The thalassemias are a group of inherited globinopathies primarily affecting Mediterranean, Middle Eastern and Southeast Asian populations. Multiple mutations are responsible for the different subtypes. The severity of the blood disorder varies widely with the particular mutation or number of mutations. With few exceptions, prognosis is generally good.
The term "thalassemia" covers a range of genetic disorders resulting from mutations during hemoglobin synthesis, specifically during synthesis of the globin portion. Hemoglobin is the molecule in red blood cells responsible for carrying oxygen and carbon dioxide to and from the lungs. Mutations in its structure affect hemoglobin's ability to perform its function.
Normal adult hemoglobin's structure consists of a heme group, a globin molecule and an iron atom in the center. The globin molecule contains two alpha chains and two beta chains. Fetal hemoglobin has two alpha chains and two gamma chains. The two major subgroups of thalassemias are alpha and beta, and determined by which structural chain is affected.
The clinical manifestations of alpha-thalassemia is related to the excess production of beta-globin. The severity is related to how many of four possible alpha-globin loci are deleted from the relevant gene. In the least severe form, only one locus is deleted, and this results in an asymptomatic carrier state. The patient is capable of passing on the deficient gene to offspring, but will not himself be affected. Where two loci are lost, a mild hemolytic (cell-destroying) anemia results. Patients lacking three loci have a worse condition where alpha-chain production is only one-quarter to one-third of the norm. The excess beta-globin forms tetramers, or Hb H. Hb H is soluble but unstable; in older cells, Hb H damages and destroys the cell.
Where there is no alpha-globin synthesis, a condition called hydrops fetalis results. All that is successfully formed is the gamma chain of fetal hemoglobin, which is incapable of carrying oxygen by itself. This is a fatal condition; the patient dies in utero.
Similar to alpha-thalassemia, the manifestations of beta-thalassemia are derived from the effects of excess alpha-globin synthesis. Alpha-globin is more destructive than beta-globin, resulting in destruction of red blood cells and their precursor cells. The body's response to the resulting anemia is to expand the bone marrow, the factories producing red blood cells, in an attempt to keep up with the body's need for oxygen-carrying bodies. More factories should mean more cells, but the cells produced are just as ineffective as before. The bone marrow expansion results in disruptions in growth and development. Other symptoms resulting from the anemia include hepatosplenomegaly, which is enlargement of the liver and spleen, as well as leg ulcers and high-output cardiac failure.
To date, there are at least 17 known mutations underlying beta-thalassemia. The two main varieties of beta-thalassemia are beta-thalassemia major and intermedia. Patients with the major variant inevitably require transfusions for survival. The intermedia variant is milder and does not require transfusion. The two asymptomatic states are called beta-thalassemia minor and trait, and reflect the heterogeneity of the patient's genes.
Genetic testing is available in utero after the ninth or 10th gestational week. In children, beta-thalassemia major is easily recognized by the hepatosplenomegaly, anemia, and elevated levels of alternative hemoglobins. Certain findings on blood smear can also be diagnostic. Currently, the only cure available for thalassemia is bone marrow transplant.
Prognosis is generally good with the exception of hydrops fetalis and beta-thalassemia major. As described above, hydrops fetalis results in death in utero; beta-thalassemia major requires substantial transfusion support as well as splenectomy (removal of the spleen). Complications can be avoided by avoiding oxidative drugs and substances, including antimalarials, sulfonamides, and fava beans. In patients receiving transplants, iron overload must be avoided also; iron chelation therapy is often conjoined with transfusion therapy. A major setback to progress is poor compliance or unavailability of treatment.
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