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

Diagnostic tests for most common hemoglobinopathies and recent advances in structural analysis of variant hemoglobins are reviewed. Routine and newly introduced methods that apply to the diagnosis of sickle cell anemia, thalassemia and the hemoglobin E disorders are presented. A brief description of the clinical course for each of these disorders is given, and potential pitfalls in diagnosis are discussed. Application of high-performance liquid chromatography and various mass spectrometric techniques (electrospray ionization mass spectrometry, liquid secondary ion mass spectrometry, and tandem mass spectrometry) for evaluation of hemoglobinopathy is presented.
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PMID:Laboratory diagnosis of hemoglobinopathies. 195 28

This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari, from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis, thalassemia-like bone changes, iron overload, high proportion of Hb F in the peripheral blood, reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes, and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents, even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation, thus making the proper diagnosis.
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PMID:Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy. 198 2

During a 10-month period, 10 couples originating from Africa (3), the tropics (1) and the thalassemia-belt region (6), living in Switzerland, requested prenatal diagnosis of hemoglobinopathies. Hb SS (twice), Hb Bart's (Hydrops fetalis) and beta-thalassemia major were diagnosed either by gene mapping or by direct detection of the mutations in DNA amplified by the PCR procedure. Whenever it was possible to obtain fetal blood or tissue, diagnosis was confirmed. In one Vietnamese man, concomitant existence of alpha-thal 1 with beta-thalassemia resulted in an unusually high Hb level because of balanced alpha and beta globin synthesis. The 10 couples examined originated from 7 different countries and presented at least 7 different Hb pathologies. This variety of pathologies represents the main difficulty for prenatal diagnosis of hemoglobinopathies in a non-endemic country. A diagnostic approach to overcome this problem is developed.
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PMID:Prenatal diagnosis of thalassemia and hemoglobinopathies in Switzerland. 200 49

In addition to local sequence elements the regulation of the high-level, development- and tissue-specific expression of the human beta globin gene cluster appears to require distant regulatory sequences which have been termed locus control region. In the chromatin of erythroid cells the locus control region is characterized by four DNaseI hypersensitive sites that are located 6-18 kb 5' of the epsilon globin gene. The definition of the sequences minimally required for locus control region activity is likely to further the understanding of its physiology and will be of interest for the development of somatic gene therapy strategies of the hemoglobinopathies. We present here the analysis of a family with a 3,030-bp deletion of sequences upstream of the epsilon globin gene including the most 3' locus control region element and cosegregating beta(0) thalassemia. The deletion is linked in cis to a structurally and functionally normal beta globin gene. The proximal element of the locus control region does not therefore appear to be necessary for beta globin gene activity in vivo.
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PMID:The proximal element of the beta globin locus control region is not functionally required in vivo. 204 Jun 96

Over the past 20 years we have studied 1781 patients with beta-thalassemia syndromes of which 1481 Yugoslav, 166 Bulgarian, 102 Turkish and 32 Albanian. In this paper we summarize the data on the heterogeneity and molecular basis of beta-thal, delta beta-thal and Lepore hemoglobinopathy in these four nationalities living in Yugoslavia and Bulgaria. Beta-thalassemia is the most frequent form of thalassemia in all four nationalities. At the phenotypic level 9 different forms were detected, while at the genotypic level 17 different mutations were characterized. DNA analysis of 377 beta-thal chromosomes showed that in Yugoslav 5 mutations (IVS I#110, IVS I#6, IVS I#1, Codon #39 and Poly A (A----G)) account for 83% of the beta-thal genes, while in Bulgarian 6 mutations (IVS I#110, Codon #39, IVS II#6, IVS II#745, Codon #8 and Codon #8/9) account for 76% of the beta-thal genes. In Turkish the most common mutation is IVS I#110, followed by IVS I#6, IVS II#1 and Codon #8, while in Albanian IVS I#110, Codon #39 and IVS I#6 are prevalent. Delta beta-thalassemia is the second most common form of thal in Yugoslav (10.8%) and Bulgarian (4.2%) but not in Turkish and Albanian. At the phenotypic level 6 different forms were detected, while at the molecular level 3 different deletions (approximately 15 kb, approximately 23 kb, and approximately 148 kb) were characterized. Hb Lepore is the third most common hemoglobinopathy among Yugoslav (9.6%) and most probably Bulgarian (3.67%). This condition was observed in homozygous (n 7) and heterozygous (n 124) state, and in association with beta zero-thal (n 5), beta(+)-thal (n 11), (delta beta)zero-thal (n 1), and Hb Beograd (n 1). Haplotype analysis of 29 lepore chromosomes from 9 unrelated families showed that Hb Lepore is associated with haplotype V.
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PMID:Beta-, delta beta-thalassemia and Hb lepore among Yugoslav, Bulgarian, Turkish and Albanian. 208 80

The authors have identified six Southeast Asian patients ranging in age from 14 to 21 years with hemoglobin E-beta(0) thalassemia and a coagulopathy involving von Willebrand factor (vWF). These patients had normal or only slightly decreased plasma clotting factor levels. The activated partial thromboplastin time was prolonged in four of the patients. The abnormal feature common to all patients was a qualitative loss of high molecular weight multimers of vWF by crossed immunoelectrophoresis (vWF:CIE). Plasma vWF antigen concentration (vWF:Ag) and ristocetin cofactor activity (vWF:RCo) also were decreased and bleeding time prolonged in three patients. Epistaxis was present in two. No family history of increased bleeding tendency was present in any patient. Coagulation parameters and vWF:CIE were normal in two first-degree relatives without this hemoglobinopathy. vWF abnormalities and clinical manifestations were greatest in those patients with the most severe anemia and hepatosplenomegaly. These six patients appear to have an acquired abnormality of vWF, although they lack the clinical characteristics of acquired von Willebrand disease. While the etiology of this abnormality is unclear, the authors speculate that proteolysis of vWF secondary to extramedullary hematopoiesis or loss through high cardiac output shear stress in these anemic patients may be involved.
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PMID:Abnormality of von Willebrand factor in patients with hemoglobin E-beta (0) thalassemia. 210 77

Patients with hemoglobinopathies can be at risk for significant maternal and fetal morbidity during pregnancy. This is especially true for those gravidas with SCD or certain thalassemia disorders. With intensive management, pregnancy outcome for these women has improved dramatically, and approximates that of the general population. Criteria for diagnosis for many of these conditions are well established. Appropriate therapeutic interventions are more controversial, but, regardless, emphasize the need for a heightened awareness of these disorders and their potential complications.
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PMID:The diagnosis and management of hemoglobinopathies during pregnancy. 218 52

Prenatal diagnoses of the genetic disorders alpha, beta thalassemia, HbS, Hb Lepore, hemophilia and cystic fibrosis were sought in 88 cases. Six unsuccessful attempts at diagnosis resulted from DNA polymorphisms which were only 50% informative (four cases) and prenatal diagnoses which had been undertaken before it was known whether DNA polymorphisms in family studies were informative (two cases). The most frequent indications for prenatal diagnosis were the hemoglobinopathies although requests for exclusion of cystic fibrosis formed the majority during 1989. Strong linkage disequilibrium between the cystic fibrosis defect and its associated DNA polymorphisms facilitated detection of this disorder. Late presentations among patients with beta thalassemia and hemophilia and the necessity for more specialised genetic counselling were the commonest problems encountered.
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PMID:Experience of a molecular genetics service in prenatal diagnosis by DNA analysis. 224 30

This paper reviews the molecular pathology of a heterogeneous group of beta-thalassemia heterozygotes which may be referred to as atypical beta-thalassemia. This group includes four different categories of heterozygous beta-thalassemia, which are characterized, respectively, by (1) normal MCV and MCH; (2) normal Hb A2; (3) normal MCV, MCH, and Hb A2 and imbalanced globin chain synthesis only or, (4) the presence of clinical manifestations. The first group is represented by a limited proportion of double heterozygotes for alpha- and beta-thalassemia. The second group includes two categories. One category is double heterozygotes for delta- and beta-thalassemia with the delta-thalassemia mutation in cis or in trans to beta-thalassemia. A number of delta-thalassemia mutations which produce this phenotype by interacting with beta-thalassemia have been described. The other category within the second group is heterozygotes for some mild beta(+)-thalassemia mutations. Within the third group, conclusive evidence for a mutation within the beta-globin gene cluster producing the silent beta-thalassemia phenotype has been obtained solely for a C----T substitution at -101 within the CACCC box of the beta-globin gene. Possible candidates are the complex rearrangements (-T, +ATA; -T, +ATATA) found at position -530 from the cap site. In the group of thalassemic hemoglobinopathies, a series of mutations mostly located in the third exon and producing elongated or truncated molecules have been recently reported. Most of the mutations are silent at the protein level, produce inclusion bodies in peripheral erythrocytes, and show a dominant transmission pattern or occur sporadically.
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PMID:Molecular analysis of atypical beta-thalassemia heterozygotes. 229 78

A 14-year-old boy with hemoglobin SC disease and alpha-thalassemia-2 experienced five episodes of acute splenic sequestration crisis (ASSC), while two of his siblings with identical globin genotypes (SC and -alpha/alpha alpha) had no such experience. To determine if an additional red blood cell (RBC) defect was responsible for the unusual occurrence of frequent ASSCs, we performed detailed rheologic characterization and membrane protein analysis on RBCs from the proband and other members of his family. Reduced surface area, increased mechanical instability, and decreased spectrin content of the membrane, distinguishing features of RBCs in hereditary spherocytosis, were observed in cells from the proband and his mother, but not in cells from other family members. These findings are consistent with the dominant inheritance of spherocytosis by the proband. We suggest that the combined effects of SC disease and spherocytosis in the proband resulted in decreased RBC deformability and led to increased splenic trapping, intrasplenic sickling, and consequently, recurrent sequestration crisis. Marked clinical and hematologic improvement occurred from splenectomy. Thus, inheritance of interacting genetic defects, sickling hemoglobinopathy, and hereditary spherocytosis appear to be responsible for the unusual clinical manifestation of recurrent ASSC in this patient.
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PMID:Recurrent acute splenic sequestration crisis due to interacting genetic defects: hemoglobin SC disease and hereditary spherocytosis. 229 90


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