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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The search for, and discovery of, a physiologic model in which the developmentally regulated switch from fetal to adult globin gene expression could be prevented has resulted in the development of a new class of therapeutic agents, consisting of simple fatty acids, such as butyric acid, for the treatment of the beta-hemoglobinopathies. Butyrate and related drugs stimulate fetal (gamma-) globin gene expression in erythroid cells cultured from patients, and in chicken, ovine, and primate animal models. The butyrates are perhaps the first class of drugs designed to transcriptionally activate specific genes--in this particular case, to reactivate the developmentally silenced fetal globin genes. Phase I-II clinical trials resulting from this basic research have been initiated on a small scale during the past 3 years. Analysis of two butyrate-derived therapeutic agents, one delivered intravenously and one orally, has shown initial efficacy in stimulating fetal hemoglobin expression in 50% to 85% of patients. Correction of the anemia from the beta-hemoglobinopathy has followed induction of fetal globin, and has been adequate to eliminate the need for erythrocyte transfusions in some patients with beta-thalassemia. These compounds have been relatively safe and without generalized cytotoxicity in patients, but drug tolerance develops in some patients after prolonged therapy. Third-generation, small two- to five-carbon butyrate derivatives are in development. The molecular basis for butyrate action is being defined. Binding of putative regulatory proteins to a specific region of the gamma-globin promoter is altered in vivo in patients receiving butyrate therapy. Further analysis of the mode of action may contribute to development of other therapeutic agents designed to regulate gene transcription.
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PMID:Butyrate in the treatment of sickle cell disease and beta-thalassemia. 937 80

Electron microscope immunocytochemical studies were performed on the bone marrow from 2 patients each with beta-thalassaemia major and beta-thalassaemia intermedia and 4 patients with HbE/beta-thalassaemia, using the immunogold technique. Studies of sections that were reacted with mouse monoclonal antibodies against human gamma-globin chains showed the presence of large quantities of gamma-chains in several erythroblasts and marrow reticulocytes containing large amounts of precipitated globin chains. At least in these cells, substantial gamma-chains synthesis did not protect against the formation of erythroblastic inclusions, indicating that factors other than the rate of gamma-chain synthesis influence the extent of globin-chain precipitation. Studies of sections of marrow that were reacted with a rabbit polyclonal antibody against human alpha-globin chains and a mouse monoclonal antibody against human beta-globin chains showed that the erythroblastic inclusions in HbE/beta-thalassaemia did not contain detectable quantities of HbE and consisted only of precipitated alpha-globin chains. Thus, the generally milder phenotype of HbE/beta-thalassaemia cannot be attributed to co-precipitation of HbE and excess free alpha-globin chains.
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PMID:Observations on the relationship between gamma-globin chain content and globin chain precipitation in thalassaemic erythroblasts and on the composition of erythroblastic inclusions in HbE/beta-thalassaemia. 941 42

We have identified the beta s-globin gene haplotypes of 85 patients with sickle cell disease attending the Dubai Thalassemia Center and assessed the influence of haplotype, alpha-thalassemia, and fetal hemoglobin on the clinical presentation. Identification of the beta s haplotypes was based on mutation analyses in the promoter sequences of the G gamma- and A gamma-globin genes. The Arabian-Indian haplotype was found in 52% of the beta s chromosomes, whereas the remaining were the Bantu and Benin haplotypes. Those with the Arabian-Indian haplotype in this group had a significantly higher fetal hemoglobin (Hb F) level (mean 27%) and a milder clinical course. In contrast, those with the African haplotypes, Bantu and Benin, expressed relatively lower Hb F levels (mean 11.3%), with a severe clinical presentation. Coinheritance of alpha-thalassemia trait in the African haplotypes had an ameliorating effect on hemolytic episodes, but vaso-occlusive crises were more frequent.
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PMID:Genotype-phenotype correlation of sickle cell disease in the United Arab Emirates. 961 21

Homozygous beta thalassemia affects thousands of people around the world. Current management of this condition includes regular transfusion of red cells, which leads to transfusional iron overload requiring chelation therapy: increasing hemoglobin levels while decreasing or eliminating iron overload is therefore a major therapeutic goal in the treatment of thalassemia. Bone marrow transplantation may achieve this goal, but it is not an option for most patients. This study reports on efforts to increase gamma-globin transcription and HbF production using sodium phenylbutyrate (SPB) and hydroxyurea (HU). It was found that 36% (4/11) of all patients or 50% (4/8) of non-transfused patients responded to SPB (increase in Hb levels of 1 g/dL). A positive correlation between baseline serum erythropoietin level and likelihood of response to SPB was observed. Since HU may also increase HbF production, evaluation of combination therapy with these drugs is underway and preliminary results are reported.
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PMID:Hemoglobin switching protocols in thalassemia. Experience with sodium phenylbutyrate and hydroxyurea. 966 30

Cooley's anemia is characterized by a deficiency of beta-globin chains, a relative excess of alpha-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the gamma-globin genes to adequately balance excess alpha-globin chains can ameliorate this disorder. Butyrates induce gamma-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent "pulsed" regimen of butyrate was evaluated. Following induction of gamma-globin mRNA and protein synthesis, total hemoglobin increased in beta-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the gamma- and beta-globin gene promoters to which new binding of transcription factors, including alpha CP2 (an activator of gamma globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce gamma globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer gamma-globin inducers (designed hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous gamma-globin genes is a realistic approach to therapy of the beta-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.
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PMID:Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis. 966 31

Beta-thalassemia and sickle cell disease (SCD) are common disorders in Turkey. Compound heterozygosity for these two disorders (betaS/beta-thalassemia) is encountered frequently. In this report we present hematological and molecular data of two Turkish siblings with betaS/beta(del)-thalassemia caused by a 290 base pair (bp) deletion and associated with increased levels of hemoglobin A2 (HbA2) and hemoglobin F (HbF). Clinical analysis of the two patients showed a mild course of the disease. Haplotypic factors involved in increasing the levels of HbF were analyzed. The two patients showed no changes from the normal sequences at the XmnI site of Ggamma-globin promoter and the (AT)xTy microsatellite 5' to the beta-globin mRNA cap site. The removal of the region between positions -125 to +78 relative to the beta-globin gene mRNA cap site by the 290 bp deletion is thought to allow the beta-locus control region to interact with the promoters of the delta- and gamma-globin genes, leading to increased HbA2 and HbF levels.
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PMID:HbS/beta(del)-thalassemia associated with high levels of hemoglobins A2 and F in a Turkish family. 972 83

We have developed a method for the separation and quantitation of human alpha-, beta-, and gamma-globins utilizing cellulose acetate electrophoresis. The relative rates of synthesis of globin chains in reticulocytes in peripheral blood is determined by: (i) incubating intact cells with [35S]methionine; (ii) preparing globin from the hemolysates; (iii) performing electrophoresis of the globin on cellulose acetate strips; and (iv) autoradiography or direct determination of the radioactivity incorporated into each globin chain. The method is simple and rapid, requires only small amounts of hemolysate (30 micrograms of globin), and provides excellent resolution and reproducible quantitation of alpha-, beta A-, beta S-, and gamma-globin chains for up to 24 peripheral blood samples at one time. Measurements by this method in patients with thalassemia variants and sickle-cell disorders correlate well with analysis of the same samples by carboxymethyl cellulose chromatography. This methodology may permit more widespread analysis of globin synthesis in the thalassemia syndromes and may also be useful in the analysis of globins synthesized from human globin mRNA in cell-free systems.
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PMID:Quantitation of human globin chain synthesis by cellulose acetate electrophoresis. 976 93

The analysis of a number of cases of beta-globin thalassemia and hereditary persistence of fetal hemoglobin (HPFH) due to large deletions in the beta-globin locus has led to the identification of several DNA elements that have been implicated in the switch from human fetal gamma- to adult beta-globin gene expression. We have tested this hypothesis for an element that covers the minimal distance between the thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-thalassemia, located 5' of the delta-globin gene. This element has been deleted from a yeast artificial chromosome (YAC) containing the complete human beta-globin locus. Analysis of this modified YAC in transgenic mice shows that early embryonic expression is unaffected, but in the fetal liver it is subject to position effects. In addition, the efficiency of transcription of the beta-globin gene is decreased, but the developmental silencing of the gamma-globin genes is unaffected by the deletion. These results show that the deleted element is involved in the activation of the beta-globin gene perhaps through the loss of a structural function required for gene activation by long-range interactions.
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PMID:Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and deltabeta-thalassemia affects beta- but not gamma-globin gene expression. 1002 37

Gene conversion is referred to as one of two types of mechanisms known to act on gene families, mainly to maintain their sequence homogeneity or, in certain cases, to produce sequence diversity. The concept of gene conversion was established 20 years ago by researchers working with fungi. A few years later, gene conversion was also observed in the human genome, i.e. the gamma-globin locus. The aim of this article is to emphasize the role of genetic recombination, particularly of gene conversion, in the evolution of the human beta-like globin genes and further to summarize its contribution to the convergent evolution of the fetal globin genes. Finally, this article attempts to re-examine the origin and spread of specific mutations of the beta-globin cluster, such as the sickle cell or beta-thalassemia mutations, on the basis of repeated gene conversion events.
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PMID:Contribution of gene conversion in the evolution of the human beta-like globin gene family. 1019 Mar 21

Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically heterogeneous conditions characterized by the continued expression of fetal hemoglobin in adulthood. These constitute natural models for understanding the mechanism(s) of the hemoglobin switch. Many large deletions in the beta-globin gene cluster and point mutations in one of the fetal globin gene promoters have been described before. In this study we describe a novel C-->A transversion (-114) in the distal CCAAT box of the Ggamma-globin gene promoter associated with the Ggammabeta+-HPFH phenotype in an Algerian family. Individuals heterozygous for this mutation exhibit moderate raise in Hb F levels (0.6-3.5%). Much higher Hb F levels (3.8-11.2%) are observed when a beta(o)-thalassemia allele is present in trans to the hereditary persistence of fetal hemoglobin allele. This novel Algerian HPFH mutation further stresses the importance of the distal CCAAT box in the postnatal regulation of gamma-globin gene expression.
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PMID:A novel C-->A transversion within the distal CCAAT motif of the Ggamma-globin gene in the Algerian Ggammabeta+-hereditary persistence of fetal hemoglobin. 1033 83


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