Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The ... Beta-thalassemia is characterized by a reduced production of hemoglobin A (HbA, alpha-2/beta-2), which results from the reduced synthesis of beta-globin chains relative to alpha-globin chains, thus causing an imbalance in globin chain production and hence abnormal erythropoiesis. The disorder is clinically heterogeneous (summary by Ottolenghi et al., 1975). 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 (1999). 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, 2001).
By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, Old et al. (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses at risk ... - Prenatal Diagnosis By means of a simplified method for trophoblast biopsy together with restriction endonuclease analysis of fetal DNA, Old et al. (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses at risk for hemoglobinopathy: 2 at risk for homozygous beta-thalassemia and 1 at risk for sickle cell anemia. Saiki et al. (1988) devised a simple and rapid nonradioactive method for detecting genetic variation and applied it to the diagnosis of sickle cell anemia and beta-thalassemia. 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. (1985) used the synthetic oligonucleotide method for prenatal detection of the beta-zero-39 (nonsense) mutation type of beta-thalassemia. In a mouse model for beta-thalassemia, Holding and Monk (1989) were able to make the diagnosis in single blastomeres removed from embryos of 4 to 8 cells by PCR amplification. Monk and Holding (1990) demonstrated reproducible amplification of a 680-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. (2004) described a method for noninvasive prenatal diagnosis by analysis of circulating nucleic acids. 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. Ding et al. (2004) developed a method based on single-allele base extension reaction and mass spectrometry which allowed for the reliable detection of fetal-specific alleles, including point mutations and SNPs, in maternal plasma. The approach was applied to exclude the fetal inheritance of the 4 most common Southeast Asian beta-thalassemia mutations in at-risk pregnancies between weeks 7 and 21 of gestation: 41/42delCTTT (141900.0326), IVS2 654C-T (141900.0368), -28A-G (141900.0381), and 17A-T (141900.0311). Fetal genotypes were correctly predicted in all cases studied. Fetal haplotype analysis based on a SNP linked to the HBB gene in maternal plasma also was achieved.
Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and ... Patients with thalassemia major present in the first year of life with severe anemia; they are unable to maintain a hemoglobin level about 5 gm/dl. Clinical details of this disorder have been detailed extensively in numerous monographs and were summarized by Weatherall et al. (1995). Modell et al. (2000) found that about 50% of UK patients with beta-thalassemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. Cao and Galanello (2010) 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 (2010) 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.e., erythroblasts). 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. The characteristic hematologic features in carriers are microcytosis (reduced red blood cell volume), hypochromia (reduced red blood cell Hb content), increased HbA2 level (the minor component of the adult Hb, alpha2delta2), and unbalanced alpha/nonalpha globin chain synthesis. 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, 2000). Wainscoat et al. (1983) showed that coinheritance of alpha-thalassemia with homozygous beta-thalassemia resulted in amelioration of the beta-thalassemia. Kulozik et al. (1987) showed that heterozygous beta-thalassemia was associated with unusually severe clinical manifestations when coinherited with an extra alpha-globin gene; in each of 5 cases 1 chromosome 16 carried 3 alpha-globin genes. Camaschella et al. (1987) found the same aggravation of the clinical picture with triplicated alpha locus. This is a particularly instructive example of gene interaction. To gain insight into the cellular and structural alterations of thalassemic bone, Mahachoklertwattana et al. (2003) studied bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease. 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 (147440) 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. (2005) studied 109 Sri Lankan hemoglobin E beta-thalassemia patients over 5 years. They found that 25 patients were not receiving transfusion, and transfusion was discontinued in an additional 37 patients without deleterious effect. Premawardhena et al. (2005) identified several genetic and environmental factors that may contribute to the phenotypic diversity of the disorder, including modifiers of hemoglobin F (see 142250) production, malaria (see 611162), and age-related changes in adaptive function. 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. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by Plasmodium falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria.
For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see 141900.
Uda et al. (2008) found that the C allele of dbSNP rs11886868 in the BCL11A gene (606557) was ... For a review of mutations in the HBB gene and the beta-globin gene cluster causing beta-thalassemia, see 141900. Uda et al. (2008) found that the C allele of dbSNP rs11886868 in the BCL11A gene (606557) was associated with an ameliorated phenotype in patients with beta-thalassemia due to increased production of fetal hemoglobin.
Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of ... Beta-thalassemia is one of the most common autosomal recessive disorders worldwide. It is highly prevalent in populations in the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East. It is also relatively common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia (Cao and Galanello, 2010). In Lebanon, beta-thalassemia is the predominant genetic defect. Makhoul et al. (2005) investigated the religious and geographic distribution of beta-thalassemia mutations in Lebanon and traced their origins. Sunni Muslims had the highest beta-thalassemia carrier rate and presented the greatest heterogeneity, with 16 different mutations. Shiite Muslims followed closely with 13 mutations, whereas Maronites represented 11.9% of all beta-thalassemic subjects and carried 7 different mutations. RFLP haplotype analysis showed that the observed genetic diversity originated from both new mutational events and gene flow from population migration. The estimated number of worldwide annual births of patients with beta-thalassemia major is 22,989; for beta-E-thalassemia, 19,128; and for S-beta thalassemia, 11,074 (Modell and Darlison, 2008 and Weatherall, 2010).