Thalassemia is an inherited disorder that affects the production of hemoglobin and causes anemia. Hemoglobin is the substance in red blood cells that enables them to transport oxygen throughout the body. It is composed of a heme molecule and protein molecules called globins. Owing to an inherited genetic trait, lower-than-normal amounts of globins are manufactured in the bone marrow. If the trait is inherited from both parents, a globin may be entirely absent. Thalassemia causes varying degrees of anemia, which can range from insignificant to life threatening. People of Mediterranean, Middle Eastern, African, and Asian descent are at higher risk of carrying the genes for thalassemia.
Hemoglobin molecules are vital for transporting oxygen throughout the body. Hemoglobin and red blood cell production is carried out in the bone marrow, a spongy tissue found within certain bones, such as the hips, skull, and breast bone. The hemoglobin molecule is actually made up of five smaller component molecules: a heme molecule and four protein molecules called globins. Normal hemoglobin molecules contain two pairs of different globin molecules.
Humans have the genes to construct six types of globins, but do not use all six at once. Different globins are produced depending on the stage of development: embryonic, fetal, or adult. During embryonic development, hemoglobin contains two zeta-globin molecules and two epsilon-globin molecules. At the fetal stage, the body switches to alpha-globin and gamma-globin production. Within weeks after birth, an infant continues to produce alpha-globin, but gamma-globin is replaced by beta-globin and a very minor amount of delta-globin. After the first two to three months of life, most hemoglobin in the body is composed of two alpha-globins and two beta-globins; approximately 0.5% is composed of two alpha-globins and two delta-globins.
There is a different gene for each type of globin, with the exception of alpha-globin, which has two genes. (Genes are inherited in pairs, one copy from each parent.) A gene mutation may lead to inadequate levels of the related globin, reduced hemoglobin formation, and anemia. Such mutations are the underlying cause of thalassemia.
Thalassemia is classified according to the globin that is affected. The most common types of thalassemia are beta-thalassemia and alpha-thalassemia. Beta-thalassemia is caused by a mutation in the gene responsible for beta-globin. If a mutated beta-globin gene is inherited from both parents, the result is beta-thalassemia major, a severe, potentially life-threatening anemia. Beta-thalassemia major may also be referred to as Cooley's anemia or erythroblastic anemia. If only one mutated copy of the beta-globin gene is inherited, mild-to-nonexistent symptoms may appear; this condition is called beta-thalassemia minor. A person with one mutated copy of the beta-globin gene is referred to as a carrier of the beta-thalassemia trait.
The alpha-thalassemias are more complex because a person inherits two alpha-globin genes from each parent, yielding a total of two pairs of alpha-globin genes. Mutations in these genes can give rise to a range of symptoms. As long as adequate levels of alpha-globins are produced, the person--called the carrier of the alpha-thalassemia trait--will have few, if any symptoms. In cases in which alpha-globin is severely reduced, or not produced at all, the consequences can be fatal during fetal development or shortly after birth.
People with Mediterranean (including North African), Middle Eastern, or Southeast Asian ancestry are at higher risk of being carriers of or developing beta-thalassemia than are other populations. Alpha-thalassemia also is more likely to affect people of Mediterranean, African, Middle Eastern, and Southeast Asian descent. In some areas, 1 in 150-200 children are born with thalassemia major. It has been estimated that 2 million people in America carry the thalassemia trait. When two carriers of the same type thalassemia produce a child, there is a 25% possibility that the child will inherit moderate or severe thalassemia.
Thalassemia arises from mutations in one or more globin genes, leading to a reduction or absence of the associated globin. The severity of symptoms is directly related to whether one or both genes in a pair is mutated. However, symptoms may be modified by other genetic or environmental factors.
The inheritance of one mutated beta-globin gene is accompanied by few, if any symptoms. A person may have mild anemia, but may not even be aware of being a carrier unless tested. Anemia may only appear during pregnancy or following severe infections.
An inheritance of two mutated beta-globin genes causes a potential cascade of symptoms. Some individuals develop mild symptoms that do not require treatment, but others experience life-threatening anemia and complications. At the earliest, symptoms appear several weeks after birth; that is, when fetal gamma-globin production gives way to beta-globin production. Alpha-globin is produced normally and, relative to beta-globin, it is over-produced. This excess alpha-globin precipitates in the immature red blood cells, destroying them.
Similar to beta-thalassemia, if enough alpha-globin is being produced, symptoms may be nonexistent. If the alpha-globin levels are low enough to produce symptoms, onset may begin early in life as alpha-globin production starts during the fetal stage.
Thalassemia may be diagnosed from the symptoms; however, with proper medical treatment, a diagnosis may be made before symptoms become life- or health-threatening. Basic information that is used in diagnosis includes race and ethnic background, family history, and age. Unexpectedly slow development, along with pallor, jaundice, enlarged spleen or liver, or deformed bones can be common signs of thalassemia. Laboratory blood tests are used to confirm a diagnosis and determine the type of thalassemia. These tests can also be used to identify carriers.
Thalassemia cannot be cured; therapy focuses on managing symptoms. Treatment is not necessary for individuals who are unaffected or only develop mild symptoms. The mainstays of thalassemia management are blood transfusions and iron chelation therapy. Blood transfusions are typically given every 6-8 weeks, but may be more frequent in some cases. These transfusions have two purposes: to keep hemoglobin at or near normal levels and to prevent the bone marrow from producing ineffective red blood cells. Thalassemia has been treated with bone marrow transplantation. However, bone marrow transplants are strictly limited by several factors, including the general health of the marrow recipient and whether a donor with compatible marrow can be found.
An individual's outlook depends on the exact type of thalassemia and the associated genes. In the carrier state, a person may never develop symptoms. Other carriers develop mild anemia at times of extreme stress, such as pregnancy or illness. Some forms of alpha-thalassemia, in which alpha-globin is severely reduced or absent, are nearly always fatal. Affected fetuses often die during weeks 34-40 of a pregnancy; some infants are born alive, but die within hours of birth.
Once the genes that determine thalassemia are inherited, the disease cannot be prevented. Screening offers the opportunity of identifying thalassemia carriers. Carriers may decide to undergo genetic counseling to assess potential risks to their children. Finally, prenatal testing, usually chorionic villus sampling or amniotic fluid testing, allows identification of thalassemia in unborn children.
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