Acquired hemoglobin H disease in a patient with aplastic anemia evolving into acute myeloid leukemia

CONTEXTO: O prognóstico da anemia aplástica grave melhorou com o advento do transplante de medula óssea e do tratamento imunossupressor com globulina antitimocitária. Em contraste com o sucesso destes protocolos, os estudos com seguimento a longo prazo mostraram a ocorrência de doenças clonais, tais como: hemoglobinúria paroxística noturna, síndrome mielodisplásica e leucemia aguda. RELATO DE CASO: Nós relatamos o primeiro caso descrito no Brasil de um paciente com anemia aplástica que evoluiu para síndrome mielodisplásica e leucemia mielóide aguda associada a presença de hemoglobina H e aumento da hemoglobina fetal.

Molecular analysis of Hb Q-H disease and Hb Q-Hb E in a Singaporean family.

Hb Q (alpha 74Asp-His) results from a mutation in the alpha-gene such that abnormal alpha Q-chains are synthesized. The alpha Q-chains combine with the normal Beta A-chains to form abnormal Hb alpha 2Q beta 2A (Hb Q). Hb Q-H disease is rare, and has been reported only in the Chinese. We report here a Chinese family, were the mother diagnosed with Hb Q-H disease and the father with Hb E heterozygosity and a child with Hb Q-E-thalassemia. Thalassemia screening of the mother's blood revealed a Hb level of 6.8g/dl with low MCV and MCH. Her blood film was indicative of thalassemia. Cellulose acetate electrophoresis showed Hb H and Hb Q with the absence of Hb A. Globin chain biosynthesis was carried out and alpha Q- and beta-chains were detected. Normal alpha- chains were absent. Digestion of the mother's DNA with Bam HI and Bgl II followed by hybridization with the 1.5 kb alpha-Pst probe showed a two alpha-gene deletion on one chromosome and the -alpha Q chain mutant with the -alpha 4.2 defect on the other chromosome. DNA amplification studies indicated the two-gene deletion to be of the -SEA/ defect. The patient was concluded to possess Hb Q-H disease (--SEA/-alpha 4.2Q). Cellulose acetate electrophoresis of the father's blood showed the presence of Hb A, F and E. Molecular analysis of the father's DNA confirmed an intact set of alpha-genes (alpha alpha/alpha alpha). Globin chain biosynthesis of fetal blood of their child showed gamma, beta A, beta E, alpha A and alpha Q-chains. Molecular analysis of the child's DNA showed one alpha-gene deletion, thus giving a genotype of alpha alpha/-alpha 4.2Q beta beta E.

Molecular mechanisms of thalassemia in southeast Asia.

Hemoglobinopathies are the most common genetic disorders in Southeast Asia. alpha-Thalassemia is most often due to a alpha-globin gene deletion. Hb Constant Spring (CS) occurs from the mutation at the termination codon of the alpha-globin gene resulting in an elongated polypeptide; alpha(CS)-globin mRNA is also unstable and only small amounts of Hb CS are produced. Thus Hb CS has an alpha-thalassemia 2-like effect. beta-Thalassemia results from a variety of molecular mechanisms, most of which are single base substitutions or deletions or insertions of one to four nucleotides. Hemoglobin E occurs from a Glu --> Lys substitution at position 26 of the beta-globin chain. The abnormal gene also results in reduced amounts of beta E-mRNA and hence of beta E-globin chains. Therefore, Hb E has a mild beta + thalassemia phenotype. Homozygous beta-thalassemia and beta-thalassemia/Hb E are the major beta-thalassemic syndromes in Southeast Asia. In spite of seemingly identical genotypes, severity of beta-thalassemia/Hb E patients can vary greatly. Some may have a severe clinical disorder approaching that seen in homozygous beta-thalassemia. A number of genetic factors have been shown to determine the differences in severity of anemia in beta-thalassemia/Hb E, including co-inheritance of alpha-thalassemia determinants and co-inheritance of other determinants which elevate Hb F expression. A correlation between the extent of beta E-globin mRNA cryptic splicing and the severity of anemia in beta(zero)-thalassemia/Hb E patients has been observed. Complete characterization of mutations causing hemoglobinopathies will help to bolster the establishment of prenatal diagnosis of these genetic disorders in the region.

Molecular analysis of the human fetal-to-adult globin switching.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by continued expression of the gamma-globin gene in adult life. Analysis of a Japanese HPFH family had revealed that the C-T transition at position -114 within the distal CCAAT box of the gamma-globin gene associated with the HPFH allele. In the vicinity of the distal CCAAT box, other two mutations (-117 C-T, 13 bp del) had been identified in individuals with a HPFH phenotype. Functional analysis of these mutant promoters in erythroid cell lines suggested that the distal CCAAT box works positively in the fetus but negatively in the adult on the expression of the gamma-globin gene. Further study on transgenic mice showed that the -114 mutation was responsible for the elevated expression of the gamma-globin gene in the adult. To elucidate the molecular mechanism underlying the persistent expression of the gamma-globin genes associated with the HPFH mutations, interaction of the mutant promoters with nuclear factors was analyzed. Relevance of the nuclear factor, NFE3, to the gamma-globin regulation was suggested by the affected binding of NFE3 to the altered distal CCAAT boxes with HPFH mutations (-117, -114, 13 bp del).

Determination of G /A +G ratio in beta thalassemia, an indicator of diseases severity

The globin chains were separated by electrophoresis on acrylamide-bis acrylamide gels containing Triton X-100, urea, 2 mercaptoethanol, and acetic acid. The G gamma/ A gamma+ G gamma ratio was determined in 25 cord blood samples and in 46 beta-thalassemic homozygotes among Iranian children. In 25 cord blood samples the mean value for G gamma / ? gamma + G gamma was 0.66. All beta-thalassemia homozygotes had an elevated HbF from 5-80% and the mean value for G gamma / G gamma + A gamma was 0.64 and their G gamma chain level in the peripheral blood was found to be intermediate between the embryonic and adult values. We conclude that HbF and G gamma chain level as well as the severity of the disease is due to Beta-thalassemia variants, but there is a poor correlation between HbF level and G gamma /G gamma + ? gamma ratio, both in cord blood samples and Beta-thalassemia samples