{"title":"1 Gaucher's disease: past, present and future","authors":"MD Roscoe O. Brady (Chief)","doi":"10.1016/S0950-3536(97)80031-5","DOIUrl":"10.1016/S0950-3536(97)80031-5","url":null,"abstract":"<div><p>A patient with what is now known as Gaucher's disease was first described by P. C. E. Gaucher in 1882. Fifty years later, Aghion reported that patients with this condition accumulated a sphingoglycolipid called glucocerebroside. Considerably more time was required for the demonstration by Brady and co-workers in 1964 that Gaucher's disease was due to reduced activity of a β-glucosidase called glucocerebrosidase. This information provided the basis for the development of reliable diagnostic tests, detection of most of the carriers of this disorder and the prenatal diagnosis of this condition. Evidence was presented in 1990 and 1991 indicating the highly beneficial effects of enzyme replacement therapy in patients with Gaucher's disease. Gene therapy for Gaucher's disease was initiated in 1995. While little indication of success was obtained in this inaugural attempt, it is expected that improvements in this technology will provide a permanent cure for patients with this disorder.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 621-634"},"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)80031-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421084","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 Diplomate ABMG Ephrat Levy-Lahad (Director, Medical Genetic Services), MD Ari Zimran (Associate Professor of Medicine, Director Gaucher Clinic)
{"title":"10 Gaucher's disease: genetic counselling and population screening","authors":"MD Diplomate ABMG Ephrat Levy-Lahad (Director, Medical Genetic Services), MD Ari Zimran (Associate Professor of Medicine, Director Gaucher Clinic)","doi":"10.1016/S0950-3536(97)80040-6","DOIUrl":"10.1016/S0950-3536(97)80040-6","url":null,"abstract":"<div><p>Genetic counselling for Gaucher's disease requires a comprehensive approach, including accurate diagnosis at both the enzymatic and molecular levels, and assessment of disease severity. These goals are particularly challenging given the great allelic and phenotypic heterogeneity encountered in this disorder. Counselling should address the specific concerns of the counsellee, which may be related to evaluation of an affected person, or to reproductive options in couples at risk. Advances in both diagnosis and treatment have led to increased ascertainment of cases and carriers through population based screening, rather than through affected probands, raising new ethical and medical dilemmas. This chapter outlines practical issues in counselling for the various forms of Gaucher's disease, based on current data and experience.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 779-792"},"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)80040-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20422309","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 A. Grabowski (Director, Professor of Paediatrics) , PhD Mia Horowitz
{"title":"2 Gaucher's disease: molecular, genetic and enzymological aspects","authors":"MD Gregory A. Grabowski (Director, Professor of Paediatrics) , PhD Mia Horowitz","doi":"10.1016/S0950-3536(97)80032-7","DOIUrl":"10.1016/S0950-3536(97)80032-7","url":null,"abstract":"<div><p>The molecular, genetic and enzymological abnormalities in Gaucher's disease have been delineated during the past decade. Although our understanding of the primary predisposition to the Gaucher's disease phenotypes has improved, the relationships remain poorly understood between the mutant alleles, the resultant enzyme variants, the saposin C (activator protein) locus and phenotypes. Of the more than 100-disease associated alleles, about 8 to 10 have significant frequencies in various ethnic and demographic groups. The N370S(1226G) allele is very frequent in Caucasian populations, but absent in Asian groups. In the Ashkenazi Jewish population, the N370S homozygosity predisposes to Gaucher's disease, but over 50% of such patients escape medical detection because of their mild to absent involvement, i.e. N370S may be a prediposing polymorphic variant. Clarification of genotype/phenotype relationships and the identification of modifier loci that impact on Gaucher's disease phenotypes remain a critical area for research. Greater understanding of these issues will facilitate genetic counselling and appropriate interventive therapy to prevent the morbid long-term manifestations of Gaucher's disease.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 635-656"},"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)80032-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421085","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 Ellen Sidransky (Chief, Unit of Clinical Genetics), MD, PhD Edward I. Ginns (Chief, Clinical Neuroscience Branch)
{"title":"6 Gaucher's disease: the best laid schemes of mice and men","authors":"MD Ellen Sidransky (Chief, Unit of Clinical Genetics), MD, PhD Edward I. Ginns (Chief, Clinical Neuroscience Branch)","doi":"10.1016/S0950-3536(97)80036-4","DOIUrl":"10.1016/S0950-3536(97)80036-4","url":null,"abstract":"<div><p>The creation of animal models of Gaucher's disease, the inherited deficiency of the enzyme glucocerebrosidase, has led to new clinical insights and to a new appreciation of the complexity of the glucocerebrosidase gene locus. Murine embryonic stem cells with targeted modifications in the glucocerebrosidase gene were used to generate mouse models of Gaucher's disease, the first having a null glucocerebrosidase allele. The resulting knockout mice have no glucocerebrosidase activity and die within 12 hours of birth. Ultrastructural studies of liver, spleen, brain and bone marrow demonstrate the characteristic storage material seen in Gaucher patients. In the nervous system, storage of lipid increased in a rostral-caudal distribution. Analysis of skin from the knockout mice revealed histological, ultrastructural and biochemical abnormalities. The null allele Gaucher mice are analogous to neonates with Type 2 Gaucher's disease who present with hydrops foetalis and/or congenital ichthyosis. Moreover, the epidermal changes seen in Type 2 mice are also found in Type 2 patients and may provide a means to presymptomatically discriminate Type 2 from Type 1 and 3 Gaucher's disease. Another targeted modification in the murine glucocerebrosidase gene locus led to the discovery of a contiguous gene, metaxin. Closer analysis of the glucocerebrosidase gene locus, including sequencing of 75 kb of genomic DNA, reveals that this is a gene-rich region coding for seven genes and two pseudogenes. Further study of these closely arrayed genes may contribute to our understanding of the clinical variation encountered among patients with Gaucher's disease.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 4","pages":"Pages 725-737"},"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)80036-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20421089","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 Joanna M. Woodcock (Senior Post-doctoral Researcher), PhD Christopher J. Bagley (Senior Post-doctoral Research Fellow, Rotary Peter Nelson Leukaemia Research Fellow), MD, PhD Angel F. Lopez (Head of Cytokine Receptor Laboratory)
{"title":"5 Receptors of the cytokine superfamily: mechanisms of activation and involvement in disease","authors":"PhD Joanna M. Woodcock (Senior Post-doctoral Researcher), PhD Christopher J. Bagley (Senior Post-doctoral Research Fellow, Rotary Peter Nelson Leukaemia Research Fellow), MD, PhD Angel F. Lopez (Head of Cytokine Receptor Laboratory)","doi":"10.1016/S0950-3536(97)80023-6","DOIUrl":"10.1016/S0950-3536(97)80023-6","url":null,"abstract":"<div><p>Cytokine receptors are members of a diverse family of proteins that serve the dual function of recognizing their cognate ligands among a plethora of other factors and of initiating a series of cellular signals that ultimately lead to multiple cellular functions. Although cytokine receptors are only activated by their specific cytokines, some functional overlap occurs as a result of receptor subunit promiscuity, kinase recruitment and the activation of coincident signalling pathways. Knock-out experiments are extremely useful in helping to elucidate functionally relevant interactions between cytokine receptor activation, signalling molecules and cellular function. Defects in cytokine receptors or associated signalling molecules continue to be identified as the underlying cause of clinical conditions. We discuss newly recognized clinical syndromes and recent research into the molecular basis of cytokine receptor activation that provides new insights into the role of cytokine receptors in normal physiology and disease.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 507-524"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80023-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349219","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 Virginia Pascula (Assistant Professor), PhD Yong-Jun Liu (Scientist), PhD Jacques Banchereau (Director)
{"title":"6 Normal human B cell sub-populations and their malignant counterparts","authors":"MD Virginia Pascula (Assistant Professor), PhD Yong-Jun Liu (Scientist), PhD Jacques Banchereau (Director)","doi":"10.1016/S0950-3536(97)80024-8","DOIUrl":"10.1016/S0950-3536(97)80024-8","url":null,"abstract":"<div><p>Seven tonsillar B cell sub-sets have been isolated according to cell surface molecular markers. The molecular characteristics of their phenotype, cell cycle, survival, somatic mutations and isotype switch status permit their inter-relationships to be followed up until the plasma cell stage. Different lymphoma types correlate with all except one of the stages and only two out of nine non-Hodgkin's B cell lymphomas cannot be presently associated to a normal peripheral B cell sub-set. The assignment of lymphomas to their normal human B cell counterparts will facilitate the identification of the causative event(s) responsible for the malignant transformation.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 525-538"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80024-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349220","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 Carol Stocking (Staff Scientist), MD Christopher Baum (Staff Scientist)
{"title":"2 Gene transfer into haemopoietic cells","authors":"PhD Carol Stocking (Staff Scientist), MD Christopher Baum (Staff Scientist)","doi":"10.1016/S0950-3536(97)80020-0","DOIUrl":"10.1016/S0950-3536(97)80020-0","url":null,"abstract":"<div><p>The therapeutic potential achievable by efficient transfer and expression of genes into haemopoietic stem cells (HSC) is enormous. In addition to inherited disorders such as haemoglobinopathies and lysosomal storage disorders, this technology can be applied to acquired disorders such as myelosuppression induced by anticancer chemotherapy or infection with human immunodeficiency virus (HIV). To date retroviral vectors are the most attractive modality for gene transfer into HSC. Unfortunately, the expectations of gene therapy are more advanced than the methodology needed to fulfil the goals. In this chapter, the current concepts and limitations in the genetic manipulation of haemopoietic cells are presented. Overcoming these limitations requires not only improvement in isolation and expansion of HSC that contribute to long-term repopulation, but also development of better retroviral transfer systems. Current restrictions occur at various levels in the viral transfer process, including efficient cell entry, regulated expression levels, and sustained expression. The analysis of retroviral mutants has proven to be a successful approach to developing effective retroviral vectors for HSC gene therapy.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 445-465"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80020-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20350591","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}
MBBS, PhD, FRACP Andrew G. Elefanty (Research Scientist), BSc, MBBS, PhD, FRACP, FRCPA Lorraine Robb (Research Scientist), MBBS, PhD, FRACP, FRCPath C. Glenn Begley (Principal Research Fellow)
{"title":"10 Factors involved in leukaemogenesis and haemopoiesis","authors":"MBBS, PhD, FRACP Andrew G. Elefanty (Research Scientist), BSc, MBBS, PhD, FRACP, FRCPA Lorraine Robb (Research Scientist), MBBS, PhD, FRACP, FRCPath C. Glenn Begley (Principal Research Fellow)","doi":"10.1016/S0950-3536(97)80028-5","DOIUrl":"10.1016/S0950-3536(97)80028-5","url":null,"abstract":"<div><p>This review describes the chromosomal abnormalities in T-cell acute lymphoblastic leukaemia (ALL) which result in the over-expression of the gene <em>SCL</em>, which encodes a helix-loop-helix transcription factor. Also described are how gene targeting studies have revealed a key role for <em>SCL</em> in normal haemopoiesis. Next, the BCR-ABL fusion protein, seen in chronic myeloid leukaemia (CML) and in some patients with ALL, is discussed. Finally, the involvement of members of the core-binding factor (CBF) gene family in leukaemogenesis are described. Members of this gene family are involved in the generation of fusion proteins as a result of t(8;21) and inv(16), the most common translocations associated with acute myeloid leukaemia (AML). They provide a useful model of the way in which aberrant transcriptional function, brought about through genetic alterations, can modify haemopoietic development.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 589-614"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80028-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349224","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 Nicholas Hole (Lecturer), BSc, PhD Gerard J. Graham (Staff Scientist and Group Head)
{"title":"3 Use of embryonal stem cells in studies of molecular haemopoiesis","authors":"PhD Nicholas Hole (Lecturer), BSc, PhD Gerard J. Graham (Staff Scientist and Group Head)","doi":"10.1016/S0950-3536(97)80021-2","DOIUrl":"10.1016/S0950-3536(97)80021-2","url":null,"abstract":"<div><p>Although the cell biology of haemopoietic stem cells (HSC) is relatively well understood, their molecular control is less well defined. Due to the rarity of this cell type, their incompletely defined phenotype and difficulty in generating null alleles by somatic transgenesis of HSC, alternative approaches to their study have been sought. Embryonal stem (ES) cells are toti-potential, can transmit transgenes through the germ line and have recently been shown to produce HSC in vitro. This chapter reviews the utility of gene knock-outs in ES cells in the study of molecular haemopoiesis, indicates how ES cells can be used in vitro as a strategy both for the identification of genes controlling early haemopoietic events and the analysis of their function, and outlines how emerging techniques that exploit the biology of ES cells might prove to be powerful tools in the genetic dissection of the mechanisms controlling haemopoiesis.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 467-483"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80021-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20350592","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}
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