{"title":"8 Enzyme replacement therapy for Gaucher's disease","authors":"MD Ernest Beutler (Professor and Chairman)","doi":"10.1016/S0950-3536(97)80038-8","DOIUrl":"10.1016/S0950-3536(97)80038-8","url":null,"abstract":"<div><p>Modified placental human glucocerebrosidase (alglucerase) and recombinant glucocerebrosidase (imiglucerase) are effective means of treating Type 1 Gaucher's disease. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within 6 months. Bone disease responds more slowly but within several years improvement is evident in most patients. Analysis of a large body of data demonstrates that the rate of response of all manifestations of Gaucher's disease is independent of dose over the range of 30 to 260 U/kg body weight per month. Even the response to 15 U/kg per month appears to be equivalent under most circumstances; treatment failures are the same in patients treated with 15, 30 and 130 U/kg per month. Patients with severe manifestations respond more rapidly than those with mild disease, and this, too, is true at all but the 15 U/kg per month dosage level. All avaiable data thus support the administration of no more than 15 to 30 U of alglucerase or imiglucerase per kg/month. Frequent dosing, i.e. three times weekly, appears to be the most effective means of administration.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 751-763"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80038-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhD Deborah Elstein (Research Coordinator) , MD Menachem Itzchaki (Chairman) , MD Henry J. Mankin (Visiting Orthopaedic Surgeon, Director, Edith M. Ashley Professor of Orthopaedics)
{"title":"11 Skeletal involvement in Gaucher's disease","authors":"PhD Deborah Elstein (Research Coordinator) , MD Menachem Itzchaki (Chairman) , MD Henry J. Mankin (Visiting Orthopaedic Surgeon, Director, Edith M. Ashley Professor of Orthopaedics)","doi":"10.1016/S0950-3536(97)80041-8","DOIUrl":"10.1016/S0950-3536(97)80041-8","url":null,"abstract":"<div><p>Perhaps the most variable of all the symptoms attributed to Gaucher's disease is that of bone involvement, both in the Type 1 and Type 3 forms of the disease. Expression of skeletal involvement in Gaucher patients ranges from asymptomatic disease, with or without radiological signs, to symptomatic disease, which can be severe and engender considerable pain and disability. Herein we discuss the imaging techniques currently available to document the presence and progression of bone involvement as well as the various forms of medical and surgical management that are employed to help the Gaucher patient cope with skeletal disease.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 793-816"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80041-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20422310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD, PhD Anders Erikson (Associate Professor) , MD Bruno Bembi (Director) , MD Raphael Schiffmann (Chief)
{"title":"5 Neuronopathic forms of Gaucher's disease","authors":"MD, PhD Anders Erikson (Associate Professor) , MD Bruno Bembi (Director) , MD Raphael Schiffmann (Chief)","doi":"10.1016/S0950-3536(97)80035-2","DOIUrl":"10.1016/S0950-3536(97)80035-2","url":null,"abstract":"<div><p>Neuronopathic Gaucher patients may have a wide variety of clinical manifestations and natural history, and can present with a range of degrees of severity of systemic disease and neurological deficit. The brain pathology of these patients has been well described, but the mechanism by which glucocerebrosidase deficiency leads to neuronal dysfunction is not yet understood. The almost 20 different mutations of the glucocerebrosidase gene that have been described in Type 2 and 3 Gaucher patients poorly predict the phenotype of individual patients. Enzyme replacement therapy (ERT), often at high doses, has been shown to reverse most of the systemic manifestations of this disease, but can rarely reverse the neurological deficits. Therefore, other forms of treatment, such as gene therapy or a more efficient and direct enzyme delivery to neurons, are being devised.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 711-723"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80035-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MA, MSc, MD, FRCP Timothy M. Cox (Professor of Medicine, Honorary Consultant Physician), BSc, MB, PhD, MRCP J. Paul Schofield (Lister Research Fellow, Honorary Consultant Physician)
{"title":"3 Gaucher's disease: clinical features and natural history","authors":"MA, MSc, MD, FRCP Timothy M. Cox (Professor of Medicine, Honorary Consultant Physician), BSc, MB, PhD, MRCP J. Paul Schofield (Lister Research Fellow, Honorary Consultant Physician)","doi":"10.1016/S0950-3536(97)80033-9","DOIUrl":"10.1016/S0950-3536(97)80033-9","url":null,"abstract":"<div><p>Gaucher's disease is an inherited disorder characterized by pathological storage of glycolipid in mononuclear phagocytes: it is a multi-system disease associated with striking variation in its clinical manifestations, severity and course. Although molecular analysis of the glucocerbrosidase gene in patients with Gaucher's disease has permitted broad correlations between genotype and phenotype to be made, with few exceptions genetic variation at this locus does not allow confident prediction of clinical phenotype or prognosis. Partial deficiency of glucocerebrosidase is associated principally with parenchymal disease of the liver, spleen, bone marrow and, in severe cases, the lung, in non-neuronopathic, Type 1, Gaucher's disease: here storage material in macrophages originates from turnover of <em>exogenous</em> glycolipids. Severe deficiency of glucocerebrosidase caused by disabling mutations is additionally associated with neurological manifestations that in part reflect a failure to degrade <em>endogenous</em> neuronal glycosphingolipids, the so-called neuronopathic, Type 2 and Type 3 disease categories. Here we describe the clinical features, complications and natural history principally of Type 1 Gaucher's disease: emphasis is placed on emerging pulmonary, osseous and other manifestations of obscure pathogenesis that respond poorly to enzyme-replacement therapy.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 657-689"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80033-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"4 Plasma and metabolic abnormalities in Gaucher's disease","authors":"PhD Johannes M.F.G. Aerts (Associate Professor) , MD, PhD Carla E.M. Hollak (Internist, Coordinator)","doi":"10.1016/S0950-3536(97)80034-0","DOIUrl":"10.1016/S0950-3536(97)80034-0","url":null,"abstract":"<div><p>An overview of the most important plasma abnormalities that can be found in Gaucher's disease is presented in this chapter. Attention is focussed on their practical applications and possible clinical relevance. In addition, the result of studies on metabolic alterations in Gaucher's disease are reviewed.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 691-709"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80034-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD, PhD J.A. Barranger, MS, CGC E.O. Rice, BS J. Dunigan, BS C. Sansieri, MD N. Takiyama, BS M. Beeler, BS J. Lancia, BS S. Lucot, BS S. Scheirer-Fochler, BS T. Mohney, BS W. Swaney, PhD A. Bahnson, MD E. Ball
{"title":"9 Gaucher's disease: studies of gene transfer to haematopoietic cells","authors":"MD, PhD J.A. Barranger, MS, CGC E.O. Rice, BS J. Dunigan, BS C. Sansieri, MD N. Takiyama, BS M. Beeler, BS J. Lancia, BS S. Lucot, BS S. Scheirer-Fochler, BS T. Mohney, BS W. Swaney, PhD A. Bahnson, MD E. Ball","doi":"10.1016/S0950-3536(97)80039-X","DOIUrl":"10.1016/S0950-3536(97)80039-X","url":null,"abstract":"<div><p>Transfer of the gene coding for glucocerebrosidase (GC) via a retroviral vector (MFG-GC) to haematopoietic progenitors results in engraftment and life-long expression of the human protein at high levels in transplanted mice. Studies of human CD34 cells were carried out to evaluate their potential use in a gene therapy approach to Gaucher's disease. High transduction efficiency and correction of the enzyme deficiency was possible in CD34 cells obtained from patients with Gaucher's disease. Based on these results, a clinical trial of gene therapy was designed and initiated. Preliminary results of this study indicate the persistence or engraftment of genetically corrected cells in the transplanted patients.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 765-778"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80039-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BSc, PhD, MBBS, MRCP Pramod K. Mistry (Senior Lecturer and Honorary Consultant Physician) , MD Ayala Abrahamov (Senior Lecturer in Paediatrics)
{"title":"12 A practical approach to diagnosis and management of Gaucher's disease","authors":"BSc, PhD, MBBS, MRCP Pramod K. Mistry (Senior Lecturer and Honorary Consultant Physician) , MD Ayala Abrahamov (Senior Lecturer in Paediatrics)","doi":"10.1016/S0950-3536(97)80042-X","DOIUrl":"10.1016/S0950-3536(97)80042-X","url":null,"abstract":"<div><p>The diagnosis of Gaucher's disease is established by demonstration of reduced acid β-glucosidase activity in peripheral blood leukocytes. Genotyping at the glucocerebrosidase gene locus can give additional prognostic information and facilitate carrier detection. However, extreme phenotypic diversity precludes reliable prediction of prognosis in individual patients. Histological diagnosis of Gaucher's disease is unnecessary and can be misleading. A range of clinical, radiological and laboratory parameters are useful for staging disease activity which is central to achieving optimal timing to initiate enzyme therapy. Treatment should be individualized to obtain maximum therapeutic response. The recent introduction of chitotriosidase measurements has provided a valuable indicator of total cellular burden of storage cells. Serial measurements of chitotriosidase activity are useful for monitoring disease progression as well as response to therapy. A number of adjuvant therapies are available for use in conjunction with enzyme treatment. Special considerations apply to management of affected children.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 817-838"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80042-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20422311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Gregory M. Pastores (Assistant Professor of Neurology and Paediatrics)
{"title":"7 Pathological features","authors":"MD Gregory M. Pastores (Assistant Professor of Neurology and Paediatrics)","doi":"10.1016/S0950-3536(97)80037-6","DOIUrl":"10.1016/S0950-3536(97)80037-6","url":null,"abstract":"<div><p>Gaucher's disease is the most common lysosomal storage disease. The pathological features are a consequence of the progressive accumulation of glucosylceramide within mononuclear phagocytes. A wide variety of gross and microscopic anatomical changes are seen, primarily in the bone marrow, liver, spleen and bones. It is probable that cellular reactions to the presence of Gaucher cells (‘lipid-engorged’ macrophages) contribute to the tissue damage observed in this disease, although only a few investigations have been undertaken to elucidate what, if any, other mechanisms may play a contributory role in defining individual disease outcome. The general clinico-pathological features of Gaucher's disease are reviewed herein, with exclusion of the central nervous system and skin involvement, which are covered elsewhere.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 739-749"},"PeriodicalIF":0.0,"publicationDate":"1997-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80037-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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