Alpha thalassemia is caused by a deletion or mutation in one or more of the four alpha globin gene copies. The mutation causes a decrease in the production of alpha globin. The more genes that are affected, the less alpha globin is produced by the body. The four different types of alpha thalassemia are classified according to the number of genes affected and include:
- Silent Carrier State (1 gene affected). People who have mutation(s) in only one alpha globin gene are silent carriers. They usually have normal hemoglobin levels and red cell indices but can pass on the affected gene to their children. These individuals have no signs or symptoms and are usually identified only after having a child with thalassemia. The only way to identify a silent carrier is by DNA analysis (see Thalassemia Tests).
- Alpha Thalassemia Trait (2 genes affected). People who have alpha thalassemia trait have red blood cells (RBCs) that are smaller (microcytic) and paler (hypochromic) than normal, have a decreased MCV (mean corpuscular volume, a measurement of the average size of a single RBC), and have a mild chronic anemia. They generally do not have other signs and sometimes may lack symptoms. This form of anemia 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 genes affected). With this condition, the large decrease in alpha globin chain production causes an excess of beta chains, which then come together into groups of 4 beta chains, known as Hemoglobin H, which is visible inside red blood cells on a specially stained blood smear. Hb H disease can cause moderate to severe anemia and serious health problems such as an enlarged spleen, bone deformities, and fatigue. The signs and symptoms associated with Hb H disease vary widely. Some individuals are asymptomatic while others have severe anemia, requiring regular medical care. Hemoglobin H disease is found most often in individuals of Southeast Asian or Mediterranean descent.
- Alpha Thalassemia Major (also called hydrops fetalis, 4 genes affected). This is the most severe form of alpha thalassemia. In this condition, no alpha globin is produced, therefore, no normal hemoglobin is produced. Fetuses affected by alpha thalassemia major become anemic early during the pregnancy. They retain excess fluids (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. There are also risks for the pregnant mother. About 80% of the time, the mother will have "toxemia" (protein in the urine, high blood pressure, swollen ankles and feet) and can develop severe postpartum bleeding (hemorrhage). Fetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth. In very rare cases, children with alpha thalassemia have survived through in utero blood transfusions and extensive medical care.
Alpha thalassemia is found most commonly in individuals of Southeast Asian, Southern Chinese, Middle Eastern, Indian, African, and Mediterranean descent.
Beta thalassemia is caused by mutations in one or both of the beta globin genes. There have been more than 250 mutations identified, but only about 20 are the most common. The severity of the anemia caused by beta thalassemia depends on which mutations are present and 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 or Beta Thalassemia Minor. Individuals with this condition have one normal gene and one with a mutation, causing a mild decrease in beta globin production. They usually have no health problems other than abnormally small red blood cells and a possible mild anemia that will not respond to iron supplements. An individual's children can inherit this gene.
- Thalassemia Intermedia. In this condition, an affected person has two abnormal genes, causing moderate to severe decrease in beta globin production. These individuals may develop symptoms later than those with thalassemia major (see below) and often with milder symptoms. They rarely require treatment with blood transfusion. The severity of the anemia and health problems experienced depends on the mutation types 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 or Cooley's Anemia. This is the most severe form of beta thalassemia. These individuals have two abnormal genes that cause either a severe decrease or complete lack of beta globin production, preventing the production of significant amounts of normal hemoglobin (Hb A). This condition usually appears within the first two years of life and causes life-threatening anemia, poor growth, and skeletal abnormalities during infancy. 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. Therefore, individuals undergoing transfusion may need chelation therapy to reduce iron overload.
Beta thalassemia is found most commonly in populations of Mediterranean, African, and Southeast Asian descent in the U.S. This is likely associated with the incidence of malaria in those regions since thalassemia can increase malaria tolerance. In those regions, thalassemia incidence may be as high as 10%.
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. It is found predominantly in people of Southeast Asian and African 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 similar to sickle cell disease but with even worse baseline anemia. The American College of Medical Genetics advises screening all newborns for hemoglobin S/beta-thalassemia as well as sickle cell anemia. It is also required in all 50 states.