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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemoglobin H disease usually occurs as a result of inheritance of the genes for alpha thalassemia; however, occasionally patients acquire hemoglobin H in association with hematologic malignancy. This report concerns a 63-year-old Filipino man with a myeloproliferative syndrome with marked thrombocytosis and apparently acquired hemoglobulin H disease. The patient had hemolytic anemia, dimorphic red blood cells (RBC) and abundant ringed sideroblasts in the marrow. The peripheral blood contained 27% hemoglobin H and about two-thirds of his RBC had hemoglobin H inclusion bodies. There was no previous history of anemia or evidence of thalassemia in two siblings or nine adult children of the patient. In vitro studies of globin chain synthesis documented markedly decreased production of alpha globin with alpha/beta biosynthetic ratios of 0.05 in peripheral blood reticulocytes and 0.10 in bone marrow cells. The relative concentration of mRNA for alpha globin was approximately 20-fold less than that of beta globin, apparently accounting for the deficiency in alpha globin synthesis.
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PMID:Myeloproliferative syndrome with sideroblastic anemia and acquired hemoglobin H disease. 735 Oct 8

The thalassemias are a heterogeneous group of disorders characterized by accumulation either of unmatched alpha or beta globin chains. These in turn cause the intramedullary and peripheral hemolysis that leads to varying anemia. A partial explanation for the hemolysis came our of our studies on material properties that showed that beta-thalassemia (beta-thal) intermedia ghosts were very rigid but unstable. A clue to this instability came from the observation that the spectrin/band 3 ratio was low in red blood cells (RBCs) of splenectomized beta-thal intermedia patients. The possible explanations for the apparent decrease in spectrin content included deficient or defective spectrin synthesis in thalassemic erythroid precursors or globin chain-induced membrane changes that lead to spectrin dissociation from the membrane during ghost preparation. To explore the latter alternative, samples from different thalassemic variants were obtained, ie, beta-thal intermedia, HbE/beta-thal, HbH (alpha-thal-1/alpha-thal-2), HbH/Constant Spring (CS), and homozygous HbCS/CS. We searched for the presence of spectrin in the first lysate of the standard ghost preparation. Normal individuals and patients with autoimmune hemolytic anemia, sickle cell anemia, and anemia due to chemotherapy served as controls. Using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, no spectrin was detected in identical aliquots of the supernatants of normals and these control samples. Varying amounts of spectrin were detected in the first lysate supernatants of almost all thalassemic patients. The identification of spectrin was confirmed by Western blotting using an affinity-purified, monospecific, rabbit polyclonal antispectrin antibody. Relative amounts of spectrin detected were as follows in decreasing order: splenectomized beta-thal intermedia including HbE/beta-thal; HbCS/CS; nonsplenectomized beta-thal intermedia, HbH/CS; and, lastly, HbH. These findings were generally confirmed when we used an enzyme-linked immunosorbent assay technique to measure spectrin in the first lysate. Subsequent analyses showed that small amounts of actin and band 4.1 also appeared in lysates of thalassemic RBCs. Therefore, the three major membrane skeletal proteins are, to a varying degree, unstably attached in severe thalassemia. From these studies we could postulate that membrane association of abnormal or partially oxidized alpha-globin chains has a more deleterious effect on the membrane skeleton than do beta-globin chains.
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PMID:The instability of the membrane skeleton in thalassemic red blood cells. 757 65

A kindred with hereditary spherocytosis and beta-thalassaemia trait was identified. Detailed studies of the red cell membrane proteins on polyacrylamide gels with sodium dodecyl sulphate (SDS-PAGE) demonstrated the presence of band 3 (anion transporter) deficiency in all HS subjects (20-25% reduction) whereas spectrin content was in the normal range. The molecular defect of beta thalassaemia in this kindred was due to a beta(0) codon 39 (C-T) mutation, as assessed by beta globin gene amplification and ASO-probe hybridization. Seven subjects of this family were studied: two were normal, two had HS alone, two co-inherited HS and beta-thalassaemia trait, and one had beta-thalassaemia trait only. The two subjects with HS alone had a typical clinical form of spherocytosis with anaemia, reticulocytosis and increased red cell osmotic fragility. The two with both HS and beta-thalassaemia trait were not anaemic and showed a small, well-compensated haemolysis. Hence the finding of red cells with abnormalities of both HS and beta-thalassaemia indicates that beta-thalassaemic trait 'silences' HS caused by band 3 deficiency.
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PMID:Coexistence of hereditary spherocytosis (HS) due to band 3 deficiency and beta-thalassaemia trait: partial correction of HS phenotype. 813 78

A 38-year-old Swedish woman was investigated because of mild anaemia resistant to iron therapy. Mild haemolytic disease was found by routine blood tests. Neither HPLC (HbA1c quantification) nor Hb-electrofocusing revealed any major abnormal fraction, although in vitro testing of haemoglobin instability indicated the presence of unstable haemoglobin. PCR was used to amplify coding regions of the beta globin gene. Direct nucleotide sequencing of this material revealed heterozygosity for a substitution corresponding to the haemoglobin variant alpha 2 beta 2 135(H13)Ala-->Pro. This clearly unstable variant, named Hb Altdorf, has earlier been described only in a family of Italian descent. Examination of beta globin genes from six family members of the proposita by PCR followed by specific cleavage with the restriction enzyme Ban I, revealed the mutation in her two children but not in her parents or siblings. This case demonstrates that haemoglobin variants can not be ruled out as a cause of haematological disease even if the parents lack symptoms and standard tests, such as HPLC and electrophoresis/electrofocusing, do not reveal major abnormalities.
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PMID:Unstable haemoglobin causing haemolytic anaemia: de novo mutation in Sweden identified by PCR. 845 Mar 1

Sickle cell anaemia is a hereditary disorder commonly seen in the black population, due to a point mutation in the beta globin gene. The sickle mutation is responsible for an increased rigidity and adherence of the red blood cell leading to haemolytic anaemia and vaso-occlusive episodes. Symptoms include dactylitis, painful crisis, splenic sequestration and the development of multi-organ damage and failure. The progressive loss of splenic function increases the risk of infections. The morbidity and mortality can be reduced by the maintenance of an adequate nutrition, the prevention of infection and the treatment of complications. In some patients severely affected, a chronic transfusion program has to be instigated to maintain a level of haemoglobin S below 50%. New therapeutic strategies include the use of hydroxyurea and maybe, in the future, butyrates to increase the level of foetal haemoglobin. Further studies are needed to evaluate the benefits of such therapies. Bone marrow transplantation represents an attractive therapeutic tool and its role in other haemoglobinopathies like thalassaemia is now well demonstrated. As far as sickle anaemia is concerned, the first report concerned a child with acute myeloblastic leukaemia. The patient is now cured of both the sickle cell anaemia and the leukemia. Since April 1986, 21 patients underwent an allogeneic bone marrow transplantation for sickle cell anaemia in our department. 20 patients became asymptomatic and have an electrophoretic pattern of the haemoglobin similar to that of the donor. One patient died of bone marrow transplantation related complications.
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PMID:Bone marrow transplantation in sickle cell anaemia. 846 26

A 20-year-old Japanese woman was admitted to our hospital with anemia and mild splenomegaly. Peripheral blood examination revealed Hb 9.4 g/dl, Ht 29.3%, RBC 4.74 x 10(6)/microliters, reticulocytes 2.4%, WBC 5,200/microliters, platelets 24.9 x 10(4)/microliters, MCV 61.7 fl, and MCH 19.9 pg. Poikilocytosis with target cells was recognized on the peripheral blood smear. A bone marrow aspirate revealed erythroid hyperplasia. Serum iron and ferritin were in the normal range. beta-thalassemia was suggested by the increase in HbA2 (6.5%) and HbF (7.5%). Analysis of beta globin DNA by single strand conformation polymorphism (SSCP) and amplification refractory mutation system (ARMS) confirmed a diagnosis of homozygous beta(+)-thalassemia due to -31 A to G mutation. A familial study revealed that her parents were heterozygous for this allele. This is the 8th case of homozygous beta(+)-thalassemia due to -31 A to G mutation in Japan.
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PMID:[Homozygous beta(+)-thalassemia due to -31 A to G mutation]. 875 83

Although study of the thalassemias has focussed on possible cure or amelioration by genetic techniques, considerable progress has been made in understanding the underlying pathobiology of these diseases. Better control of childhood infectious diseases has led to a clearer understanding of the frequency and clinical severity of some of these disorders. The striking differences between alpha- and beta-thalassemia are now well documented and the role of oxidant attack in the pathobiology is becoming clearer. Some authors believe that severe beta-thalassemia induces a hypercoagulable state that could be partially caused by scrambling of the phospholipid bilayer of affected erythrocytes. There is growing appreciation that double heterozygosity for hemoglobin E/beta-thalassemia, while causing variable anemia, can produce a clinical condition as severe as Cooley's anemia (beta-thalassemia major). Anemia severity may be related to the extent of oxidant attack on the unstable hemoglobin E. Studies of the hemoglobin Constant Spring variants demonstrate the consequences of accumulating excess unmatched beta globin as well as the unique alpha CS. Studies on marrow erythroid precursors in the beta-thalassemias have already shown accelerated programmed cell death and abnormal assembly of membrane proteins. Such studies in the future will likely further delineate the underlying differences between alpha- and beta-thalassemias.
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PMID:Pathobiology of thalassemic erythrocytes. 910 22

A ribozyme-mediated approach has made it possible to replace the region in beta globin mRNA containing the sickle-cell-anaemia mutation with a gamma-globin-encoding sequence. This is an interesting new way of correcting monogenic disease, but there are major problems to overcome before it could be applied in the clinic.
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PMID:Gene therapy: repairing haemoglobin disorders with ribozymes. 976 57

The most common Hb D variant, Haemoglobin D (Hb D) Los Angeles is caused by a glutamic acid to glutamine substitution at codon 121 of the beta globin gene. Although asymptomatic in the heterozygous form, inheritance together with an Hb S allele can result in a severe disease similar to sickle-cell anaemia that is referred to as Hb SD disease. Prenatal diagnosis for Hb SD disease was requested by an at-risk couple of Irish/English descent. Prenatal diagnosis was performed on DNA isolated from chorionic villi at 12 weeks' gestation using dot blot and allele-specific oligonucleotide hybridization for the HbS mutation, and two independent approaches, restriction fragment analysis and ARMS (amplification refractory mutation system) for the detection of the Hb D Los Angeles mutation. The fetus was found to be heterozygous for the HbS mutation, but did not inherit the HbD mutation. Thus, a reliable and rapid prenatal diagnosis for the Hb SD disease can be achieved by molecular diagnosis.
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PMID:Molecular exclusion of haemoglobin SD disease by prenatal diagnosis. 1007 9

As the defective genes for more and more genetic disorders become unravelled, it is clear that patients with apparently identical genotypes can have many different clinical conditions even in simple monogenic disorders. Beta thalassemia occurs when there is a deficiency in the synthesis of beta globin chains. The clinical manifestations of beta thalassemia are extremely diverse, spanning a broad spectrum from severe anemia and transfusion-dependency to the asymptomatic state of thalassemia trait. The remarkable phenotypic diversity of the beta thalassemias is prototypical of how a wide spectrum of disease severity can be generated in single gene disorders. The most reliable and predictive factor of disease phenotype is the nature of the mutation at the beta globin locus itself. However, relating phenotype to genotype is complicated by the complex interaction of the environment and other genetic factors at the secondary and tertiary levels, some implicated from family studies, and others, as yet unidentified. This article reviews the clinical and hematologic diversity encountered in beta thalassemia with an overview of the modifier genes that moderate their disease expression.
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PMID:Genetic modifiers of beta-thalassemia. 1592 80


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