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PubMed1991

Multiple recombination events are responsible for the heterogeneity of alpha(+)-thalassemia haplotypes among the forest tribes of Andhra Pradesh, India.

The presence of several polymorphic markers along the alpha-globin gene complex allows the identification of haplotypes associated with alpha-thalassemia determinants. These are found at very high frequencies in geographic areas where malaria is or has been endemic which suggests a positive selective role by the parasitic disease in favour of alpha(+)-thalassemia mutants. A population survey among forest tribal communities from Andhra Pradesh, India, revealed the prevalence and molecular heterogeneity of alpha(+)-thalassemia determinants presumably due to a long backdated malaria endemicity among these populations. Analysis of the tribal alpha-thalassemia haplotypes has shown a great degree of genetic heterogeneity which can be explained as the result of multiple recombination events in the presence of natural selection by malaria.

Alleles↗
PubMedDate not supplied

Scanning of beta-globin gene for identification of beta-thalassemia mutation in Romanian population.

Beta-thalassemia is uncommon (0.5%) in the Romanian population, but it must be considered in the differential diagnosis of hypochromic anemia. The molecular characterization of beta-thalassemia is absolutely necessary for molecular diagnosis, as well as any genetic epidemiological study in this region. Molecular analyses consist of mutation detection by molecular scanning of beta-globin gene. This gene has 3 exons and 2 introns, involved in beta-thalassemic pathogenesis. Clinical application of DNA analysis on beta-thalassemic chromosomes allowed characterization of 29 persons with different beta-thalassemia mutations among 58 patients with anemia. The experimental strategy was based on sequential PCR amplification of most of the beta-globin gene and running on denaturing gradient gel electrophoresis of amplification products. Definitive characterization of mutations in samples identified with shifted DGGE patterns was performed ARMS-PCR and/or PCR-restriction enzyme analysis methods. Eight different beta-thalassemia alleles were identified, the most common being IVS I-110 (G-A) and cd 39 (C-T). Comparison of overall frequency of mutations in the neighboring countries, shows that these results are in the frame of overall distribution of these mutations in Mediterranean area, especially in Greece and in Bulgaria. Molecular diagnosis is useful for differentiating mild from severe alleles, for genetic counseling, as well as for mutation definition in carriers, identified by hematological analysis necessary for prenatal testing and genetic counseling.

Adolescent↗
PubMed2005

Two beta-globin cluster-linked polymorphic loci in thalassemia patients of variable levels of fetal hemoglobin.

OBJECTIVE: To correlate different polymorphisms of the beta-globin cluster with fetal hemoglobin (HbF) level in beta-thalassemia and E-beta thalassemia patients. METHODS: Fifteen thalassemia patients, seven with high HbF and not requiring transfusion, eight with lower HbF and requiring transfusion were studied for beta-globin mutation, concurrent inheritance of alpha-thalassemia, RFLP haplotype, a C-->T polymorphism at -158 of Ggamma and configuration of an (AT)(x)T(y) motif at -540 of beta-globin gene. RESULTS: Senegal 5'beta-haplotype and the polymorphism at -158 of G(gamma) was (P = 0.063) was linked to the high-HbF phenotype but the (AT)(9)T(5) configuration of the (AT)(x)T(y) motif was not (P = 0.6). Study of 30 chromosomes revealed 7 different configurations of the (AT)(x)T(y) motif. Association of these motifs with specific beta-globin mutations of this region has also been determined. CONCLUSION: The senegal haplotype and the polymorphism at -158 of G(gamma) was linked to the high-HbF phenotype.

Female↗
PubMed1998

Thalassemia in the next millennium. Keynote address.

Over the next decade it will be essential to make the thalassemia problem more visible to governments and international health agencies that are involved in health care in the emerging countries. This will require detailed population surveys to determine the gene frequencies of the important forms of thalassemia, together with a better understanding of their natural history and of the factors that modify their clinical phenotypes. In particular, more needs to be learnt about the natural history and ways of managing the intermediate forms of beta thalassemia. While research should continue towards definitive forms of treatment it is important, in the meantime, to pursue the development of cheap and safe oral chelating agents and to carry out clinical trials of drugs that may interact one with another to elevate the level of fetal hemoglobin, particularly in patients with different types of beta thalassemia intermedia. The partial control of the disease by carrier detection and prenatal diagnosis will only be feasible in emerging countries if it is possible to obtain the financial support of the major international agencies and the cooperation of their governments and communities; the remarkable success of this approach in some of the Mediterranean islands is a good example of what can be achieved.

Female↗
PubMed1984

Multiple mutations produce delta beta 0 thalassemia in Sardinia.

In Sardinia the common form of beta thalassemia is a beta 0 thalassemia due to a nonsense mutation at codon 39. delta beta 0 Thalassemia is rare in Sardinia and is associated with increased production of hemoglobin F of the A gamma type. In this study we used a synthetic oligomer assay and detected the beta 39 nonsense mutation on the delta beta 0 thalassemia chromosome. Hence at least two different mutations have occurred on this chromosome; one that increases A gamma globin synthesis and another that silences the beta globin gene.

Chromosomes, Human↗
PubMed2005

Molecular basis of thalassemia syndromes in Serbia and Montenegro.

This study reports the molecular characterization of thalassemia syndromes in Serbian and Montenegrin populations. We identified eight beta-thalassemia mutations [codon 39 (C-->T), IVS-I-110 (G-->A), IVS-II-745 (C-->G), codon 44 (-C), -87 (C-->G), IVS-II-1 (G-->A), IVS-I-6 (T-->C), IVS I-1 (G-->A)] in 70 members of 29 families using polymerase chain reaction, reverse dot blot, amplification refractory mutation system and direct sequencing analysis. Hemoglobin (Hb) Lepore was found to be the most common cause of the thalassemia phenotype. Hb Sabine and alpha-thalassemia were detected as well. We also studied beta-globin gene cluster haplotypes and their association with the most common mutations. A novel haplotype associated with the Hb Lepore gene was identified. The results presented herein allowed the implementation of a prenatal diagnosis program in Serbia and Montenegro.

Codon↗
PubMed1997

Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter.

The author summarizes the Hb A2 levels in over 600 beta-thalassemia heterozygotes with 32 different base changes or frameshifts and in 22 heterozygotes for 1 of 5 large deletions. Three major groups are recognized: persons with beta zero-thalassemia or beta (+)-thalassemia (severe) have Hb A2 levels between 4.5 and 5.5%, those with mild beta (+)-thalassemia alleles have levels between 3.6 and 4.2%, with still lower values for those with silent mutations. High values were observed in subjects with the 2 mild beta + alleles with mutations in the beta-globin gene promoter (-88, C-->T and -29, A-->G); unusually high Hb A2 values were also present in several -88 and -29 homozygotes. Data for several members of 8 families in which the -88 (C-->T) or the -29 (A-->G) mutation, or the -1,393-bp deletion, is present in cis or in trans to a delta-globin gene mutation support earlier observations that an increase in delta-chain synthesis occurs in cis to either one of these 3 alleles. A review of these data confirms the suggestion that the increase in Hb A2 levels results from at least two mechanisms: in a posttranslational system, the formation of alpha delta-dimers is promoted when excess alpha-chains are available, while certain promoter mutations increase the transcription of the delta-globin gene in cis because of a change in the binding of transcription factors.

Adult↗
PubMed1997

Recombinant erythropoietin trial in children with transfusion-dependent homozygous beta-thalassemia.

Augmentation of gamma-gene synthesis by using recombinant human erythropoietin (r-Hu-EPO) represents a new approach to the therapy of beta-thalassemia. A prospective study was conducted in 26 transfusion-dependent beta-thalassemia major patients. r-Hu-EPO (Eprex/Cilag, Switzerland) was given to the patients at an initial dose of 500 IU/kg s.c. 3 times a week for at least 2 months during which no transfusion was applied. A sustained hemoglobin (Hb) level greater than 8 g/dl was considered as a response to EPO treatment. In the patients whose Hb levels remained under 8 g/dl or did not increase in comparison to pretreatment levels within 4 weeks, the dose of r-Hu-EPO was increased to 1,000 IU/kg 3 times a week and applied for another 4 weeks. Only 16 cases also received oral iron supplementation. The whole blood and reticulocyte counts, the biochemical tests including BUN, creatinine, AST, ALT, alkaline phosphatase and ferritin were done and the percentages of HbF and F cells were analyzed regularly. At the end of the 2nd month, 6 cases qualified to continue with the trial. At the end of the 6th month, r-Hu-EPO therapy was ceased in 3 cases of the 6 since their Hb levels had decreased below 7 g/dl. Only 3 cases (11.5%) continued with the r-Hu-EPO therapy without transfusion for up to 12 months. In conclusion, r-Hu-EPO may be useful in some selected transfusion-dependent patients with beta-thalassemia major. Selection criteria should include a mild beta-genotype of coinheritance of alpha-thalassemia, splenectomy and pretreatment reticulocyte response of the patients as well as the patients' compliance.

Adolescent↗
PubMed1990

Compound heterozygosity for a mild beta (+) and a rare beta(0)-thalassemia allele.

Hematological and hemoglobin composition data are presented for 14 members of a Surinam family (and for 1 unrelated subject) with either a beta-thalassemia heterozygosity [5 with the -29 (A----G) beta + mutation and 5 with the IVS II-849 (A----G) beta(0) mutation] or a compound heterozygosity (the 5 remaining patients). Identification of the mutation was by hybridization of amplified DNA with 32P-labelled synthetic oligonucleotides. The data indicate distinct differences between the two groups of heterozygotes, mainly in degree of microcytosis and hypochromia, in Hb A2 level, and in the level of G gamma (high in the -29 heterozygotes and low in the IVS II-849 heterozygotes). The 5 compound heterozygotes had a thalassemia intermedia with high Hb F levels (high G gamma), elevated Hb A2, and Hb A levels comparable to those seen in patients with a homozygosity for the -29 mutation or with the combination of this beta(+)-thalassemia and Hb S. An alpha-thalassemia-2 heterozygosity (-3.7 kb deletion) was present in 2 patients. Their hematological data were improved over those for the patients with four alpha globin genes; one was the mother of two sets of twins. The high G gamma value in the Hb F of the compound heterozygotes suggests that the high Hb F production in the condition is mainly directed by the chromosome with the -29 (A----G) mutation.

Adult↗
PubMed1988

T cell functions in infants and children with beta-thalassemia.

Thirty-five infants and children with beta-thalassemia major and 12 with beta-thalassemia trait were studied. Their ages ranged between 6 months and 12 years. Thirty-three were males and 14 females. Spontaneous rosette (E1-RFC), total rosette (E2-RFC), enumeration of T lymphocyte subsets using monoclonal antibodies (OKT3, OKT4, and OKT8), migration inhibition factor (MIF) assay and in vivo delayed hypersensitivity skin reactions were tested. Lower mean T cell population was present in thalassemia major but not the trait. The helper/suppressor ratio was decreased in patients with evidence of hypersplenism. Patients who had suffered from pneumonia or hepatitis manifested lower mean T cell count, depletion of helper cells and decreased helper/suppressor ratio. They also showed depressed delayed cutaneous hypersensitivity and MIF activity. Study of the cell-mediated immunity in patients with thalassemia might be useful to detect those who could be-more susceptible to infections.

Child↗
PubMed1985

Hemoglobin content of single erythrocytes from fetuses with parents having heterozygous beta-thalassemia.

The hemoglobin content of single erythrocytes was determined by microspectrophotometry as total extinction (TE) at 415 nm in subjects with a wide spectrum of hemoglobin levels and erythrocyte indices. Precise measurements of the cellular area (A) and the ratio TE/A were also recorded. A significant correlation was found between TE and mean corpuscular hemoglobin (MCH), A and mean corpuscular volume, and TE/A and mean cell hemoglobin concentration (MCHC) for the cases studied. In addition, TE, A and TE/A were determined in fetal erythrocytes obtained by fetoscopy at the 20th week of gestation for prenatal diagnosis of beta-thalassemia. The mean red cell TE and TE/A of the group of fetuses diagnosed to have thalassemia major were significantly lower than those of the group of normal controls and with heterozygous beta-thalassemia. The significant differences of TE, A and TE/A between maternal and fetal blood allowed a safe distinction of the latter. The calculated MCH of the fetuses with thalassemia major was 12% less than that of the normal controls; the respective difference of the mean cell size was 5% and that of MCHC 3% lower than normal.

Erythrocyte Indices↗
PubMed1975

Hemoglobin Beograd (alpha2beta2 121 Glu leads to Val) interacting with beta-thalassemia.

Hematological and biochemical findings in a family with hemoglobin (Hb) Beograd interacting with beta-thalassemia are presented. Hb Beograd (alpha2beta2 121 Gul leads to Val) was found in 3 members. In two members it interacted with beta-thalassemia. These two double heterozygotes had anemia of intermediate severity and splenomegaly. Studies with 51Cr and 59Fe showed a shortened life span of red cells and ineffective erythropoiesis. The abnormal Hb amounted to 86-87%, and Hb F to 5-7%. No Hb A was present. One subject of the family was heterozygous for Hb Beograd. He showed normal clinical and hematological findings. The abnormal hemoglobin was 38%. Four members of the family were heterozygotes for beta-thalassemia. The interaction between beta-thalassemia and beta-chain variants is discussed.

Adult↗
PubMed1993

Quantitative ultrasonic analysis of myocardium in patients with thalassemia major and iron overload.

BACKGROUND: Patients with beta-thalassemia major present with severe anemia and need continuous transfusion therapy. The consequent iron overload leads to hemochromatosis. Initial cardiac dysfunction has been documented even in thalassemics without clinical manifestations of heart failure as well as by conventional echocardiographic-Doppler techniques. The purpose of this study was to assess the acoustic quantitative properties of myocardium in patients with iron overload. METHODS AND RESULTS: Thirty-eight patients with beta-thalassemia major, without clinical signs of cardiac failure, and 20 age- and sex-matched young controls were studied by echocardiography. An on-line analysis of the ultrasonic radiofrequency signal was performed to obtain quantitative operator-independent measurements of the integrated backscatter (IB) signal of the ventricular septum and the posterior wall. The integrated values of the radiofrequency signal were normalized for the pericardial interface and expressed in percent (IB%). Thalassemic patients had been receiving transfusion therapy for 16 +/- 5 years and had received 313 +/- 138 transfusion units; they all had received chelation treatment (desferroxiamine) for 9 +/- 2 years. Patients and controls showed comparable values of echocardiographically assessed percent fractional shortening (32 +/- 3% versus 36 +/- 4%, p = NS), whereas thalassemics showed higher values of left ventricular mass index (118 +/- 30 versus 98 +/- 15 g/m2, p < 0.05). The IB% values were higher in patients with thalassemia major than in controls for both septum (35 +/- 14% versus 21 +/- 6%, p < 0.001) and posterior wall (16 +/- 6% versus 11 +/- 3%, p < 0.001). In thalassemic patients, no significant correlation was found between the septum IB% value and hematological parameters, such as the total number of transfusions (r = 0.2, p = NS) or the mean ferritin value (r = 0.1, p = NS). No significant correlation was also found between the septum IB% value and the echocardiographically assessed left ventricular mass index (r = 0.2, p = NS). CONCLUSIONS: These data demonstrate that myocardial reflectivity is abnormally increased in patients with thalassemia major under transfusion treatment, probably due to myocardial iron deposits and/or secondary structural changes. These quantitatively assessed abnormalities in regional reflectivity can be detected when conventional echocardiographic parameters of systolic left ventricular function are undistinguishable from normal controls.

Adolescent↗
PubMed1993

Left ventricular diastolic Doppler characteristics in beta-thalassemia major.

BACKGROUND: Diastolic left ventricular function expressed by diastolic Doppler characteristics of the left ventricle has never been properly investigated. METHODS AND RESULTS: Left ventricular inflow and pulmonary vein flow patterns were assessed by Doppler echocardiography in 88 beta-thalassemia major patients with normal left ventricular systolic function; 34 were young (age, 15.1 +/- 3.2 years) and 54 were adults (age, 25.1 +/- 3.6 years). The findings were compared with those obtained from 22 young (age, 13.8 +/- 2.4 years) and 24 adult (age, 25.3 +/- 4.1 years) normal individuals. In both groups of patients, peak flow velocities in early (E) and late (A) diastole were higher than in the control subjects (young E: P < .01; adult E: P < .001; young A: P < .05; adult A: P < .05), whereas no difference was found in the E/A ratio, deceleration time, or isovolumic relaxation time. Pulmonary vein systolic (S) and diastolic (D) velocities were also higher in beta-thalassemia major patients compared with the control subjects (young S: P < .05; adult S: P < .05; young D: P < .05; adult D: P < .05). Restrictive left ventricular abnormalities were only found in 7 patients who were among the oldest beta-thalassemia major population of the adult group (P < .01) with highly elevated mean serum ferritin. In comparison to the remaining adult patients, interventricular septum and left ventricular posterior wall thickness were increased (P < .01 and P < .01, respectively). The left atrium and right ventricle were dilated (P < .05 and P < .01, respectively). CONCLUSIONS: Doppler diastolic indexes in beta-thalassemia major patients with normal left ventricular systolic function are similar to those seen in conditions with an increased preload, probably because of chronic anemia. Only severe iron loading and deposition in the myocardium leads to the restrictive abnormalities of left ventricular filling.

Adolescent↗
PubMed1971

Defect in messenger RNA for human hemoglobin synthesis in beta thalassemia.

Functional messenger RNA for human hemoglobin synthesis was prepared from reticulocyte lysates of patients with homozygous beta thalassemia and sickle cell anemia. The messenger RNA stimulated the synthesis of human globin chains by a cell-free system derived from Krebs mouse ascites cells. In the presence of beta thalassemia messenger RNA, the system synthesized much less beta chain than alpha chain whereas in the presence of sickle cell anemia messenger RNA, nearly equal amounts of alpha and beta chains were synthesized. The beta/alpha synthetic ratios obtained in the cell-free system were similar to those obtained by incubating intact beta thalassemia and sickle cell anemia reticulocytes in the presence of radioactive leucine. The experiments provide direct evidence of a defect in messenger RNA for beta chains as a cause for the decreased synthesis of beta chains observed in beta thalassemia.

Anemia, Sickle Cell↗
PubMed1973

Beta-thalassemia in the American Negro.

In Italian patients with high hemoglobin A(2) beta-thalassemia trait, the synthesis of beta-chains of adult hemoglobin in the peripheral blood is approximately one-half that of alpha-chains. In this study the relative rates of beta- and alpha-chain synthesis were determined in 26 Negro heterozygotes and five homozygotes for beta-thalassemia in six families. The beta/alpha ratio of globin synthesis was decreased in only 15 heterozygotes, whereas in the other 11, beta/alpha globin synthesis was in the normal range or was slightly increased. These unusual findings did not appear to be due to the presence of alpha-thalassemia or a hyperactive "normal" beta-allele. This study demonstrates that the beta/alpha ratio of globin synthesis in the peripheral blood is normal in some patients with beta-thalassemia trait. In five Negro homozygotes with relatively mild clinical disease the beta/alpha ratios were similar to those of Caucasians with Cooley's anemia. Further studies are needed to explore the relationship between normal synthesis ratios in many Negro heterozygotes and milder clinical disease in homozygotes in the same families.

Adolescent↗
PubMed1979

Hemoglobin Indianapolis (beta 112[G14] arginine). An unstable beta-chain variant producing the phenotype of severe beta-thalassemia.

Hemoglobin (Hb) Indianapolis is an extremely labile beta-chain variant, present in such small amounts that it was undetectable by usual techniques. Clinically, it produces the phenotype of severe beta-thalassemia. Biosynthetic studies showed a beta:alpha ratio of 0.5 in reticulocytes and about 1.0 in marrow after a 1-h incubation. These results, similar to those seen in typical heterozygous beta-thalassemia, suggested that betaIndianapolis was destroyed so rapidly that its net synthesis was essentially zero. To examine the kinetics of globin synthesis, reticulocyte incubations of 1.25--20 min were performed with [3H]leucine. The betaIndianapolis:beta A ratio at 1.25 min was 0.80 suggesting that beta Indianapolis was synthesized at a near normal rate. At 20 min, this ratio was 0.46 reflecting rapid turnover of beta Indianapolis. The erythrocyte ghosts from these incubations contained only betaIndianapolis and alpha-chains, and the proportion of betaIndianapolis decreased with time, indicating loss of betaIndianapolis. Pulse-chase studies showed little change in beta A:alpha ratio and decreasing betaIndianapolis:alpha and betaIndianapolis:beta A with time. The half-life of betaIndianapolis in the soluble hemoglobin was approximately equal to 7 min. There was also rapid loss of beta Indianapolis from the erythrocyte membrane. From these results, it may be inferred that betaIndianapolis is rapidly precipitated from the soluble cell phase to the membrane, where it is catabolized. Heterozygotes for beta 0-thalassemia usually have minimal hematologic abnormalities, whereas heterozygotes with betaIndianapolis, having a similar net content of beta-chain, have severe disease. The extremely rapid precipitation and catabolism of betaIndianapolis and the resulting excess of alpha-chains, both causing membrane damage, may be responsible for the severe clinical manifestations associated with this variant. It seems likely that other, similar disturbances in the primary sequence of globin polypeptide chains may produce clinical findings similar to those seen with hemoglobin Indianapolis and thus produce the phenotype of severe beta-thalassemia.

Adolescent↗
PubMed1979

Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes.

The alpha-thalassemia syndromes are a group of inherited anemias, the clinical severity of which has been shown to increase with the number of alpha-globin structural genes deleted. Employing restriction endonuclease gene mapping, we defined the organization of the alpha-globin genes in cellular DNA from Chinese subjects with various alpha-thalassemia syndromes. The four alpha-globin genes of normals are at two loci located on a 23.0-kilobase pair (kb) Eco RI fragment. In deletion type hemoglobin-H disease the 5' alpha-globin locus is deleted and the single 3' alpha-globin locus is found on a 19.0-kb Eco RI fragment. In alpha-thalassemia-2 there are two alpha-globin genes on a 23.0-kb Eco RI fragment and one on a 19.0-kb fragment. In alpha-thalassemia-1 and the nondeletion type of hemoglobin-H disease the two alpha-globin genes are at two loci on one chromosome and none reside on the other chromosome.

China↗