro J, Pujol M, Castella CC, Franco L, Nisnovich G, Veloso M, Pacheco I, Savarino M, Marino A, Saavedra JL. Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients. Am J Hematol 2016; 91:E448-53. [PMID: 27420181 DOI: 10.1002/ajh.24486] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 07/12/2016] [Accepted: 07/13/2016] [Indexed: 12/21/2022]
Abstract
Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
| | | | | | | | | | | | - Marina Szlago
- Laboratorio de Neuroquímica “Dr. N.A Chamoles”, CABA
| | | | - Alcyra Fynn
- Hospital de Niños “Sor María Ludovica”, La Plata; Prov. Buenos Aires
| | | | - Marcela Aznar
- Hospital de Niños “Sor María Ludovica”, La Plata; Prov. Buenos Aires
- Hospital CEPSI Eva Perón; Santiago del Estero
- Hospital Provincial de Niños “Santa Trinidad”; Córdoba
- Hospital Ramos Mejía, CABA
- Hospital de Niños “Pedro de Elizalde”, CABA. Hospital “Dr. Julio C. Perrando”; Chaco. Hospital del Niño Jesús; Tucumán. Hospital Iturraspe; Santa Fe. Instituto Médico Platense; La Plata
| | - Ramiro Fernández
- Hospital de Niños “Sor María Ludovica”, La Plata; Prov. Buenos Aires
| | - Alba Ruiz
- Hospital CEPSI Eva Perón; Santiago del Estero
| | | | | | - Hugo Robledo
- Hospital Provincial de Niños “Santa Trinidad”; Córdoba
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Victoria Lanza
- Hospital Materno Infantil de Mar del Plata, Pcia. Buenos Aires
| | - Alba Sanabria
- Hospital Materno Infantil de Mar del Plata, Pcia. Buenos Aires
| | | | | | | | | | | | | | | | | | - Hugo Donato
- Hospital de Niños de San Justo, Pcia. Buenos Aires
| | | | | | - Roberto Albina
- Consultorio Particular, Mar del Plata; Prov. Buenos Aires
| | | | - María Brun
- Hospital Centenario, Gualeguaychu, Entre Ríos
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - David Verón
- Hospital Nacional “Profesor Alejandro Posadas”, L
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Bennett LL, Turcotte K. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:4639-47. [PMID: 26345314 PMCID: PMC4554398 DOI: 10.2147/dddt.s77760] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The purpose of this article is to review eliglustat tartrate, a substrate reduction therapy, for the treatment of Gaucher disease type 1 (GD1). GD is an rare inborn error of metabolism caused by accumulation of lipid substrates such as glucosylceramide within the monocyte-macrophage system that affects the body by causing enlargement of the spleen and liver, destruction of bone, and abnormalities of the lungs and blood, such as anemia, thrombocytopenia, and leukopenia. GD is classified into three types: GD1, a chronic and non-neuronopathic disease accounting for 95% of GD cases; and types 2 and 3 (GD2 GD3) which are more progressive diseases with no approved drugs available at this time. Treatment options for GD1 include enzyme replacement therapy and substrate reduction therapy. Eliglustat works by inhibiting UDP-glucosylceramide synthase, the first enzyme that catalyzes the biosynthesis of glycosphingolipids, thus reducing the load of glucosylceramide influx into the lysosome. Eliglustat was approved by the US Food and Drug Administration after three Phase I, two Phase II, and two Phase III clinical trials. The dose of eliglustat is 84 mg twice a day or once daily depending on the cytochrome P450 2D6 genotype of the patient.
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Macrophage-derived soluble CD163 level in young patients with Gaucher disease: relation to phenotypes, disease severity and complications. Int Immunopharmacol 2015; 24:416-422. [PMID: 25587690 DOI: 10.1016/j.intimp.2014.12.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 12/20/2014] [Accepted: 12/29/2014] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Bone and lung involvement are two major causes of morbidity in Gaucher disease (GD). The soluble form of CD163 (sCD163) is a valuable diagnostic biomarker for monitoring diseases with increased macrophage activation. We determined sCD163 levels in 30 children and adolescence with GD compared with 30 healthy controls and assessed the relation to phenotypes, disease severity and complications. METHODS Thirty GD patients (10 had type 1 and 20 had type 3) were studied stressing on skeletal, pulmonary or neurological manifestations, enzyme replacement therapy (ERT), hematological profile, plasma chitotriosidase activity, D-dimer and sCD163. Liver and spleen volumes and bone mineral density (BMD) were assessed. RESULTS sCD163 levels were markedly elevated in patients compared with controls. D-dimer, chitotriosidase activity and sCD163 levels were significantly increased in type 3 GD patients compared with type 1. sCD163 was significantly elevated in GD patients with dysphagia, developmental delay, pulmonary hypertension risk or abnormal BMD (osteopenia/osteoporosis) than those without. GD patients receiving ERT every 2weeks had lower levels than those under ERT for more than 2weeks. sCD163 was positively correlated with age, disease duration, severity score index, D-dimer and chitotriosidase activity. The cutoff value of sCD163 at 9400ng/mL could differentiate GD patients with and without pulmonary hypertension risk with a sensitivity of 90% and specificity of 95%. CONCLUSIONS sCD163 is a biomarker for the clinical assessment of macrophage proliferation and activity that would help in risk prediction of bone and lung involvement and monitoring treatment response.
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Essabar L, Meskini T, Lamalmi N, Ettair S, Erreimi N, Mouane N. Gaucher's disease: report of 11 cases with review of literature. Pan Afr Med J 2015; 20:18. [PMID: 25995815 PMCID: PMC4431408 DOI: 10.11604/pamj.2015.20.18.4112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 10/09/2014] [Indexed: 12/16/2022] Open
Abstract
Gaucher's disease (GD) is a lysosomal storage disorder due to glucocerebrosidase deficiency; it's one of the rare genetic diseases for which therapy is now available. The purpose of this work is to study the epidemiological features of the disease and to highlight the diagnostic difficulties. We performed an 11-year retrospective study of 11 patients with GD followed-up in the department of paediatric hepatology gastroenterology and nutrition of Rabat children's Hospital. We observed 11 patients with GD: 6 males and 5 females. Age at onset ranged from 3 months to 10 years with an average of 3.41 years. Mean age at diagnosis was 4 years (range 3months-14years). Parental consanguinity was noted in 85% cases. According to the clinical presentation, we classified our patients into: 9 cases of type 1 (81%) and two cases of type 2 (19%), none of the patients presented GD type 3. GD type 1: The age at diagnosis ranged from 2 years to 14 year with an average of 6 years. Main symptoms were: splenomegaly, hepatomegaly, pallor, haemorrhagic appearance (40%), bone pain (40%). The diagnosis was based on histology showing the Gaucher's cells in various tissues (100%). Enzymatic activity dosage confirmed the diagnosis of GD for 4 patients (44.5%). The treatment was always symptomatic (analgesics, transfusion). A splenectomy was performed in one case presenting with multiple splenic abscesses and high transfusion requirements. None of the patients received a specific treatment (substitutive enzymotherapy). The follow-up period ranged from 3 months to 6 years with an average follow-up of 4 years. We noticed stability in 4 cases, 2 worsening cases with bone and spleen complications. Three patients were lost to follow-up. GD type 2: we observed two cases of GD type 2 diagnosed at 3 and 18 months. The visceral symptoms were serious and the neurological features included seizures, hypertony, squint, physical developmental milestones delay. Both of them died. Gaucher's disease is not exceptional in Morocco. Type 1 is the most common type. We noted through this study some diagnostic difficulties as the diagnosis was delayed and the enzymatic dosage was performed in only 42% of the cases as well as therapeutic difficulty with no prescription of the specific treatment given the high cost of the enzyme.
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Affiliation(s)
- Laila Essabar
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Toufik Meskini
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Najat Lamalmi
- FMPR, University Mohammed V Souissi, Department of Anatomo-Pathology, Rabat Children's Hospital
| | - Said Ettair
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Naima Erreimi
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Nezha Mouane
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
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Chaves R, Pereira LDV, de Araújo F, Rozenberg R, Carvalho M, Coelho J, Michelin-Tirelli K, Chaves MDF, Cavalcanti G. Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil. Clin Genet 2014; 88:391-5. [DOI: 10.1111/cge.12515] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/26/2014] [Accepted: 09/29/2014] [Indexed: 11/26/2022]
Affiliation(s)
- R.G. Chaves
- UFRN Postgraduate Program; Natal Brazil
- Municipal Department of Health; Tabuleiro do Norte Brazil
| | - L. da Veiga Pereira
- Department of Genetics and Evolutionary Biology; USP Institute of Biosciences; São Paulo Brazil
| | - F.T. de Araújo
- Department of Genetics and Evolutionary Biology; USP Institute of Biosciences; São Paulo Brazil
| | - R. Rozenberg
- Department of Genetics and Evolutionary Biology; USP Institute of Biosciences; São Paulo Brazil
| | | | - J.C. Coelho
- UFRGS/ICBS Department of Biochemistry; Porto Alegre Brazil
| | | | | | - G.B. Cavalcanti
- UFRN/CCS Department of Clinical and Toxicological Analysis; Rio Grande do Sul Brazil
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Abstract
OBJECTIVE To review the epidemiology, pathophysiology, and treatments of Gaucher disease (GD), focusing on the role of enzyme replacement therapy (ERT), andsubstrate reduction therapy (SRT). DATA SOURCES A literature search through PubMed (1984-May 2013) of English language articles was performed with terms: Gaucher's disease, lysosomal storage disease. Secondary and tertiary references were obtained by reviewing related articles. STUDY SELECTION AND DATA EXTRACTION All articles in English identified from the data sources, clinical studies using ERT, SRT and articles containing other interesting aspects were included. DATA SYNTHESIS GD is the most common inherited LSD, characterized by a deficiency in the activity of the enzyme acid β-glucosidase, which leads to accumulation of glucocerebroside within lysosomes of macrophages, leading to hepatosplenomegaly, bone marrow suppression, and bone lesions. GD is classified into 3 types: type 1 GD (GD1) is chronic and non-neuronopathic, accounting for 95% of GDs, and types 2 and 3 (GD2, GD3) cause nerve cell destruction. Regular monitoring of enzyme chitotriosidase and pulmonary and activation-regulated chemokines are useful to confirm the diagnosis and effectiveness of GD treatment. CONCLUSIONS There are 4 treatments available for GD1: 3 ERTs and 1 SRT. Miglustat, an SRT, is approved for mild to moderate GD1. ERTs are available for moderate to severe GD1 and can improve quality of life within the first year of treatment. The newest ERT, taliglucerase alfa, is plant-cell derived that can be produced on a large scale at lower cost. Eliglustat tartrate, another SRT, is under phase 3 clinical trials. No drugs have been approved for GD2 or GD3.
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Tantawy AAG, Sherif EM, Adly AAM, Hassanine S, Awad AH. Evoked potentials and neurocognitive functions in pediatric Egyptian Gaucher patients on enzyme replacement therapy: a single center experience. J Inherit Metab Dis 2013; 36:1025-37. [PMID: 23508695 DOI: 10.1007/s10545-013-9597-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 01/27/2013] [Accepted: 02/07/2013] [Indexed: 01/17/2023]
Abstract
BACKGROUND Effectiveness of enzyme replacement therapy (ERT) in reverting hematologic, skeletal, and visceral symptoms in Gaucher disease (GD) has been demonstrated, although, its efficacy in neurologic involvement is still debated. AIM We evaluated the extent of neuro-cognitive dysfunction using brain stem evoked potential in GD3 patients, age-matched controls, and GD1 patients without neurological manifestations served as disease control group. METHODS Study included 56 GD (36 had type 1, 20 had type 3) under ERT. Investigations included complete blood count, beta glucosidase assay in peripheral leucocytes, plasma chitotriosidase and bone marrow examination, electroencephalography, brain stem auditory (AEP), somatosensory (SSEP) and visual evoked potentials (VEP) as well as IQ testing. RESULTS Both types of GD showed significantly higher mean latency at 75 on left eye, lower PP amplitude ratio, higher latency at 75, 100, 145, lower amplitude, and higher Lat Diff LT-RT ms and Lt-Rt % compared to controls (p < 0.05) with no difference between both groups in other values of VEP. Both groups showed significantly prolonged latency of N 13-19 compared to controls (p < 0.05) with positive correlation between age and duration of therapy with parameters of SSEP (p < 0.01). Both groups of GD had significantly prolonged latency of the mean waves of AEP compared to controls (p < 0.05) with no significant difference between both groups. There was a negative correlation between age and waves II, III, I-III, I-V and threshold values of AEP. IQ level was positively correlated with AEP values. Severity scoring tool was positively correlated with AEP and SSEP values. CONCLUSIONS Electrophysiological abnormalities were present in both types of GD and have been correlated to cognitive function and disease characteristics.
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Affiliation(s)
- Azza Abdel Gawad Tantawy
- Pediatrics Department, Faculty of Medicine, Ain Shams University Children's Hospital, Abbassya, Cairo, Egypt,
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Doneda D, Netto CB, Moulin CC, Schwartz IVD. Effects of imiglucerase on the growth and metabolism of Gaucher disease type I patients: a systematic review. Nutr Metab (Lond) 2013; 10:34. [PMID: 23570288 PMCID: PMC3630065 DOI: 10.1186/1743-7075-10-34] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/22/2013] [Indexed: 11/10/2022] Open
Abstract
Background Gaucher disease (GD) type I is the most common type of GD. Its main clinical manifestations are hepatosplenomegaly as well as bone and hematological abnormalities. The objective of the present study was to perform a literature review on the growth and metabolism of GD type I patients. Methods We searched Pubmed and Scielo.br databases with predetermined study limits: case series (n≥5), clinical trials, systematic reviews, and meta-analyses, and enzyme replacement therapy (ERT) with alglucerase or imiglucerase. The outcomes of interest were the following: growth and development, weight, height, malnutrition, overweight, obesity, basal metabolism, hypermetabolism, insulin resistance, and diabetes. A total of 175 articles were found, of which 28 met the inclusion criteria; these articles were grouped into three central themes: 1) growth of children and adolescents before and after ERT; 2) metabolic changes that remained during ERT; and 3) changes in metabolic status resulting from the treatment. Results and discussion The articles included in the present literature review are very heterogeneous, which hinders the analysis of data. They indicated that GD patients usually show low weight and height before ERT, which are improved with treatment in children and adolescents. Studies evaluating the energy metabolism by indirect calorimetry have indicated that the disease is associated with hypermetabolism. In adults, some changes in energy metabolism remain on ERT, and alterations, such as insulin resistance, seem to be associated with the treatment. It is not clear which are the required doses of imiglucerase for obtaining an adequate cost-effective relation, as well as the advisable therapeutic measures to avoid possible long-term adverse effects related to ERT. Conclusions ERT tends to normalise the growth of children and adolescents with GD type I, it seems to cause a partial response in relation to some metabolic changes associated with the disease, and it can causes metabolic changes such as weight gain in adult patients. Therefore, additional research is necessary.
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Affiliation(s)
- Divair Doneda
- Post Graduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
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D-dimer assay in Egyptian patients with Gaucher disease: correlation with bone and lung involvement. Blood Coagul Fibrinolysis 2011; 22:176-84. [PMID: 21346558 DOI: 10.1097/mbc.0b013e3283424809] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Gaucher disease is the most frequent lysosomal storage disorder. Bone and lung involvement are two major causes of morbidity in this disease. D-dimer is a reliable indicator of active microvascular thrombosis, even in patients without overt hypercoagulation. This study aimed to assess D-dimer levels in Gaucher disease, correlating this marker to clinical characteristics and radiological parameters to investigate its role as a potential predictor for the occurrence and severity of skeletal and pulmonary manifestations. The study population consisted of 56 Egyptian patients with Gaucher disease, 36 had type 1 Gaucher disease (64.3%) and 20 had type 3 Gaucher disease (35.7%). Thirty healthy individuals were enrolled as a control group. D-dimer levels were significantly higher in all patients with Gaucher disease compared with controls (P < 0.001). Patients with type 3 showed significantly higher D-dimer concentrations compared with type 1 (P < 0.001). Pulmonary involvement was present in a significant proportion among type 3 Gaucher patients (P < 0.05), whereas bone changes were present in a higher percentage in type 1 compared with type 3 Gaucher patients. D-dimers were significantly higher in patients with abnormal MRI findings of the long bones and in those with ground glass appearance on high-resolution computerized tomography of the chest compared with patients with normal radiology (P < 0.001). Splenectomized patients displayed significantly higher D-dimer levels compared with nonsplenectomized patients (P < 0.001). Our results suggest that D-dimer is significantly elevated in Gaucher disease, particularly type 3, and may be considered as a potential marker of risk prediction of bone and lung involvement that could be used to monitor treatment response.
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Chaves RG, Coelho JC, Michelin-Tirelli K, Maurício TF, de Freitas Maia Chaves E, de Almeida PC, Maurício CRF, Cavalcanti GB. Successful screening for Gaucher disease in a high-prevalence population in tabuleiro do Norte (northeastern Brazil): a cross-sectional study. JIMD Rep 2011; 1:73-8. [PMID: 23430831 DOI: 10.1007/8904_2011_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2010] [Revised: 01/31/2011] [Accepted: 02/04/2011] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gaucher disease (GD) is a hereditary lysosomal storage disorder characterized by the accumulation of glucosylceramide, mainly in the cells of the reticuloendothelial system, due to a deficiency of the enzyme acid β-glucosidase (GBA). Diagnosis is usually based on measurement of GBA activity in peripheral leukocytes. The purpose of this study was to evaluate the ability of screening for GBA and chitotriosidase activity using dried blood spots on filter paper (DBS-FP) to identify individuals at high risk for GD in high-risk populations such as that of Tabuleiro do Norte, a small town in Northeastern Brazil. METHODS Between 1 June 2007 and 31 May 2008, 740 consented residents and descendants of traditional families from Tabuleiro do Norte were submitted to screening with DBS-FP. Subjects with GBA activity < 2.19 nmol/h/mL were referred to the analysis of GBA and chitotriosidase activity in peripheral leukocytes and in plasma, respectively. Subjects at highest risk for GD (GBA activity in peripheral leukocytes < 5.6 nmol/h/mg protein) were referred to molecular analysis to confirm diagnosis. RESULTS Screening with DBS-FP identified 135 subjects (18.2%) with GBA activity < 2.19 nmol/h/mL, 131 of whom remained in the study. In ten of these (7.6%), GBA activity in leukocytes was 2.6-5.5 nmol/h/mg protein. Subsequent molecular analysis confirmed six cases of heterozygosity and four normals for GD. CONCLUSION DBS-FP assay was shown to be an effective initial GD-screening strategy for high-prevalence populations in developing regions. Diagnosis could not be established from GBA activity in leukocytes alone, but required confirmation with molecular analysis.
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Affiliation(s)
- Rigoberto Gadelha Chaves
- Programa de Pós-Graduação do Centro de Ciências da Saúde- UFRN, Rua Capitão José Rodrigues 4774, Centro, Tabuleiro do Norte, Ceará, Brazil,
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Novo JB, Oliveira MLS, Magalhães GS, Morganti L, Raw I, Ho PL. Generation of polyclonal antibodies against recombinant human glucocerebrosidase produced in Escherichia coli. Mol Biotechnol 2011; 46:279-86. [PMID: 20574770 DOI: 10.1007/s12033-010-9303-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Deficiency of the lysosomal glucocerebrosidase (GCR) enzyme results in Gaucher's disease, the most common inherited storage disorder. Treatment consists of enzyme replacement therapy by the administration of recombinant GCR produced in Chinese hamster ovary cells. The production of anti-GCR antibodies has already been described with placenta-derived human GCR that requires successive chromatographic procedures. Here, we report a practical and efficient method to obtain anti-GCR polyclonal antibodies against recombinant GCR produced in Escherichia coli and further purified by a single step through nickel affinity chromatography. The purified GCR was used to immunize BALB/c mice and the induction of anti-GCR antibodies was evaluated by enzyme-linked immunosorbent assay. The specificity of the antiserum was also evaluated by western blot analysis against recombinant GCR produced by COS-7 cells or against endogenous GCR of human cell lines. GCR was strongly recognized by the produced antibodies, either as cell-associated or as secreted forms. The detected molecular masses of 59-66 kDa are in accordance to the expected size for glycosylated GCR. The GCR produced in E. coli would facilitate the production of polyclonal (shown here) and monoclonal antibodies and their use in the characterization of new biosimilar recombinant GCRs coming in the near future.
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Affiliation(s)
- Juliana Branco Novo
- Centro de Biotecnologia, Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP, 05503-900, Brazil.
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Doneda D, Lopes AL, Oliveira ÁR, Netto CB, Moulin CC, Schwartz IV. Gaucher disease type I: Assessment of basal metabolic rate in patients from southern Brazil. Blood Cells Mol Dis 2011; 46:42-6. [DOI: 10.1016/j.bcmd.2010.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Accepted: 10/10/2010] [Indexed: 10/18/2022]
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Martins AM, Valadares ER, Porta G, Coelho J, Semionato Filho J, Pianovski MAD, Kerstenetzky MS, Montoril MDFP, Aranda PC, Pires RF, Mota RMV, Bortolheiro TC. Recommendations on diagnosis, treatment, and monitoring for Gaucher disease. J Pediatr 2009; 155:S10-8. [PMID: 19765407 DOI: 10.1016/j.jpeds.2009.07.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Ana Maria Martins
- Centro de Referência em Erros Inatos, Universidade Federal de São Paulo, São Paulo, Brazil.
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Abstract
Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human alpha-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.
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Affiliation(s)
- Ans T van der Ploeg
- Department of Paediatrics, Division of Metabolic Diseases and Genetics, Erasmus MC, Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands.
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Rohrbach M, Clarke JTR. Treatment of lysosomal storage disorders : progress with enzyme replacement therapy. Drugs 2008; 67:2697-716. [PMID: 18062719 DOI: 10.2165/00003495-200767180-00005] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Enzyme replacement therapy (ERT) as treatment for lysosomal storage diseases (LSDs) was suggested as long ago as 1966 by De Duve and Wattiaux. However, it took >35 years to demonstrate the safety and effectiveness of ERT for type 1 Gaucher's disease. An important breakthrough was certainly the enactment of legislation in the US, designed to encourage commercialisation of products developed in academic institutions for pharmaceutical companies to invest in treatments for rare diseases. The principles elaborated in the development of the treatment of Gaucher's disease were subsequently applied to the development of ERT of other LSDs. The safety and effectiveness of ERT for Fabry's disease, mucopolysaccharidoses (MPS) I, MPS II and MPS VI, as well as for Pompe's disease have been demonstrated in well designed clinical trials, and the treatments are now commercially available throughout the world. Several questions remain to be answered. The long-term effectiveness of most of the treatments has not yet been established. What is reversible by ERT and what may not be reversible but is preventable, is not yet clear. The pathology in some tissues, such as the brain, is inaccessible to ERT, indicating that some manifestations of the LSD will not respond to the treatment. The extent of this problem is still unclear. The cost of ERT is very high, creating problems for third-party payers, which has strained reimbursement schemes based on the demonstration of acceptable cost effectiveness. ERT of LSDs represents the most important advance in the treatment of this class of diseases. The information that is currently being collected as part of large-scale observational studies will help to establish the full potential of the treatment.
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Affiliation(s)
- Marianne Rohrbach
- Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
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Levrat V, Forest I, Fouilhoux A, Guffon N. Maladie de Gaucher : particularités cliniques chez l’enfant. Rev Med Interne 2007; 28 Suppl 2:S183-6. [DOI: 10.1016/s0248-8663(07)78879-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease. J Pediatr 2007; 151:197-201. [PMID: 17643778 DOI: 10.1016/j.jpeds.2007.02.057] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2006] [Revised: 12/19/2006] [Accepted: 02/16/2007] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To document the effects of interrupting enzyme replacement therapy (ERT) for at least 1 year in a group of children with type 1 Gaucher disease. STUDY DESIGN All children with type 1 Gaucher disease who were treated at 2 pediatric centers and who were required to suspend ERT for at least 1 year were studied before, during, and after treatment interruption. Hemoglobin and platelet levels, organomegaly, growth, and bone manifestations were monitored. RESULTS Five of 32 children experienced treatment interruptions. Before ERT, all children had splenomegaly, 4 children had hepatomegaly, 4 children had growth retardation, 3 children had skeletal manifestations, 3 children had thrombocytopenia, and 1 child had anemia. After 1 to 7 years of ERT, all children were growing normally, none had skeletal manifestations, organomegaly had decreased or disappeared, and hematologic features had improved. After 15 to 36 months of ERT interruption, splenomegaly recurred or worsened in all children, hepatomegaly and hematologic features recurred or worsened in 4 children, serious bone manifestations developed in 4 children, and 3 children experienced growth retardation. After at least 11 months of resumed ERT in 4 children, 2 had hepatomegaly, 2 had splenomegaly, and all had persistent skeletal manifestations. CONCLUSION Interruption of ERT in children with type 1 Gaucher disease should be avoided because it can cause recurrent organomegaly, growth delays, and skeletal manifestations that do not resolve after treatment reinstatement.
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Mistry PK, Sadan S, Yang R, Yee J, Yang M. Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention. Am J Hematol 2007; 82:697-701. [PMID: 17492645 DOI: 10.1002/ajh.20908] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 +/- 123.6 months. More than two-thirds were evaluated and managed by a hematologist-oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated.
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Affiliation(s)
- Pramod K Mistry
- Department of Pediatric Gastroenterology and Hepatology, Yale University, School of Medicine, New Haven, Connecticut 06520, USA.
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McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JMFG, Cheng SH, Copeland DP, Marshall J. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab 2007; 91:259-67. [PMID: 17509920 DOI: 10.1016/j.ymgme.2007.04.001] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Revised: 04/03/2007] [Accepted: 04/04/2007] [Indexed: 01/05/2023]
Abstract
An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical characterization of Genz-112638 showed good potency (IC(50) approximately 24nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels of glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted in arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher disease.
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Ellinwood NM, Colle MA, Weil MA, Casal ML, Vite CH, Wiemelt S, Hasson CW, O'Malley TM, He X, Prociuk U, Verot L, Melniczek JR, Lannon A, Aguirre GD, Knox VW, Evans SM, Vanier MT, Schuchman EH, Walkley SU, Haskins ME. Bone marrow transplantation for feline mucopolysaccharidosis I. Mol Genet Metab 2007; 91:239-50. [PMID: 17482862 PMCID: PMC2736908 DOI: 10.1016/j.ymgme.2007.03.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Revised: 03/05/2007] [Accepted: 03/05/2007] [Indexed: 11/25/2022]
Abstract
Severe mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT. Herein we report on bone marrow transplantation to treat feline mucopolysaccharidosis I (MPS I). Five MPS I stably engrafted kittens, transplanted with unfractionated bone marrow (6.3x10(7)-1.1x10(9) nucleated bone marrow cells per kilogram) were monitored for 13-37 months post-engraftment. The tissue total glycosaminoglycan (GAG) content was reduced to normal levels in liver, spleen, kidney, heart muscle, lung, and thyroid. Aorta GAG content was between normal and affected levels. Treated cats had a significant decrease in the brain GAG levels relative to untreated MPS I cats and a paradoxical decrease relative to normal cats. The alpha-l-iduronidase (IDUA) activity in the livers and spleens of transplanted MPS I cats approached heterozygote levels. In kidney cortex, aorta, heart muscle, and cerebrum, there were decreases in GAG without significant increases in detectable IDUA activity. Treated animals had improved mobility and decreased radiographic signs of disease. However, significant pathology remained, especially in the cervical spine. Corneal clouding appeared improved in some animals. Immunohistochemical and biochemical analysis documented decreased central nervous system ganglioside storage. This large animal MPS I study will serve as a benchmark of future therapies designed to improve on BMT.
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Affiliation(s)
- N Matthew Ellinwood
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Sobreira E, Pires RF, Cizmarik M, Grabowski GA. Phenotypic and genotypic heterogeneity in Gaucher disease type 1: a comparison between Brazil and the rest of the world. Mol Genet Metab 2007; 90:81-6. [PMID: 16996765 DOI: 10.1016/j.ymgme.2006.08.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2006] [Accepted: 08/01/2006] [Indexed: 11/17/2022]
Abstract
Type 1 Gaucher disease, the most common lysosomal storage disorder, results from deficiency of glucocerebrosidase causing pathologic accumulation of glucocerebroside. The disease is characterized by marked variation in age of onset and degree of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. Most published data on Gaucher disease come from populations with large proportions of Ashkenazi-Jewish patients, who tend to have less severe disease. We compared selected demographic, clinical, and genetic parameters for Brazilian (N = 221) and rest-of-world (N = 1477) type 1 Gaucher disease patients entered into the ICGG Gaucher Registry since 1991. We also compared Brazilian patients to non-Ashkenazi rest-of-world patients (N = 692) to determine if differences were the result of fewer Brazilian Ashkenazi-Jewish patients (0.5% vs 45.0%). The Brazilian cohort differed significantly (p < 0.05) from the rest-of-world and rest-of-world non-Ashkenazi cohort, respectively, in the following measures: higher proportion of females (59.7% vs 50.4% and 49.7%), lower mean age at diagnosis (17.1 vs 24.1 and 18.8), and higher proportions of patients with anemia (55.5% vs 29.9% and 35.7%), bone pain (57.7% vs 33.7% and 35%), bone crises (16.1% vs 6.5% and 7.4%), and lytic lesions (17.0% vs 7.6% and 7.4%). The most common genotype in Brazil was N370S/L444P (c1448T-->C/c1226A-->C) (46.8% versus 16.3% and 25.7%). These data highlight the genetic and phenotypic heterogeneity among geographic populations of type 1 Gaucher patients and suggest that as a group, Brazilian patients may have a more aggressive form of the disease than rest-of-world patients. The findings also emphasize the need for caution in making generalizations about Gaucher disease across demographic groups.
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Weinreb NJ, Barranger JA, Charrow J, Grabowski GA, Mankin HJ, Mistry P. Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol 2005; 80:223-9. [PMID: 16247743 DOI: 10.1002/ajh.20504] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat.
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Affiliation(s)
- Neal J Weinreb
- University Research Foundation for Lysosomal Storage Diseases and Northwest Oncology Hematology Associates PA, Coral Springs, Florida.
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Beutler E, Gelbart T, Scott CR. Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 2005; 35:355-64. [PMID: 16185900 DOI: 10.1016/j.bcmd.2005.07.005] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2005] [Accepted: 07/12/2005] [Indexed: 11/22/2022]
Affiliation(s)
- Ernest Beutler
- The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Roversi FM, Galdieri LC, Grego BHC, Souza FG, Micheletti C, Martins AM, D'Almeida V. Blood oxidative stress markers in Gaucher disease patients. Clin Chim Acta 2005; 364:316-20. [PMID: 16125160 DOI: 10.1016/j.cca.2005.07.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2005] [Revised: 07/26/2005] [Accepted: 07/28/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND Gaucher disease (GD) is the most common glycosphingolipidosis resulting in accumulation of glucoceramide. The most effective treatment for this disease is enzyme replacement therapy (ERT) which involves recombinant enzyme infusion. Enzymatic deficiency in GD patients may induce a cascade of events culminating in secondary effects such as the production of reactive oxygen species (ROS). We investigated the relationship between ROS and GD by analyzing blood oxidative stress markers in GD patients submitted to ERT at different stages during the treatment. METHODS Blood were collected before and just after enzyme infusion. Red blood cell catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and total glutathione (tGSH), and plasma thiobarbituric acid reactive substances (TBARS) were assayed by spectrophotometry. Homocysteine concentrations and related polymorphisms were also studied. Control individuals matched for sex and age were also analyzed. RESULTS Concentrations of homocysteine and TBARS, and GPx enzyme activity were not different in ERT-treated GD patients. CAT activity was higher while SOD was lower in patients compared to controls. No variations in any of these parameters were found before and just after ERT. Regarding tGSH, a significant increase was observed in GD patients after infusion. Genotypic frequencies studied did not differ from controls or other Brazilian samples. CONCLUSION ERT-treated GD patients show an improvement in antioxidant capacity, which is further increased just after recombinant enzyme infusion.
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Affiliation(s)
- Fernanda M Roversi
- Department of Pediatrics, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), Rua Napoleão de Barros, 925, 3rd floor, ZIP: 04024-002, São Paulo, SP, Brazil
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Ron I, Horowitz M. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum Mol Genet 2005; 14:2387-98. [PMID: 16000318 DOI: 10.1093/hmg/ddi240] [Citation(s) in RCA: 246] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid beta-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.
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Affiliation(s)
- Idit Ron
- Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel
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Roth P, Sklower Brooks S, Potaznik D, Cooma R, Sahdev S. Neonatal Gaucher disease presenting as persistent thrombocytopenia. J Perinatol 2005; 25:356-8. [PMID: 15861202 DOI: 10.1038/sj.jp.7211262] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Mutations in the beta-glucocerebrosidase gene cause Gaucher disease with the type 1 variant generally presenting later in life with mild disease and type 2 in infancy with severe neuronopathic symptoms. We describe a neonate homozygous for the D409 H mutation with thrombocytopenia, splenomegaly and cholestasis at birth as the major features.
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Affiliation(s)
- Philip Roth
- Division of Neonatology, Department of Pediatrics, Staten Island University Hospital, SUNY - Downstate Medical Center, Staten Island, NY 10305, USA
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