Thalassemia

I

Introduction

Thalassemia, inherited blood disease resulting from defective production of hemoglobin, the protein that transports oxygen in the blood. People with thalassemia typically develop anemia, a condition that results in inadequate delivery of oxygen to the body’s tissues, which can produce symptoms ranging from fatigue to organ damage. Two main types of thalassemia exist, alpha thalassemia and beta thalassemia. While the severity of these two thalassemia types varies, in general, alpha thalassemia is less severe. Patients living with this form of the disease usually have mild to moderate symptoms, which are often manageable without treatment. Beta thalassemia, on the other hand, is generally much more severe. Untreated, it is usually fatal in the first few years of life.

More common worldwide than beta thalassemia, alpha thalassemia occurs throughout Southeast Asia and China and sometimes among people of Mediterranean descent. Beta thalassemia primarily affects people of Mediterranean or Middle Eastern descent. Approximately 100,000 babies are born with thalassemia worldwide each year, according to the March of Dimes, an organization devoted to the prevention of birth defects.

II

Cause

Produced in red blood cells, hemoglobin is a protein made up of four chains of amino acids: two identical alpha chains and two identical beta chains. Thalassemia is caused by an imbalance in the production of alpha and beta chains, an imbalance that is caused by a mutation, or change, in the genes that direct their production. A mutation to the alpha genes decreases the production of alpha chains, resulting in alpha thalassemia. A mutation to the beta genes decreases the production of beta chains, resulting in beta thalassemia.

Many different mutations cause thalassemia, but all the mutations can be divided into two main groups. Some mutations affect the structure of alpha or beta chains, while others affect the rate at which the chains are produced. The severity of disease in any thalassemia patient depends on the degree of imbalance between alpha and beta chain production. In general, mutations that affect the structure of the chains result in more severe disease than mutations that affect the rate at which the chains are produced.

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Thalassemia is an autosomal recessive genetic disorder. Each person has two copies of the beta gene, one inherited from each parent. Beta thalassemia results when both copies of the beta gene are abnormal. A person with only one abnormal copy of the beta gene does not develop the disease but is a carrier of beta thalassemia. When two carriers of beta thalassemia have children, each child has a 25 percent chance of inheriting two abnormal copies of the beta gene and, therefore, developing the disease. Each child has a 50 percent chance of inheriting one abnormal gene and being a carrier, and a 25 percent chance of inheriting two normal beta genes.

The inheritance of alpha thalassemia is more complicated because each person normally has four copies of the alpha gene, two inherited from each parent. People with one or two abnormal alpha genes are carriers and do not develop the disease. Children who inherit three abnormal alpha genes have a form of alpha thalassemia that makes them anemic but typically does not shorten their life span. Those who inherit four abnormal alpha genes have a severe form of alpha thalassemia that results in death in the womb or within the first few hours of life.

Carriers of thalassemia typically do not have symptoms of thalassemia and do not require treatment. In fact, carriers of thalassemia are partially resistant to malaria, a serious and often fatal parasitic disease that is prevalent in tropical and subtropical regions of the world. In some areas where malaria is common, up to 20 percent of people are thalassemia carriers. Scientists believe that the thalassemia genes have become widespread in these areas because of the advantage these genes confer on carriers.

III

Symptoms

An imbalance in alpha and beta chain production has several consequences for red blood cells. The amount of normal hemoglobin in a thalassemia patient’s red cells is reduced, so less oxygen is carried to the tissues. In addition, the chain that is produced in normal quantities forms insoluble clumps inside red cells. These clumps damage the cells, which are rapidly removed from the bloodstream, resulting in anemia.

An infant born with beta thalassemia initially appears normal, but within a few months the baby becomes anemic and develops symptoms including poor growth, irritability, fatigue, and sometimes jaundice, a yellow discoloration of the skin that results from excess destruction of red cells. As the child’s body attempts to correct the anemia, production of red blood cells increases in the bone marrow—a spongy tissue in the center of bones that is the site of blood cell formation. But these new red cells are destroyed almost as quickly as they are produced because they too are abnormal. Eventually, the bone marrow expands, causing bones to become thin and weak, and the child suffers repeated fractures. The expansion of the marrow also changes the shape of the bones, stunting the child’s growth and distorting the shape of the head and face. The liver and spleen become greatly enlarged because red cell production also occurs in these organs. In addition, for reasons scientists do not understand, children with thalassemia are prone to infections. If untreated, beta thalassemia is usually fatal within a few years. The lack of oxygen gradually damages various organs in the body, and most patients die of heart failure.

In alpha thalassemia, relatively few insoluble clumps of beta chains form, and red cells are not destroyed as rapidly as in beta thalassemia. Patients with alpha thalassemia usually have mild to moderate anemia and may develop an enlarged spleen. However, they do not usually suffer from bone abnormalities or growth retardation, and most patients survive to adulthood. In many cases, no treatment is necessary.

IV

Diagnosis

Symptoms such as poor growth and enlargement of the liver and spleen may suggest that a child has thalassemia. To establish a firm diagnosis, a physician usually takes a careful family medical history and performs several types of blood tests. A blood count, a test that measures the number of each type of cell in the blood, identifies the low number of red cells characteristic of anemia. A technique known as electrophoresis measures the different types of hemoglobin in a patient’s blood, usually enabling doctors to distinguish between normal individuals, carriers, and people with thalassemia. Using the electrophoresis method to test a child’s parents and establish that they are both carriers helps confirm the diagnosis. Recently, scientists have developed technologies to pinpoint which of the hundreds of known thalassemia mutations an individual patient has. This may allow doctors to predict the severity of the patient’s disease.

In the past, the only ways to reduce the incidence of beta thalassemia were programs to screen prospective parents, identify thalassemia carriers, and counsel people about the risk of having children with the disease. Today prenatal diagnosis of thalassemia through procedures such as amniocentesis and chorionic villus sampling is available in many medical centers, and some couples may choose to abort severely affected fetuses.

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