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The thalassemias are the commonest monogenic diseases in man. They occur at a high gene frequency throughout the Mediterranean populations, the Middle East, the Indian subcontinent, and Myanmar, and in a line stretching from southern China through Thailand and the Malay peninsula into the island populations of the Pacific. They are also seen commonly in countries in which there has been immigration from these high-frequency populations.

There are two main classes of thalassemias, α and β, in which the α- and β-globin genes are involved, and rarer forms caused by abnormalities of other globin genes. Some extremely rare congenital and acquired thalassemia that have intact globin genes are caused by either mutations of nonglobin genes or factors yet to be elucidated. All thalassemias have in common an imbalanced rate of production of the globin chains of adult hemoglobin, excess α chains in β-thalassemia and excess β chains in α-thalassemia. Several hundred different mutations at the α- and β-globin loci have been defined as the cause of the reduced or absent output of α or β chains. The high frequency and genetic diversity of the thalassemias is related to past or present heterozygote resistance to malaria.

The pathophysiology of the thalassemias can be traced to the deleterious effects of the globin-chain subunits that are produced in excess. In β-thalassemia, excess α chains cause damage to the red cell precursors and red cells and lead to profound anemia. This causes expansion of the ineffective marrow, with severe effects on development, bone formation, and growth. The major cause of morbidity and mortality is the effect of iron deposition in the endocrine organs, liver, and heart, which results from increased intestinal absorption and the effects of blood transfusion. The pathophysiology of the α-thalassemias is different because the excess β chains that result from defective α-chain production form β4 molecules, or hemoglobin H, which is soluble and does not precipitate in the marrow. However, it is unstable and precipitates in older red cells. Hence, the anemia of α-thalassemia is hemolytic rather than dyserythropoietic.

The clinical pictures of α- and β-thalassemia vary widely, and knowledge is gradually being amassed about some of the genetic and environmental factors that modify these phenotypes.

Because the carrier states for the thalassemias can be identified and affected fetuses can be diagnosed by DNA analysis after the ninth to tenth week of gestation, these conditions are widely amenable to prenatal diagnosis. Currently, marrow transplantation is the only way in which they can be cured. Symptomatic management is based on regular blood transfusion, iron chelation therapy, and the judicious use of splenectomy. Experimental approaches to their management include the stimulation of fetal hemoglobin synthesis and attempts at somatic cell gene therapy.

Acronyms and Abbreviations:

AATAAA, the polyadenylation signal site; ATR-16, α-thalassemia chromosome 16-linked mental retardation syndrome; ATR-X, α-thalassemia X-linked mental retardation syndrome; BCL11A...

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