β-Thalassemias are disorders where the synthesis of β-globin chains is reduced or absent. This is usually caused by point mutations that impact the production of functional mRNA. However, the synthesis of α-globin chains remains normal. The excess α-globin chains cannot form stable tetramers, leading to their precipitation and premature death of cells that were meant to become mature red blood cells (RBC). An increase in α2δ2 (HbA2) and α2γ2 (HbF) also occurs. Each cell only contains two copies of the β-globin gene, one on each chromosome 11. Therefore, individuals with defects in the β-globin gene have either β-thalassemia trait (β-thalassemia minor) if they have one defective gene or β-thalassemia major (Cooley anemia) if both genes are defective. The physical symptoms of β-thalassemias appear several months after birth since the β-globin gene is expressed late in prenatal development. Those with β-thalassemia minor produce some β chains and usually do not require specific treatment. However, infants born with β-thalassemia major appear healthy at birth but develop severe anemia during the first or second year of life due to ineffective erythropoiesis. Skeletal changes resulting from extramedullary hematopoiesis are also observed. These patients need regular blood transfusions, but it should be noted that the cumulative effect of transfusions is iron overload. The use of iron chelation therapy has improved the overall health outcomes. Hematopoietic stem cell transplantation is the only curative option available.

In α-thalassemias, the synthesis of α-globin chains is reduced or absent, primarily due to deletional mutations. Each individual's genome contains four copies of the α-globin gene, two on each chromosome 16, resulting in different levels of α-globin chain deficiencies. If one of the four genes is defective, the individual is known as a "silent" carrier of α-thalassemia, as no physical symptoms of the disease are present. If two α-globin genes are defective, the individual is diagnosed with α-thalassemia trait. If three α-globin genes are defective, the individual experiences hemoglobin H (β4) disease, which is a hemolytic anemia with varying severity. If all four α-globin genes are defective, the individual develops hemoglobin Bart (γ4) disease, resulting in hydrops fetalis and fetal death since α-globin chains are necessary for HbF synthesis. Both α-and β-thalassemias exhibit a heterozygote advantage against malaria.

Chapter Summary: β-thalassemias are characterized by reduced or absent synthesis of β-globin chains, while α-thalassemias involve decreased or absent synthesis of α-globin chains. Defects in the β-globin gene lead to β-thalassemia trait or β-thalassemia major, while defects in the α-globin gene result in silent carriers of α-thalassemia, α-thalassemia trait, hemoglobin H (β4) disease, or hemoglobin Bart (γ4) disease. Treatment for β-thalassemias involves regular blood transfusions and iron chelation therapy, while the only curative option is hematopoietic stem cell transplantation. Both α-and β-thalassemias provide a heterozygote advantage against malaria.
β-Thalassemias: In these disorders, synthesis of β-globin chains is decreased or absent, typically as a result of point mutations that affect the production of functional mRNA. However, α-globin chain synthesis is normal. Excess α-globin chains cannot form stable tetramers and so precipitate, causing the premature death of cells initially destined to become mature RBC. Increase in α2δ2 (HbA2) and α2γ2 (HbF) also occurs. There are only two copies of the β-globin gene in each cell (one on each chromosome 11). Therefore, individuals with β-globin gene defects have either β-thalassemia trait (β-thalassemia minor) if they have only one defective β-globin gene or β-thalassemia major (Cooley anemia) if both genes are defective (Fig. 3.23). Because the β-globin gene is not expressed until late in prenatal development, the physical manifestations of β-thalassemias appear only several months after birth. Those individuals with β-thalassemia minor make some β chains and usually do not require specific treatment. However, those infants born with β-thalassemia major are seemingly healthy at birth but become severely anemic, usually during the first or second year of life, due to ineffective erythropoiesis. Skeletal changes as a result of extramedullary hematopoiesis also are seen. These patients require regular transfusions of blood. [Note: Although this treatment is lifesaving, the cumulative effect of the transfusions is iron overload. Use of iron chelation therapy has improved morbidity and mortality.] The only curative option available is hematopoietic stem cell transplantation.
2.
α-Thalassemias: In these disorders, synthesis of α-globin chains is decreased or absent, typically as a result of deletional mutations. Because each individual’s genome contains four copies of the α-globin gene (two on each chromosome 16), there are several levels of α-globin chain deficiencies (Fig. 3.24). If one of the four genes is defective, the individual is termed a “silent” carrier of α-thalassemia, because no physical manifestations of the disease occur. If two α-globin genes are defective, the individual is designated as having α-thalassemia trait. If three α-globin genes are defective, the individual has hemoglobin H (β4) disease, a hemolytic anemia of variable severity. If all four α-globin genes are defective, hemoglobin Bart (γ4) disease with hydrops fetalis and fetal death results, because α-globin chains are required for the synthesis of HbF. [Note: Heterozygote advantage against malaria is seen in both α-and β-thalassemias.]
V. CHAPTER SUMMARY