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What is thalassemia?

Elizabeth McPherson, M.D., associate professor of human genetics at the University of Pittsburgh, explains:

hemoglobin
Image: BRYN MAWR COLLEGE
HEMOGLOBIN. A normal molecule has two a globin chains and two b globin chains, each having a heme group with an iron center.

Thalassemia is a genetic disorder in which there is decreased production of one of the globin chains found in hemoglobin. This oxygen-transporting molecule in blood normally contains four globin chains, two alpha (a) and two non-a, each with its own heme group (made of an iron atom bound in protoporphyrin ring). In adults, more than 90 percent have type A1 hemoglobin, containing two a and two beta (b) globin chains. A small amount carry a variant called hemoglobin A2, having two a and two delta (d) chains. Infants are born with a slightly different type called fetal hemoglobin, with two a chains and two gamma (g) chains. If the body fails to produce enough of any one type of globin, a deficiency of hemoglobin can result, causing anemia.

Sometimes the body manufactures abnormal hemoglobin, containing yet another combination of chains. Such abnormal hemoglobins often do not transport oxygen efficiently and may also be unstable. The presence of unstable hemoglobins is extremely harmful; the bone marrow must overwork to make more hemoglobin and the liver and spleen become stressed by the need to remove wastes from the breakdown of the unstable hemoglobin. In the case of sickle cell disease, the problem is the characteristic behavior of abnormal sickle hemoglobin. But thalassemia is different: Instead of abnormal hemoglobin, the main problem is a decreased amount of normal globin.

Thalassemias differ in severity and in the type of globin chain that is deficient. The most common type in the United States is b thalassemia, also known as Mediterranean anemia in its mild form or Cooley's anemia in its severe form. A pair of genes controls the production of the b globin chain.

If a person has total absence or severe defects in both b globin genes, he or she will have no b globin and so no hemoglobin A1. Other hemoglobins such as A2 and fetal hemoglobin that do not contain b chains will be made. After the first few months of life, however, the quantity of these other hemoglobins diminishes.

A person with b thalassemia major, in which both genes are affected, develops severe anemia starting at a few months of age. Because the bone marrow must struggle to make enough hemoglobin, the marrow cavities enlarge, causing deformities especially in the facial bones. In addition, because the spleen is constantly working to remove abnormal blood cells from the circulation, it too enlarges. Patients with b thalassemia major can survive only with the help of frequent blood transfusions. Another danger for people with b thalassemia is an iron overload from the gradual breakdown of the transfused blood. A treatment called chelation is then needed to remove excess iron.

People who have an absence or severe abnormality of only one of their b globin genes have b thalassemia minor. This non-life threatening form of the disease causes only mild anemia and does not generally require treatment. Even so, it is important to diagnose b thalassemia minor (also called thalassemia trait) because iron treatment for affected individuals does not help their anemia and may even be harmful. Also if two people with b thalassemia minor have a child, the child may inherit a defective b globin gene from both parents and be born with b thalassemia major.

Because changes in the b globin gene are common in the Mediterranean area, people whose ancestors came from such areas as Greece or Italy may wish to be screened for thalassemia. Simple inexpensive screening is done by looking at the MCV (cell volume) on a standard blood count. If the cells are small, suggesting b thalassemia minor, further testing can be done to confirm the diagnosis. Also, prenatal diagnosis is available for pregnancies at risk for severe thalassemia.

Disorders of a globin synthesis are little more complicated because there are four genes involved, two on each copy of chromosome 16. Screening for these disorders is also readily available. If a baby is missing all four a globin genes, there will be no fetal hemoglobin to transport oxygen before birth. The fetal heart fails and the baby is usually stillborn, showing a swelling of the entire body called hydrops fetalis. This problem is especially common in Asia. It happens only if both parents have a condition called athal1, in which one chromosome 16 is lacking both copies of the a globin gene. Despite mild anemia, people with athal1 are usually healthy. And because this anemia is not due to iron deficiency, iron therapy is not helpful.

It is also possible to have a change in just one a globin gene. This condition is called athal2 and it causes no recognizable abnormalities, either clinically or on standard blood tests. If a person with athal2 and a partner with athal1 have children, some of the children may inherit changes in three of their a globin genes.

This causes a condition called hemoglobin H disease, which is common in both Asia and the Mediterranean. People with hemoglobin H disease have only moderate anemia, but they produce an abnormal hemoglobin called hemoglobin H containing of four b chains. Due to the breakdown of this abnormal hemoglobin, the spleen enlarges and may have to be removed. Nevertheless, people with hemoglobin H disease enjoy a prolonged survival.

A very rare form of a thalassemia is due to a deletion of a larger area of chromosome 16 including the a globin genes. This causes only mild thalassemia, but because other genes are deleted as well, there are additional problems--such as birth defects and mental retardation--that do not occur in most thalassemias. Another rare congenital anomaly-mental retardation syndrome called ATR-X results from a mutation of a gene on the X chromosome. For unknown reasons, the ATR-X mutation causes mild a thalassemia even though the a globin gene is normal. Unlike other thalassemias, these very rare a thalassemia-mental retardation syndromes do not preferentially affect any specific ethnic groups. If a severe thalassemia or one of the thalassemia-mental retardation syndromes is diagnosed in a family, prenatal diagnosis during pregnancies at risk is advised.

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