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Beta-thalassemia may also be due to deletion of the entire beta-globin gene cluster or of sequences 5-prime from the beta-globin gene cluster; these sequences are referred to as the locus control region beta LCRB; The disorder is clinically heterogeneous summary by Ottolenghi et al.
Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major transfusion dependent , thalassemia intermedia of intermediate severity , and thalassemia minor asymptomatic, carrier state. The molecular and clinical aspects of the beta-thalassemias were reviewed by Olivieri The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors Weatherall, Clinical details of this disorder have been detailed extensively in numerous monographs and were summarized by Weatherall et al.
Modell et al. Cao and Galanello reviewed the clinical features of the 3 forms of beta-thalassemia. Affected infants with thalassemia major fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and enlargement of the abdomen, caused by splenomegaly, may occur. If an adequate transfusion program is followed, growth and development are normal until age 10 to 11 years. Afterwards, affected individuals are at risk of developing severe complications related to posttransfusional iron overload, depending on their compliance with chelation therapy.
Patients with thalassemia intermedia show a markedly heterogeneous clinical picture. The principal symptoms are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from a hypercoagulable state because of the lipid membrane composition of the abnormal red blood cells particularly in splenectomized patients.
Transfusions are usually not required. Iron overload occurs mainly from increased intestinal absorption of iron caused by ineffective erythropoiesis. Carriers of beta-thalassemia are clinically asymptomatic.
Cao and Galanello also reviewed the hematologic findings in the 3 forms. Patients with thalassemia major have a severe microcytic and hypochromic anemia, associated with increased number of red blood cells and low mean corpuscular volume MCV and mean corpuscular Hb MCH. Peripheral blood smear shows, in addition to microcytosis and hypochromia, anisocytosis, poikilocytosis spiculated tear drop and elongated cells , and nucleated red blood cells i. The number of erythroblasts is related to the degree of anemia and is markedly increased after splenectomy.
Patients with thalassemia intermedia have a moderate anemia and show a markedly heterogeneous hematologic picture, ranging in severity from that of the beta-thalassemia carrier state to that of thalassemia major. However, several environmental or genetic factors may modify this phenotype, leading either to thalassemia intermedia, despite the presence of a single beta-globin gene affected, or to hematologically atypical carrier state.
Some atypical beta-thalassemia heterozygotes have either normal red cell indices or normal HbA2 level, or both, with a completely silent hematologic phenotype. This condition is detected only by the imbalanced alpha-nonalpha globin chain synthesis and is referred to as silent beta-thalassemia Cao and Moi, Wainscoat et al.
Kulozik et al. Camaschella et al. This is a particularly instructive example of gene interaction. To gain insight into the cellular and structural alterations of thalassemic bone, Mahachoklertwattana et al. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Most patients had growth retardation and delayed bone age. Bone mineral density BMD was low especially at the lumbar spine. Serum IGF1 levels were almost always low.
Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization.
In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. The authors concluded that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. They suggested that iron deposits in bone and low circulating IGF1 levels may partly contribute to the above findings. Premawardhena et al. They found that 25 patients were not receiving transfusion, and transfusion was discontinued in an additional 37 patients without deleterious effect.
They proposed that hemoglobin E beta-thalassemia can be managed without transfusion in many patients and that age-related changes in the adaptation to anemia indicate that more cost-effective management approaches should be explored. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P.
A higher frequency was also found in patients who had undergone splenectomy. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation Hartl et al. Arlet et al. Consequently, HSP70 is sequestered in the cytoplasm and GATA1 is no longer protected, resulting in end-stage maturation arrest and apoptosis.
Saiki et al. The procedure involved the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. In Sardinia, Rosatelli et al. In a mouse model for beta-thalassemia, Holding and Monk were able to make the diagnosis in single blastomeres removed from embryos of 4 to 8 cells by PCR amplification.
Monk and Holding demonstrated reproducible amplification of a basepair sequence within the human beta-globin gene from individual human oocytes and the first polar bodies isolated from them. They used restriction enzyme digestion of the amplified DNA to confirm the identity of the fragment.
The authors proposed that analysis of the DNA from the first polar body will facilitate preimplantation diagnosis of sickle cell anemia. Ding et al. Circulating fetal-specific DNA sequences have been detected and constitute a fraction of the total DNA in maternal plasma. The robust discrimination of single-nucleotide differences between circulating DNA species is technically challenging and demanded the adoption of highly sensitive and specific analytical systems.
Fetal genotypes were correctly predicted in all cases studied. An increase in hemoglobin concentration occurred. Hypomethylation of both the gamma-globin and the epsilon-globin gene was shown, as well as an increase in gamma-globin mRNA. Lucarelli et al. The results were analyzed, in particular, in the consecutive patients treated since June The allogeneic marrow came from HLA-identical donors, and the patients all had beta-thalassemia and were less than 16 years old.
They concluded that bone marrow transplantation offered a high probability of complication-free survival, if the recipient did not have hepatomegaly or portal fibrosis.
Gene Therapy Gene therapy for beta-thalassemia is particularly challenging given the requirement for massive hemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected hematopoietic stem cells.
The beta-E-globin allele The abnormally spliced form is noncoding, whereas the correctly spliced mRNA expresses a mutated beta-E-globin with partial instability. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have a human leukocyte antigen HLA -matched, genoidentical donor, and those who do still risk rejection or graft-versus-host disease GVHD; see
BETA THALASSEMIE MAJEURE PDF
Beta-thalassemia may also be due to deletion of the entire beta-globin gene cluster or of sequences 5-prime from the beta-globin gene cluster; these sequences are referred to as the locus control region beta LCRB; The disorder is clinically heterogeneous summary by Ottolenghi et al. Absence of beta globin causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia is divided into thalassemia major transfusion dependent , thalassemia intermedia of intermediate severity , and thalassemia minor asymptomatic, carrier state.
Kelkis Access to the full text of this article requires a subscription. T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients. Molecular Genetic Testing The recommended molecular genetic testing approach for beta-thalassemia is single- gene testing: Once both HBB pathogenic variants have been identified in the couple at risk, prenatal testing and preimplantation genetic diagnosis are possible. Blood Cells Mol Dis. He was the right arm of his mentor Professor Antonio Cao in the program of thalassemia control in Sardinia. He was best known for his leadership role in understanding, diagnosing, preventing, and treating thalassemia.