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Thalassemia

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Thalassemia Classifications

Alpha thalassemia is due to a deletion or mutation in one or more of the four alpha globin gene copies. The more genes affected, the less alpha globin produced. The four different types of alpha thalassemia include:

  • Silent Carrier State (1 affected gene). The silent carrier will have normal hemoglobin levels and red cell indices but can pass on the affected gene to their offspring. Often, these individuals are identified only after having a child with Hb H disease or alpha thalassemia trait (see below). The only way to diagnose this condition is by DNA analysis (see next page).
  • Alpha Thalassemia Trait (2 affected genes). People who have alpha thalassemia trait have red blood cells that are microcytic, hypochromic, have a decreased MCV, and have a mild chronic anemia, but they do not generally experience any other symptoms. This is an anemia that does not respond to iron supplements. Diagnosis of alpha thalassemia trait is usually done by exclusion of other causes of microcytic anemia. Confirmatory testing by DNA analysis is available but is not routinely done.
  • Hemoglobin H Disease (3 affected genes). With this condition, the large decrease in the amount of alpha globin chains produced causes an excess of beta chains, which then aggregate into beta tetramers (groups of 4 beta chains), known as Hemoglobin H. Hb H disease can cause moderate to severe anemia and an enlarged spleen. The clinical picture associated with Hb H disease is extremely variable. Some individuals are asymptomatic while others have severe anemia. Hemoglobin H disease is found most often in individuals of Southeast Asian or Mediterranean descent.
  • Alpha Thalassemia Major (also called hydrops fetalis, 4 affected genes). This is the most severe form of alpha thalassemia. In this condition, no alpha globin is produced, therefore, no Hb A or Hb F are produced. Fetuses affected by alpha thalassemia major become anemic early in pregnancy. They become hydropic and frequently have enlarged hearts and livers. This diagnosis is frequently made in the last months of pregnancy when a fetal ultrasound indicates a hydropic fetus. About 80% of the time, the mother will have toxemia and can develop severe postpartum bleeding (hemorrhage). Fetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth.

Alpha thalassemia is found most commonly in individuals with an ethnic background of Southeast Asia, Southern China, the Middle East, India, Africa and the Mediterranean.

Beta thalassemia is due to mutations in one or both of the beta globin genes. There are 100 to 200 mutations that have been identified, but only about 20 are common. The severity of the anemia caused by beta thalassemia depends on which mutations are present and on whether there is decreased beta globin production (called beta+ thalassemia) or if production is completely absent (called beta0 thalassemia). The different types of beta thalassemia include:

  • Beta Thalassemia Trait. A person with this condition has one normal gene and one with a mutation. They will usually experience no health problems other than microcytosis and a possible mild anemia that will not respond to iron supplements. This gene mutation can be passed on to an individual’s children.
  • Thalassemia Intermedia. In this condition, an affected person has two abnormal genes but is still producing some beta globin. The severity of the anemia and health problems experienced depends on the mutations present. The dividing line between thalassemia intermedia and thalassemia major is the degree of anemia and the number and frequency of blood transfusions required. Those with thalassemia intermedia may need occasional transfusions but do not require them on a regular basis.
  • Thalassemia Major (also called Cooley's Anemia). This is the most severe form of beta thalassemia. The person has two abnormal genes that cause either a severe decrease or complete lack of beta globin production, preventing the production of significant amounts of Hb A. This condition usually appears in an infant after three months of age and causes life-threatening anemia. This anemia requires lifelong regular blood transfusions and considerable ongoing medical care. Over time, these frequent transfusions lead to excessive amounts of iron in the body. Left untreated, this excess iron can deposit in the liver, heart and other organs and can lead to a premature death from organ failure.

Other forms of thalassemia occur when a gene for beta thalassemia is inherited in combination with a gene for a hemoglobin variant. The most important of these are:

  • Hb E – beta thalassemia. Hb E is one of the most common hemoglobin variants, found predominantly in people of Southeast Asian descent. If a person inherits one Hb E gene and one beta thalassemia gene, the combination produces Hb E-beta thalassemia, which causes a moderately severe anemia similar to beta thalassemia intermedia.
  • Hb S – beta thalassemia or sickle cell – beta thalassemia. Hb S is one of the most well known of the hemoglobin variants. Inheritance of one Hb S gene and one beta thalassemia gene results in Hb S-beta thalassemia. The severity of the condition depends on the amount of beta globin produced by the beta gene. If no beta globin is produced, the clinical picture is almost identical to sickle cell disease. The American College of Medical Genetics advises screening all newborns for hemoglobin S/beta-thalassemia as well as sickle cell anemia. 

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