Hemoglobinopathies are diseases caused by the production of abnormal hemoglobin or by a deficiency of hemoglobin synthesis. Hemoglobin is the protein in red blood cells (erythrocytes) that binds to oxygen, to distribute it throughout the body. The major hemoglobinopathies are sickle cell disease and several forms of thalassemia.
Hemoglobin Structure and Function
In the lungs, where oxygen concentration is high, each hemoglobin molecule can bind with one molecule of oxygen. The erythrocyte containing the hemoglobin then travels through the bloodstream to the body's cells, where oxygen concentration is low, and the hemoglobin releases the oxygen for use by local tissue. It also picks up carbon dioxide, and this waste product is transported back to the lungs, where it can be released and exhaled.
Hemoglobin is made up of heme and globin. Heme is an iron-containing pigment that binds to oxygen. Globin, which holds the heme and influences how easily it stores and releases oxygen, is a protein consisting of two pairs of polypeptide chains. Globin can contain several different types of polypeptide chains, termed alpha, beta, and gamma. Each is coded for by a separate gene. The genes are evolutionarily related, and their differences are the result of ancient mutation events in an ancestral form that gave rise to each modern type.
The type of hemoglobin found in healthy adults contains two alpha chains and two beta chains. This form of hemoglobin is called HbA (hemoglobin A). As discussed below, sickle cell disease is due to mutations in the beta chains in HbA. A fetus or newborn baby does not produce HbA. Instead, it produces fetal hemoglobin, or HbF. Like HbA, fetal hemoglobin contains a pair of alpha chains. But in place of the beta chains, it contains a pair of gamma chains. As infants grow older, their bodies produce less and less HbF and more and more HbA.
The Genetics of Hemoglobinopathies
Each person possesses two copies of the beta globin gene, on separate homologous chromosomes. In most people, the two copies are identical. A person with two identical gene copies is said to be homozygous.
In some people, the two beta copies are not identical. These people, who have two different alleles of the beta globin gene, are said to be heterozygous. The beta globin allele that leads to sickle cell disease is called the hemoglobin S (HbS) allele.
People who have inherited one HbA and one HbS allele are heterozygous for the beta chain gene. They are said to have the sickle cell trait, but not sickle cell disease. As long as they have one HbA allele, these individuals produce sufficient HbA to remain healthy, and they usually do not have any medical problems, or they experience only very mild symptoms. When both alleles must be abnormal to cause a disease, the condition is said to be recessive. Sickle cell disease is a recessive condition.
Sickle cell disease can occur when two individuals who have the sickle cell trait (they are called carriers) have children. Recall that the two beta chain alleles occur on different chromosomes. These homologous chromosomes separate during gamete formation, so that each gamete has a fifty-fifty chance of possessing an HbS allele. There is a one-in-four chance that a child conceived by two carriers will inherit a recessive, abnormal allele from each parent, and therefore be homozygous for the abnormal allele and develop sickle cell disease.
Homozygous forms of hemoglobinopathy can be very serious. Some cause so much damage that the fetus dies before birth, while others require lifelong treatment.
Sickle Cell Disease
Sickle cell disease is the most prevalent genetically based disease in the United States. Approximately 1 in 12 Americans of African descent are carriers, having one allele coding for HbS and one gene for HbA. About 1 in 375 Americans of African descent are homozygous for HbS and have the active disease. High occurrence of the HbS allele also occurs in people who live, or whose ancestors lived, in certain parts of Asia, the Mediterranean, and the Middle East.
The alpha chain gene is found on chromosome 11. Each gene is made up of a very long strand of nucleotides. In sickle cell disease, there is a change in only one nucleotide in the sequence that codes for the beta chain: A thymine is substituted for an adenine.
Genes code for proteins. Because of that change in one nucleotide, a slightly different protein is produced. HbS differs from HbA by only one amino acid: Glutamic acid in HbA is replaced by valine in the sixth position on the beta chain. The substitution does not affect the hemoglobin molecule's ability to bind with oxygen. HbS can carry oxygen just as effectively as HbA. However, glutamic acid is a hydrophilic ("water-loving") amino acid, whereas valine is hydrophobic ("water-hating"). The valine occurs on the outside of the beta chain. The hydrophobic portions of HbS molecules are attracted to each other. When the concentration of oxygen is low, as it is deep in the body's tissues, HbS molecules will attach to each other. Since a single red blood cell contains about 250 million hemoglobin molecules, this can result in very long chains, or polymers.
The polymerization that occurs distorts the red blood cell into a curved, sickle shape. Whereas normal erythrocytes travel smoothly through the blood vessels, these unusually elongated and pointed erythrocytes move much more slowly and can block smaller blood vessels. Both the slow movement and the blockages further reduce the amount of oxygen in the blood, promoting even more polymerization and sickling.
The decreased amount of oxygen in the blood also damages local tissues and will cause permanent damage if it lasts long enough. The lack of oxygen is very painful. This progressive cycle of worsening symptoms, called a vaso-occlusive crisis, can last for more than a week.
People with sickle cell disease often develop other health problems. For example, the crescent shaped erythrocytes have shorter life spans than normally shaped cells do. A healthy red blood cell lives about 120 days, while a sickle cell lives only for 10 to 30 days. The body is unable to replace the red blood cells quickly enough, resulting in anemia.
Situations that cause the body to use up oxygen, such as exercise, can precipitate a vaso-occlusive crisis. Also, because dehydration causes the hemoglobin molecules to be packed more tightly together within the erythrocyte, insufficient fluid intake can also cause red blood cells to sickle.
Treatment Options and Continuing Research
Therapy for sickle cell disease used to focus on easing symptoms and treating infections, which are the most common cause of death in children who have this disease. Newer therapies actually treat the disease.
Hydroxyurea and erythropoietin, for example, are two medications that stimulate the bone marrow to produce more fetal hemoglobin, HbF. Production of both red blood cells and hemoglobin occurs in this spongy tissue, which is located in certain bones.
Fetal hemoglobin can transport oxygen but does not polymerize, so the red blood cells cannot sickle. Thus these drugs can prevent vaso-occlusive crises. However, they do have side effects that can limit their usefulness. Hydroxyurea, for example, can suppress bone marrow function.
Normally, the production of HbF is turned off shortly after birth. Scientists are trying to determine how to reactivate the gene for HbF so that the bone marrow of people with sickle cell disease can continually produce fetal hemoglobin without the use of medications. Other research focuses on learning how to insert normal beta chains and regulatory genes into stem cells, which are cells that develop into erythrocytes.
Bone marrow transplants are a new treatment and have largely been conducted in Europe. The donor bone marrow will produce normal hemoglobin and normal red blood cells. However, the tissue must come from an immunologically compatible donor. Also, a bone marrow transplant is a complicated process, and some people have died during the procedure.
Hemoglobin C Disease
Hemoglobin C (Hbc), which is also found in people of African or Mediterranean descent, is very similar in structure to HbS. Both are caused by a change in the sixth residue of the beta chain. While valine replaces glutamic acid to form HbS, the amino acid lysine is found in this position, in HbC.
The substitution of lysine does not cause pathological changes in the hemoglobin molecule. People who are homozygous for HbC typically have red blood cells that appear unusual, but they do not sickle. These individuals have no symptoms, and they do not require treatment.
Some people have one gene for HbC and another for HbS. They have hemoglobin SC disease, which usually is much less severe than sickle cell disease.
The Thalassemias
The thalassemias are a group of hemoglobinopathies that, like sickle cell disease, are caused by a genetic change. Unlike sickle cell disease, however, the genetic change does not result in the production of an abnormal form of the globin molecule. Instead, the bone marrow synthesizes insufficient amounts of a hemoglobin chain. This, in turn, reduces the production of red blood cells and causes anemia.
Either the alpha or beta chain may be affected, but beta thalassemias are more common. Individuals who are heterozygous for this disorder have one allele for this disease and one normal allele and are said to have thalassemia minor. They usually produce sufficient beta globin so that they have only mild anemia. They may not have any symptoms at all. Thalassemia minor is sometimes misdiagnosed as iron deficiency anemia.
If two individuals with thalassemia minor have children, there is a onein-four chance that each child will inherit an abnormal gene from both parents and will be homozygous for the disorder.
Individuals who are homozygous for this condition may develop either thalassemia intermedia or thalassemia major. Newborn babies are healthy because their bodies are still producing HbF, which does not have beta chains. During the first few months of life, the bone marrow switches to producing HbA, and symptoms start to appear.
In thalassemia major, also called Cooley's anemia, the bone marrow does not synthesize beta globin at all. Children affected by thalassemia major become very anemic and require frequent blood transfusions. They are so ill that they often die by early adulthood.
In thalassemia intermedia, the production of beta globin is decreased, but not completely. People with this disease have anemia, but they do not require chronic blood transfusions to stay alive.
Alpha thalassemia is more complicated, because an individual inherits two alpha globin genes from each parent for a total of four alpha globin genes. Thus a person can inherit anywhere from zero to four normal genes.
The more abnormal alpha genes that are inherited, the greater the symptoms. If an individual does not have any functional alpha genes, the body cannot produce any alpha globin. Since HbF requires alpha chains, the developing fetus does not produce healthy hemoglobin and shows severe symptoms even before birth. This condition is almost always fatal, with affected infants dying either before or shortly after delivery.
The loss of three functional alpha genes produces severe anemia, the loss of two functional genes typically causes mild anemia, and the loss of only one gene usually does not produce any symptoms. The thalassemias most commonly occur in people from Italy, Greece, the Middle East, Africa, and Southeast Asia; and in their descendants.
Treatment Options and Continuing Research
Blood transfusions have been a common therapy for severe thalassemia, but transfusions do not cure the disease, and frequent transfusions can cause iron overload, an illness caused by excessively high levels of iron. A drug, called an iron chelator, may be given to bind with the excess iron. Iron chelators can produce additional side effects, such as hearing loss and reduced growth.
As with sickle cell disease, gene therapy and bone marrow transplants are very promising therapies for severe thalassemias. While transplants are risky procedures and can cause death, they are more likely to be successful when performed on young and relatively healthy children.
The Heterozygous Advantage
Being homozygous for either sickle cell disease or thalassemia can result in serious illness, but being heterozygous for either condition may actually be beneficial under certain circumstances. Both diseases occur primarily in people who live, or whose ancestors lived, in parts of the world where malaria occurs.
Malaria is spread by a mosquito, but it is caused by plasmodia, single-celled organisms that, during an infection, reproduce inside red blood cells. Before the development of modern sanitation and medicine, malaria was a common cause of death. But people who had either the sickle cell trait or thalassemia minor—people who were heterozygous for either condition—were much more likely to survive an infection than were people homozygous for HbA.
This "heterozygote advantage" meant that these individuals tended to live longer, have children and pass their genes on to the next generation. While some of their children died from thalassemia or sickle cell disease, about half of them were heterozygous and benefited from the heterozygote advantage. This survival advantage explains the high prevalence of these alleles in these populations.
Today, especially in developed countries, there are effective methods for preventing and treating malaria. Nevertheless, the genes for sickle cell disease and thalassemia still exist and are passed down to children who will never be exposed to malaria. It is likely that these genes will very slowly be lost from the gene pool.
Bibliography
Weatherall, D. J. "ABC of Clinical Haematology: The Hereditary Anaemias." British Medical Journal 314 (1997): 492-496.
Internet Resources
"Bioelectronics Laboratory Index." Seikei University. http://www.ee.seikei.ac.jp/user/seiichi/lecture/Biomedical/02/graphics/hemoglobin.gif.
Facts about Sickle Cell Disease. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/health/public/blood/sickle/sca_fact.txt.
Joint Center for Sickle Cell and Thalassemic Disorders. http://sickle.bwh.harvard.edu.
—Sue Wallace
