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The thalassemia syndromes are the commonest monogenic diseases in humans; they result from mutations in the genes regulating globin expression. The 2 main classes of thalassemia, α and β, involve the α-globin and β-globin genes; rarer forms are caused by abnormalities of the other globin genes, γ and δ, which are expressed in smaller amounts in adults. Thalassemia is found predominantly in populations originating around the Mediterranean, through the Middle East, the Indian subcontinent, and throughout Southeast Asia, including Myanmar, Thailand, Cambodia, Laos, Vietnam, the Malay peninsula, and extending to southern China and the Pacific islands, areas historically endemic for falciparum malaria. With migration, patients with thalassemia syndromes now live all over the world, including Europe and the Americas. The high frequency and genetic diversity of thalassemia is related to past or present heterozygote resistance to malaria.

Normal hemoglobin A is a heterodimer of α-globin and β-globin chains. The common theme in α-thalassemia and β-thalassemia is the decreased production of α-globin and β-globin chains, respectively, resulting in imbalanced globin and hemoglobin production, and anemia. Hundreds of mutations at the α-globin and β-globin loci have been defined as the cause of the reduced or absent synthesis of α-globin or β-globin chains. Rarer forms of thalassemia include γ-thalassemia, δ-thalassemia, or combinations, such as γδ-thalassemia or γδβ-thalassemia that are associated with hereditary persistence of fetal hemoglobin. Other rare forms of thalassemia, εγδβ, lead to absent production of ε-globin, γ-globin, δ-globin, and β-globin chains, and are lethal in the homozygous condition.

Throughout human development, production of the α-like and β-like globin chains are balanced, such that β-thalassemia will lead to excess α-globin chains and α-thalassemia, to excess β-globin chains. The pathophysiology and clinical manifestations of thalassemia result from the effects of this chain imbalance between the globin chain subunits. In β-thalassemia, excess α-globin chains cause damage to intramedullary red cell precursors and red cells, leading to apoptosis, impaired red cell production, and anemia. This signature ineffective erythropoiesis leads to marrow expansion and extramedullary hematopoiesis, which causes many of the manifestations of the disease when not treated optimally. Complications of treatment and inadequate treatment lead to significant morbidity and mortality. Iron overload results from increased intestinal iron absorption relating to ineffective erythropoiesis, and from transfusional loading; they account for the majority of complications in transfused thalassemia patients, whereas extramedullary hematopoiesis and iron toxicity account for the major manifestations in nontransfused or undertransfused patients. α-Thalassemia leads to an excess of β-globin chains that form β4 molecules (β tetramers or hemoglobin H), which is soluble and does not precipitate in the precursors in the marrow, but hemoglobin H is unstable and precipitates in circulating red cells. Hence, the anemia of α-thalassemia tends to be more hemolytic rather than dyserythropoietic.

The clinical presentation and course of α-thalassemia and β-thalassemia vary widely based on the causative mutations, coinherited genetic variants, and other disease modifying factors, such as access to treatment, and therapy-related complications, including iron overload, infections, and ...

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