Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen throughout the body. There are two basic groups of thalassemia disorders: alpha thalassemias and beta thalassemias. These conditions cause varying degrees of anemia, which can range from insignificant to fatal.
Thalassemia is a genetic disorder. It cannot be acquired from contact with other people or from the environment. In all types of thalassemia, the quantity of hemoglobin produced is reduced or absent. This circumstance affects the ability of the blood to carry oxygen to all parts of the body. Although both alpha and beta thalassemias affect hemoglobin, these diseases affect the body in distinctly different ways. Hemoglobin is made up of three components: alpha globin, beta globin, and heme. Thalassemias are classified according to the globin that is deficient.
Individuals inherit from each parent a gene controlling alpha globin production. Two spots (called loci) on these genes control alpha globin production. Alpha thalassemias result from changes (mutations) in these genes. There are two main types of alpha thalassemia disease: hemoglobin H disease and alpha thalassemia major. The two diseases are quite different from beta thalassemia, as well as from one another.
Individuals with hemoglobin H disease have inherited one completely defective gene and one gene that has one rather than two functional loci. This circumstance substantially reduces the amount of alpha globin that the body produces. As a result, individuals with hemoglobin H disease can experience events of hemolytic anemia—anemia caused by the rapid breakdown of the red blood cells. These events are thought to be triggered by various environmental causes, such as infection and/or exposure to certain chemicals. Hemoglobin H disease is milder than alpha thalassemia and usually milder than beta thalassemia.
Individuals with alpha thalassemia major have inherited two completely defective genes, one from each parent. Alpha thalassemia major, sometimes called hemoglobin Barts or hydrops fetalis, is a fatal disease that results in severe anemia that begins even before birth. Most affected babies do not survive to be born or die shortly after birth.
Beta thalassemia, also called Cooley's anemia, is the most well known type of thalassemia. It is caused by a change in the gene for the beta globin component of hemoglobin. Beta thalassemia causes variable anemia that can range from moderate to severe, depending in part on the exact genetic change underlying the disease.
Beta thalassemia major causes severe anemia that usually occurs within three to six months after birth. If left untreated, severe anemia can result in stunted growth and development, as well as other characteristic physical complications that can lead to a dramatically decreased life expectancy. In developed countries, screening in the newborn period usually identifies beta thalassemia before symptoms have developed. Children who are identified early can be started on ongoing blood transfusion therapy as needed.
Beta thalassemia minor describes a disease where only one gene of the pair that control beta hemoglobin production is defective. There are few or mild events. However, the individual can pass the defective gene on to his or her offspring
Beta thalassemia intermedia is a clinical term that describes the disease in individuals who have moderate anemia that only requires blood transfusions intermittently.
The thalassemias are among the most common genetic diseases worldwide. Both alpha and beta thalassemia have been described in individuals of almost every ancestry, but the conditions are more common among certain ethnic groups. Unaffected carriers of all types of thalassemia traits do not experience health problems.
Determining the prevalence for alpha thalassemia is difficult due to limitations in diagnostic testing. In the United States, up to 30 percent of African Americans are thought to be carriers for alpha thalassemia traits, meaning that they show no symptoms of the disorder but can pass the trait to their offspring. Despite this estimate, the number of babies born with hemoglobin H disease or alpha thalassemia major is very low. The highest frequency of alpha thalassemia diseases occurs in individuals of Southeast Asian and Chinese descent. Individuals of Greek, Middle Eastern, and North African descent also carry genes for the disease more frequently than individuals of Northern European descent. One study of 500 pregnant women in northern Thailand estimated a frequency of one in 500 pregnancies affected by alpha thalassemia major, for example. Prevalence of alpha thalassemia disease is significantly lower in the United States owing primarily to immigration patterns. However, at least one state, California, has observed growing hemoglobin H disease rates that are high enough to justify universal newborn screening for the condition.
Beta thalassemia trait is seen most commonly in people with the following ancestry: Mediterranean (including North African, and particularly Italian and Greek), Middle Eastern, Indian, African, Chinese, and Southeast Asian (including Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian). It is difficult to obtain accurate prevalence figures for various types of thalassemia within different populations.
Two studies reflect prevalence figures that can be helpful counseling families and determining who to screen for beta thalassemia. Between the years of 1990 and 1996, the State of California screened over 3.1 million newborns for beta thalassemia. Approximately one in 114,000 infants had beta thalassemia major, with prevalence rates being highest among Asian Indians (about one in 4,000), Southeast Asians (about one in 10,000), and Middle Easterners (about one in 7,000). The pattern observed in California is expected to be different in other areas of the United States and the world. For example, Italians are underrepresented in this population when compared to the population of the East Coast of the United States.
Causes and symptoms
Humans normally make several types of hemoglobin. An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins. All types of hemoglobin are made of three components: heme, alpha globin, and beta globin. All types of thalassemia are caused by changes in either the alpha- or beta-globin gene. These changes cause little or no globin to be produced. All types of thalassemias are recessively inherited, meaning that a genetic change must be inherited from both the mother and the father to produce the disease in the child. The severity of the disease is influenced by the exact thalassemia mutations inherited, as well as other genetic and environmental factors. There are rare exceptions, notably with beta thalassemia, where globin gene mutations exhibit a dominant pattern of inheritance in which only one gene needs to be altered in order to see disease expression.
Most individuals have four normal copies of the alpha globin gene, two copies on each chromosome 16. These genes make the alpha globin component of normal adult hemoglobin, which is called hemoglobin A. Alpha globin is also a component of fetal hemoglobin. Since there are four genes (instead of the usual two) to consider when looking at alpha globin gene inheritance, there are several alpha globin types that are possible.
Absence of one functioning alpha globin gene leads to a condition known as silent alpha thalassemia trait. This condition causes no health problems and can be detected only by special genetic testing. Alpha thalassemia trait occurs when two alpha globin genes are missing or not functioning. There are no associated health problems, although the trait status may be detected by more routine blood screening.
Hemoglobin H disease results from the deletion of three of the four alpha globin genes. Hemoglobin H symptoms can also be a part of a unique condition called alpha thalassemia mental retardation syndrome. This syndrome can be caused by a deletion of a significant amount of chromosome 16, affecting the alpha globin genes. This situation is usually not inherited, but rather occurs sporadically in the affected individual. Affected individuals have mild hemoglobin H disease, mild-to-moderate mental retardation, and characteristic facial features, as well as various other developmental processes that mimic hemoglobin H disease.
Alpha thalassemia major results from the deletion of all four alpha globin genes, such that there are no functioning alpha globin genes. In this situation, there is a 25 percent chance for alpha thalassemia major in each of such a couple's children.
Most individuals have two normal copies of the beta globin gene, which is located on chromosome 11 and makes the beta globin component of normal adult hemoglobin. There are approximately one hundred genetic mutations that have been described that cause beta thalassemia, designated as either beta0 or beta+ mutations. No beta globin is produced with a beta0 mutation, and only a small fraction of the normal amount of beta globin is produced with a beta+ mutation.
When an individual has one normal beta globin gene and one with a beta thalassemia mutation, he or she is said to carry the beta thalassemia trait. Carrying the trait is generally thought not to cause health problems, although some women with beta thalassemia trait may have an increased tendency toward anemia during pregnancy.
When both parents carry the beta thalassemia trait, there is a 25 percent chance that each of their children will inherit beta thalassemia disease by inheriting two beta thalassemia mutations, one from each parent. The clinical severity of the beta thalassemia disease depends largely on whether the mutations inherited are beta0 thalassemia or beta+ thalassemia mutations. Two beta0 mutations generally lead to beta thalassemia major, and two beta+ thalassemia mutations generally lead to beta thalassemia intermedia, a milder form of the disease. Inheritance of one beta0 and one beta+ thalassemia mutation tends to be less predictable.
Hemoglobin H disease
Hemoglobin H disease is a relatively mild form of thalassemia that may go unrecognized. It is not generally considered a condition that will reduce one's life expectancy. Education is an important part of managing the health of an individual with hemoglobin H disease. It is important to be able to recognize the signs of severe anemia that require medical attention. It is also important to be aware of the medications, chemicals, and other exposures to avoid due to the theoretical risk they pose of precipitating a severe anemia event. When severe anemia occurs, it is treated with blood transfusion therapy. For many individuals with hemoglobin H disease, this is rarely required. For those with a more severe form of the disease, the need for transfusions may be intermittent or ongoing, perhaps on a monthly basis, and require desferoxamine treatment. This treatment removes excess iron from the body. Individuals with this more severe form of the disease may also have an increased chance of requiring removal of an enlarged and/or overactive spleen.
Alpha thalassemia major
Because alpha globin is a necessary component of hemoglobin, absence of all functioning alpha globin genes leads to serious medical consequences that begin even before birth. Affected fetuses develop severe anemia as early as the first trimester of pregnancy. The placenta, heart, liver, spleen, and adrenal glands may all become enlarged. Fluid can begin collecting throughout the body as early as the start of the second trimester, causing damage to developing tissues and organs. Growth retardation is also common. Affected fetuses usually miscarry or die shortly after birth. In addition, women carrying affected fetuses are at increased risk of developing complications of pregnancy and delivery. Up to 80 percent of such women develop toxemia, a disturbance of metabolism that can potentially lead to convulsions and coma. Other maternal complications include premature delivery and increased rates of delivery by cesarean section , as well as hemorrhage after delivery.
Beta thalassemia major is characterized by severe anemia that can begin several months after birth. In the United States and other developed countries beta thalassemia is identified and treated early and effectively. Therefore, the following discussion of symptoms applies primarily to affected individuals in the past and in some underdeveloped countries as of the early 2000s. If untreated, beta thalassemia major can lead to severe lethargy, paleness, and growth and developmental delay . The body attempts to compensate by producing more blood, which is made inside the bones in the marrow. However, this effort is ineffective without the needed genetic instructions to make enough functioning hemoglobin. Instead, obvious bone expansion and changes occur that cause characteristic facial and other changes in appearance, as well as increased risk of fractures . Severe anemia taxes other organs in the body such as the heart, spleen, and liver, which must work harder than usual. This stress can lead to heart failure, as well as enlargement and other problems of the liver and spleen. When untreated, beta thalassemia major generally results in childhood death, usually due to heart failure. In developed countries, diagnosis is usually made early, often before symptoms have begun. This factor allows for treatment with blood transfusion therapy, which can prevent most of the complications of the severe anemia caused by beta thalassemia major.
Individuals with beta thalassemia intermedia have a more moderate anemia that may only require treatment with transfusion intermittently, such as when infections stress the body. As a person with beta thalassemia intermedia gets older, however, the need for blood transfusions may increase to the point that they are required on a regular basis. When this occurs the disease becomes more similar to beta thalassemia major. Other genetic and environmental factors can influence the course of the disease as well. For example, co-inheritance of one or two alpha thalassemia mutations can tend to improve some of the symptoms of beta thalassemia disease, which results in part from an imbalance in the amount of alpha- and beta-globin present in the red blood cells.
When to call the doctor
Signs of thalassemia diseases are often noted by the doctor during newborn screening. Parents should contact their doctors if they suspect any developmental delays, especially if the parents belong to one of the ethnic groups at higher risk for the disease.
Diagnosis of thalassemia can occur under various circumstances and at various ages. Several states offer thalassemia screening as part of the usual battery of blood tests done on newborns. This arrangement allows for early identification and treatment. Thalassemia can be identified before birth using prenatal diagnosis. Chorionic villus sampling (CVS) can be done as early as 10 weeks of pregnancy. It involves removing a sample of the placenta and testing the cells. CVS carries a risk of causing a miscarriage that is between 0.5 percent and 1 percent. Amniocentesis is generally done between 15 and 22 weeks of pregnancy but can sometimes be offered earlier. Two to three tablespoons of the fluid surrounding the baby are removed. This fluid contains fetal cells that can be tested. The risk of miscarriage associated with amniocentesis ranges from 0.33 to 0.5 percent.
Pregnant women and couples may choose prenatal testing in order to prepare for the birth of a baby that may have thalassemia. Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination. Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo. Only the embryos unaffected by the disease are transferred back into the uterus.
Thalassemia may be suspected if an individual shows signs that are suggestive of the disease. In all cases, however, laboratory tests are essential to confirm the exact diagnosis and to allow for the provision of accurate genetic counseling about recurrence risks and testing options for parents and affected individuals. Screening is likewise recommended to determine trait status for individuals of high-risk ethnic groups.
The following tests are used to screen for thalassemia disease and/or trait:
- complete blood count
- hemoglobin electrophoresis
- free erythrocyte-protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood cells, and other red blood cell abnormalities that are characteristic of a thalassemia diagnosis. Since thalassemia trait can sometimes be difficult to distinguish from iron deficiency, tests to evaluate iron levels are important.
Hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual. This test uses an electric field applied across a slab of gel-like material. Hemoglobins migrate through this gel at various rates and to specific locations, depending on their size, shape, and electrical charge. Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins. They can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types and quantities of hemoglobin present. Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia. Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that may be co-inherited with a thalassemia trait. Sometimes DNA testing is needed in addition to the above screening tests. This test can be performed to help confirm the diagnosis and establish the exact genetic type of thalassemia.
Because alpha thalassemia major is most often a fatal condition in the prenatal or newborn period, treatment has previously been focused on identifying affected pregnancies in order to provide appropriate management to reduce potential maternal complications. Pregnancy termination provides one form of management. Increased prenatal surveillance and early treatment of maternal complications is an approach that is appropriate for mothers who wish to continue their pregnancy with the knowledge that the baby will most likely not survive. In the last decade of the twentieth century and early 2000s, a handful of infants with this condition have survived long-term. Most of these infants received experimental treatment including transfusions before birth, early delivery, and bone marrow transplantation before birth, although the latter procedure had, as of 2004, not yet been successful. For those infants who survive to delivery, there seems to be an increased risk of developmental problems and physical effects, particularly heart and genital malformations. Otherwise, the medical outlook is similar to a child with beta thalassemia major, with the important exception that ongoing, lifelong blood transfusions begin at birth.
Individuals with beta thalassemia major receive regular blood transfusions, usually on a monthly basis. This helps prevent severe anemia and allow for growth and development that is more normal. Transfusion therapy does have limitations, however. Individuals can develop reactions to certain proteins in the blood, called a transfusion reaction. Such a reaction can make locating appropriately matched donor blood more difficult. Although blood supplies in the United States are very safe, there remains an increased risk of exposure to such blood-borne infections as hepatitis.
An additional side effect of repeated transfusions is that the body is unable to get rid of the excess iron that accompanies each transfusion. A medication called desferoxamine is administered, usually five nights per week over a period of several hours, using an automatic pump that can be used during sleep or taken anywhere the person goes. This medication is able to bind to the excess iron, which can then be eliminated through urine.
If desferoxamine is not used regularly or is unavailable, iron overload can develop and cause tissue damage and organ damage and failure. The heart, liver, and endocrine organs are particularly vulnerable. Desferoxamine itself may produce on rare occasions allergic or toxic side effects, including hearing damage. Signs of desferoxamine toxicity are screened for and generally develop in individuals who overuse the medication when body iron levels are sufficiently low. Overall, however, transfusion and desferoxamine therapy have increased the life expectancy of individuals with the most severe types of beta thalassemia major to the fourth or fifth decade.
As of 2004, new treatments including medications that target the production of red blood cells (e.g. erythropoeitin) or fetal hemoglobin (e.g. hydroxyurea and butyrate) and bone marrow transplantation may offer more effective treatment of beta thalassemia major. Other possible treatments may include gene therapy techniques aimed at increasing the amount of normal hemoglobin the body is able to make.
Prognosis, as noted above, depends on the type and severity of the disease. Individuals with severe disease may be stillborn or die shortly after birth. On the other hand, some individuals with mild disease have a relatively normal life expectancy.
Thalassemias are inherited diseases that cannot be prevented. It is, however, possible to identify carriers of the disease and provide them with genetic counseling and appropriate information concerning the chance of their offspring having thalassemia disease.
Individuals with hemoglobin H disease can reduce the likelihood of symptoms by avoiding infections and certain environmental triggers.
If parents are thinking of having a child and believe they might be carriers of defective hemoglobin genes, they can be screened and receive genetic counseling so that they can assess their options.
Anemia —A condition in which there is an abnormally low number of red blood cells in the bloodstream. It may be due to loss of blood, an increase in red blood cell destruction, or a decrease in red blood cell production. Major symptoms are paleness, shortness of breath, unusually fast or strong heart beats, and tiredness.
Bilirubin —A reddish yellow pigment formed from the breakdown of red blood cells, and metabolized by the liver. When levels are abnormally high, it causes the yellowish tint to eyes and skin known as jaundice. Levels of bilirubin in the blood increase in patients with liver disease, blockage of the bile ducts, and other conditions.
Bone marrow —The spongy tissue inside the large bones in the body that is responsible for making the red blood cells, most white blood cells, and platelets.
Bone marrow transplantation —A medical procedure in which a quantity of bone marrow is extracted through a needle from a donor, and then passed into a patient to replace the patient's diseased or absent bone marrow.
Desferoxamine —The primary drug used in iron chelation therapy. It aids in counteracting the life-threatening buildup of iron in the body associated with long-term blood transfusions.
Globin —One of the component protein molecules found in hemoglobin. Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules.
Heme —The iron-containing molecule in hemoglobin that serves as the site for oxygen binding.
Hemoglobin —An iron-containing pigment of red blood cells composed of four amino acid chains (alpha, beta, gamma, delta) that delivers oxygen from the lungs to the cells of the body and carries carbon dioxide from the cells to the lungs.
Hemoglobin A —Normal adult hemoglobin that contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules.
Hemoglobin electrophoresis —A laboratory test that separates molecules based on their size, shape, or electrical charge. It is used to identify abnormal hemoglobins in the blood.
Hydroxyurea —A drug that has been shown to induce production of fetal hemoglobin. Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin. Higher-than-normal levels of fetal hemoglobin can ameliorate some of the symptoms of thalassemia.
Iron overload —A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs, particularly the heart, and cause life-threatening damage.
Jaundice —A condition in which the skin and whites of the eyes take on a yellowish color due to an increase of bilirubin (a compound produced by the liver) in the blood. Also called icterus.
Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.
Placenta —The organ that provides oxygen and nutrition from the mother to the unborn baby during pregnancy. The placenta is attached to the wall of the uterus and leads to the unborn baby via the umbilical cord.
Red blood cell —Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.
Screening —A process through which carriers of a trait may be identified within a population.
Lawson, Jack P., and Leon Lenchik. "Thalassemia," June 22, 2001. Available online at http://www.emedicine.com/radio/topic686.htm (accessed October 4, 2004).
"Thalassemia," April 10, 2002. Available online at http://sicle.bwh.Harvard.edu/menu_thal.html (accessed October 4, 2004).
Children's Blood Foundation. 333 East 38th St., Room 830, New York, NY 10016–2745. Web site: http://www.childrensbloodfoundation.org.
Cooley's Anemia Foundation Inc. 129–09 26th Ave. #203, Flushing, NY 11354. Web site: http://www.thalassemia.org.
March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. Web site: http://www.modimes.org.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812–8923. Web site: http://www.rarediseases.org.
"Alpha-thalassemia Mental Retardation Syndrome, Nondeletion Type." Online Mendelian Inheritance of Man. Available online at http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=301040 (accessed October 4, 2004).
Children's Hospital Oakland, Northern California Comprehensive Thalassemia Center Web site. Available online at http://www.thalassemia.com (accessed October 4, 2004).
Tish Davidson, A.M.