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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thalassemia syndromes were the first of human diseases to become thoroughly examined for the underlying molecular lesions by the application of molecular genetic strategies and recombinant DNA methods. Students of thalassemia have now enjoyed over two decades of experience with this research paradigm. These experiences reveal both the awesome power and the limitations of the "reductionist, deterministic" approach of gene cloning and analysis. Incredibly precise and abundant information about the exact molecular lesions responsible for various forms of thalassemia were rapidly obtained by the use of molecular genetic approaches. The mechanisms by which these mutations deranged globin gene expression could be documented with extraordinary precision and efficiency. Precise, powerful methods for detecting disease early in fetal life were rapidly developed, made practical for field use, and disseminated widely. This resulted in a dramatic reduction in the incidence of new births of patients with homozygous beta thalassemia. These experiences demonstrate the extraordinary impact that recombinant DNA technology has upon our ability to understand disease processes, to detect disease long before its phenotypic expression is apparent, and to influence the prevalence of the abnormal alleles in the population. Experience with the antenatal diagnosis of the thalassemias also demonstrates, and should alert us to, the relative ease with which genetic information can be applied to societal and governmental initiatives to alter the reproductive behavior of individuals. While the benefits of reducing the incidence of beta thalassemia are clearcut, application of the strategies that were applied in this narrow situation to broader aspects of disease or genetic manipulation does raise concerns. The thalassemia syndromes demonstrate that genetic information does have more than a theoretical potential to have a major impact upon society. The struggles of many investigators to develop effective pharmacologic agents for the treatment of hemoglobinopathies have also revealed some of the limitations of an isolated molecular approach to the understanding of disease. The tortuous course by which a class of reagents has been identified for stimulation of HbF synthesis illustrates an important point. The application of recombinant DNA methods revealed an entirely new array of pathophysiologic facts that stimulated new hypotheses about the regulation of gene expression and opportunities to manipulate that regulation therapeutically. However, practical application and proper understanding of the molecular information were achieved only when those data were placed in the context of cell biology, tissue and organ-based clinical pathophysiology, and clinical pharmacology. Progress was possible only because of the productive interaction of talented individuals with expertise in these different fields. Our two decades of experience with the thalassemias illustrate very clearly the fact that biology and disease are extraordinarily complex, non-deterministic processes. They will be understood and treated properly only if thriving centers exist within which individuals with diverse interests, expertise, and perspectives about basic science and clinical medicine can exist, interact, and have sufficient time to employ their imaginations to the fullest benefit.
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PMID:The thalassemia syndromes: lessons from molecular medicines index case. 872 57

beta-Thalassemia major (TM), a congenital hemoglobinopathy, is associated with hemodynamic disorders and with structural red blood cell (RBC) anomalies that may indicate impairment of RBC rheological properties. To gain insight into the possible contribution of RBC to the hemodynamic disorders, we studied RBC aggregability, which plays a central role in blood flow, particularly in the microcirculation. RBC aggregate size distribution and morphology of TM RBC were determined using a novel system for image analysis of blood cells in a flow chamber. It was found that the aggregability of RBC of TM patients is markedly enhanced. These cells form large clusters, as opposed to normal rouleaux, and higher shear stress is required to disperse them. The aggregate size of TM RBC is reduced to the normal range after the patients have received a blood transfusion. This study suggests that the hemodynamic disorders observed in TM may be linked to the enhanced RBC aggregability and that improvement of RBC rheological properties may be considered in the treatment of thalassemia.
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PMID:Enhanced aggregability of red blood cells of beta-thalassemia major patients. 876 43

Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revealed that for effective stimulation of HbF in erythroid precursors: (1) the ideal length for the aliphatic side chain is four carbons; (2) oxygen or sulfur substitutions in the carboxylic chain are allowed, as evidenced by the equal or increased activity of phenoxypropionate, benzylthioglycolate, and benzyloxyacetate compared with phenylbutyrate; and (3) blocking the carboxylate group by conversion to the amide form greatly reduces potency. Molecular analysis indicated that the prototype agent, phenylbutyrate, increases HbF production through transcriptional activation of the gamma-globin gene. The latter contains a butyrate responsive promoter known to up-regulate transcription in the presence of short-chain fatty acids of three to five carbons. To determine whether stimulation of an element in this promoter by phenylbutyrate and its analogues might contribute to their mechanism of action, we used a transient expression system involving K562 erythroleukemia cells transfected with a luciferase reporter gene driven by the minimum gamma-globin promoter. Transcriptional activation in this experimental system correlated well with the capacity of an aromatic fatty acid to increase HbF production in erythroid precursors (r = 0.94). Our studies identify potent analogues of phenylbutyrate for the treatment of beta-chain hemoglobinopathies, and suggest that stimulation of a butyrate responsive promoter may be responsible for their activity.
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PMID:Transcriptional upregulation of gamma-globin by phenylbutyrate and analogous aromatic fatty acids. 893 30

Beta-thalassemia is one of the most common inherited hemoglobin disorders in Pakistan. The carrier frequency is estimated to be 5.4%. To determine the spectrum of beta-globin gene defects causing beta-thalassemia, we have analyzed a representative sample of 602 alleles from six ethnic groups in Pakistan; 99.2% alleles were characterized, while 0.8% remained unidentified. The spectrum of mutations is heterogeneous and we have found 19 different mutations in all ethnic groups. The four most common mutations, IVS-I-5 (G-->C) (37.7%), codons 8/9 (+G) (21.1%), the 619 bp deletion (12.4%), and IVS-I-1 (G-->T) (9.5%), account for 80.7% of the alleles. There are differences between the ethnic groups and also between provinces. In the four provinces of Pakistan, the IVS-I-5 (G-->C) mutation is more prevalent in Sindh and Balochistan, bordering India in the south and Iran in the southwest, while the codons 8/9 (+G) mutation is more common in the Punjab and the North West Frontier Province, bordering India in the northeast and Afghanistan, respectively. The 619 bp deletion is high (46%) in Gujratis and Memons residing in the Province of Sindh, neighboring the Indian Gujrat.
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PMID:Molecular characterization of beta-thalassemia in Pakistan. 973 Mar 64

beta Thalassemia (Thal) mutations were studied in DNA from 80/159 patients with hemolytic anemia and high levels of Hb A2 by the amplification refractory mutation system technique (ARMS-PCR). This method detects point mutations and insertions or deletions of just a few nucleotides in the beta globin gene by the polymerase chain reaction of allele-specific priming. In 43/80 patients with different clinical presentations of beta Thalassemia and 37/80 compound heterozygous for hemoglobinopathies and beta Thalassemia the most frequent mutation found was the -29 (of African origin), followed by the CD39 (of Mediterranean origin) and in a lower frequency also was found the -88, the IVSI-6 and the IVSI-110. We conclude that this technique is an useful approach in determining the beta thalassemia mutations in population surveys, because it allows to make a differential diagnosis between beta Thalassemia minor and individuals with high levels of Hb A2. It helps to clarify the diagnosis of patients with structural hemoglobinopathies that also presents high levels of Hb A2.
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PMID:[Detection of beta thalassemia by the technique of refractory amplification of mutation systems (ARMS-PCR)]. 1053 53

In this study, protein C (PC), protein S (PS), heparin cofactor II (HCFII), prothrombin fragment 1+2(PF1,2), thrombin-antithrombin III complex (TAT), von Willebrand factor (vWF) and thrombomodulin (TM) were investigated in 13 patients with beta thalassemia intermedia (TI) not requiring transfusion, six patients with sickle cell disease (SCD), and seven patients with HbS-beta thalassemia (S-BT) who were not in crisis. These hemostatic parameters were also studied in 12 healthy children assigned as a control group. Protein C and Protein S (PC-PS) were found to be decreased in TI patients and normal in S-BT patients. PC was decreased in SCD patients. In the patients with TI and SCD, the mean PF1,2 level was elevated, whereas the TAT level was not statistically different from that of the control group. These results suggested that in patients with hemoglobinopathies: a) decreased natural anticoagulants and b) enhanced procoagulant activation have been encountered. Other unexpected and interesting results of this study are the decreased vWF and elevated HCFII levels in all three patient groups.
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PMID:Changes of hemostatic factors in patients with hemoglobinopathies. 1077 92

Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.
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PMID:Iron overload and iron-chelating therapy in hemoglobin E-beta thalassemia. 1113 36

The development of clinical and histopathologic manifestations of a diffuse elastic tissue defect, resembling inherited pseudoxanthoma elasticum (PXE), has been encountered with a notable frequency in patients with beta thalassemia, sickle cell disease, and sickle thalassemia. The PXE-like clinical syndrome, consisting of skin, ocular, and vascular manifestations, has a variable severity in these hemoglobinopathies and it is age-dependent, with a generally late onset, after the second decade of life. The defect is believed to be acquired rather than inherited and related to the consequences of the primary disease. The high prevalence of the findings implicates the elastic tissue injury as one of the main comorbid abnormalities encountered in beta thalassemia and the sickling syndromes. In these patients a number of complications, sometimes serious, has been recognized to be related to ocular and vascular elastic tissue defects. Because several organ systems are involved, each medical specialty should be aware of the phenomenon. This coexistence, on the other hand, introduces a novel pathogenetic aspect of PXE and an important research challenge.
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PMID:Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. 1175 49

Hemoglobinopathies are very common in Greece, the incidence of beta-thalassemia trait being 8% and that of sickle cell trait ranging from 1 to 32% in various districts. In Greek populations, sickle cell disease (SCD) is mainly represented by S-beta thalassemia.
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PMID:Avascular necrosis of the femoral head among children and adolescents with sickle cell disease in Greece. 1209 Nov 29

Beta-thalassemia minor is a hemoglobinopathy which has been known as a symptomless carrier state. Although there are many causes leading to renal tubular dysfunction, beta-thalassemia minor has not been reported among them in reviewing the literature. In a 20-year-old male patient referred to us because of glucosuria detected with dipstick, there was also anemia (hemoglobin, 11.5 g/dl; mean cell volume, 60 fl; and mean cell hemoglobin concentration, 19.5 pg). The 24-hour urinary glucose excretion rate was 5 g and, additionally, he had tubular proteinuria (albumin/beta(2)-microglobulin ratio in urine was 17.32). Based upon the detailed evaluation for both asymptomatic urinary abnormality and anemia, he was diagnosed as having renal tubular dysfunction and beta-thalassemia minor (hemoglobin A(1)was 91%, and hemoglobin A(2)was 9%). In conclusion, further reports are needed to reveal whether there is an association between these two distinct disorders.
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PMID:Renal tubular dysfunction in a patient with beta-thalassemia minor. 1218 8


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