Cases reported "beta-Thalassemia"

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1/7. association of unstable hemoglobin variants and heterozygous beta-thalassemia: example of a new variant Hb Acharnes or [beta53(D4) Ala --> Thr].

    We report here the functional and structural characterization of Hb Acharnes [beta53(D4) Ala --> Thr], an unstable and electrophoretically silent variant, that was found associated in trans with a beta(0)-thalassemic mutation (IVSI-1 G --> A), in a patient with thalassemia intermedia syndrome. This case is discussed in comparison with other sporadic cases that we have previously investigated, resulting from the co-inheritance of a beta(0)-thalassemic mutation (CD39 C --> T) with two other types of unstable hemoglobins, Hb Koln [beta98(FG5) Val --> Met], and Hb Arta [beta45(CD4) Phe --> Cys]. It may be concluded that, in these associated forms, both the degree of instability of the variant and the altered oxygen binding properties (affecting the degree of tissue hypoxia) are major determinants of their clinical expression.
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2/7. Non-anemic homozygous beta(o) thalassemia in an African-American family: association of high fetal hemoglobin levels with beta thalassemia alleles.

    We have studied a four-generation (23 subjects) African-American family with beta(o) thalassemia and high fetal hemoglobin (HbF) levels. The beta(o) thalassemia in this family is due to the splicing site mutation, beta IVS2 1G-->A, that leads to aberrant mRNA processing and the absence of beta globin. Two members of this family are homozygous for beta(o) thalassemia and are non-anemic. All family members who are heterozygous for the beta IVS2 1G-->A mutation have elevated HbF, with the exception of two individuals who also have severe alpha-globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromosomes 6 and X. We also excluded the presence of all previously described determinants in the beta globin gene cluster associated with elevated HbF production. One thalassemia allele is in the cameroon-like (HS2)/benin-like beta globin gene cluster haplotype, and the other is in the senegal-like (HS2)/benin-like beta globin gene cluster haplotype. We speculate that in the homozygotes, those erythroid cells that express low to absent levels of gamma globin are selectively destroyed. In contrast, in the heterozygotes, the presence of the normal beta globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnormal transcript, leading to a typical beta(o) thalassemia phenotype. Thus, the heterocellular gamma globin expression together with in vivo preferential survival of HbF-containing erythroid cells ameliorates Cooley's anemia in the beta(o) thalassemia homozygotes. It remains to be determined what sequences linked to each thalassemia allele and what trans-acting factors contribute to high HbF levels.
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3/7. The homozygous state of Hb J Sardegna.

    Hb J Sardegna is a well known innocent Hb variant which is widespread in Sardinia. As yet, homozygosity for Hb J Sardegna has not been documented. This report deals with the homozygous state for Hb J which we demonstrate by molecular analysis in two Sardinian siblings in which beta-thalassemia coexists. The Hb J specific mutation was determined both by enzyme digestion and by sequencing specific segments of PCR amplified alpha-globin genes. A pregnant girl showed mild non-sideropenic microcytic anemia, normal Hb A(2) levels (2.4%) on DE-52 microchromatography, 50% of Hb variant on HPLC and 2.1 alpha/beta globin chain biosynthetic ratio. She proved to be a carrier of the beta degrees 6(-A) thalassemia determinant. The alpha-globin gene mapping did not reveal alpha-thalassemia. Btg I restriction analysis of both alpha(2)-globin genes showed a recognition site defect for this enzyme in both chromosomes, which resulted to be the C-->A point mutation in homozygosity at the first nt of alpha(2)-globin gene 50th codon by sequencing. This defect, typical of Hb J Sardegna, was also present in her brother. From a practical point of view, this study demonstrates that the association of beta-thalassemia with Hb J, may show falsely reduced Hb A(2) levels on routine Hb A(2) quantitation techniques, such as DE-52 microchromatography. This possibility implies that identification methods such as simple Hb electrophoresis, which permit visualization of Hb A(J)(2) should be used in thalassemia screening involving populations in which Hb J and beta-thalassemia coexist.
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4/7. Molecular characterization of thalassemia intermedia associated with HPFH-6/beta-thalassemia and HPFH-6/Hb E in Thai patients.

    We report the molecular and hematological characterizations of thalassemia caused by interactions of the hereditary persistence of fetal hemoglobin (HPFH)-6 with beta-thalassemia in 2 Thai patients and the HPFH-6 with Hb E in another Thai patient. Marked hypochromic microcytosis, characteristics of thalassemia intermedia, were obvious in the former 2 cases but the latter had much milder clinical phenotype with normal Hb and a slightly reduced mean corpuscular volume (MCV) value. Hb analysis revealed no Hb A but Hb A(2)F patterns in the compound HPFH-6/beta-thalassemia patients and the EF pattern in the HPFH-6/Hb E patient. The (G)gamma-globin chain predominated in all cases. Globin gene analyses demonstrated that all patients carried the 101-kb HPFH-6 deletion in trans to the beta-thalassemia genes with the IVS1#5 G-C mutation and the G insertion between codons 8/9 and the beta(E)-gene, respectively. Hematologic data of the patients were compared to those of the HPFH-6 heterozygotes found in their family members and different genotype-phenotype interactions of this HPFH determinant in these Thai patients are illustrated.
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5/7. Compound heterozygote state for GgammaAgamma(deltabeta) degrees -thalassemia and hereditary persistence of fetal hemoglobin.

    We report a hitherto undescribed interaction of a deletional (deltabeta) degrees -thalassemia and a deletional hereditary persistence of fetal hemoglobin (HPFH) in an adult Thai individual. He was a 40-year-old Thai male who had the following hematologic data: Hb 13.9 g/dL, Hct 43.8%, MCV 78.0 fL, MCH 24.7 pg, MCHC 31.6 g/dL, and RDW 17.1%. Hemoglobin analysis revealed 97% Hb F with Ggamma-globin chain predominant. Globin gene analyses demonstrated that he carried the GgammaAgamma(deltabeta) degrees -thalassemia deletion in trans to the HPFH-6. Hematologic data of the patient were compared to those of the heterozygotes for these high-Hb F determinants found in his parents and an unrelated Thai patient with a compound HPFH-6/deletion-inversion Ggamma(Agammadeltabeta) degrees -thalassemia previously described.
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6/7. A novel Mediterranean "delta beta-thalassemia" determinant containing the delta ( ) 27 and beta (0) 39 point mutations in cis.

    The term delta beta-thalassemia with normal HbF has been recently proposed to define heterogenous delta and beta globin gene molecular defects involving the same chromosome in cis. Here, we describe a Sardinian family in which three members showing microcytosis, border-line HbA2 levels and normal HbF proved to be heterozygotes for delta( ) 27 and beta(0) 39 point mutations in cis by allele specific oligonucleotide hybridization as well as by ECO 0 109 I endonuclease digestion and electrophoresis. As some of these beta-thalassemia carriers shows normal HbA2 levels, knowledge of the molecular basis of this novel delta beta-thalassemia silent phenotype would be useful in thalassemia screening and genetic counselling.
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7/7. Severity of beta-thalassemia due to genotypes involving the IVS-I-6 (T-->C) mutation.

    Among individuals of Mediterranean or Middle Eastern descent, the IVS-I-6 (T-->C) mutation is one of the most common causes of beta-thalassemia. In this report, we describe the clinical phenotypes of a group of beta-thalassemia patients who are compound heterozygotes for the relatively mild IVS-I-6 (T-->C) beta-thalassemia mutation and more severe beta( )- or beta (0)-thalassemia mutations. Although most of these patients are transfusion-dependent, the requirement for regular transfusions generally occurred late in childhood. A correlation between concomitant alpha-thalassemia and a mild transfusion-independent phenotype is not apparent, indicating the involvement of other ameliorating determinants.
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