The hemoglobin molecule is composed of four separate polypeptide chains of amino acids, two alpha chains and two beta chains, as well as four iron-bearing heme groups that bind oxygen. The alpha chains are coded for by two similar genes on chromosome 16; the beta chains by a single gene on chromosome 11. Mutations and deletions in these genes cause one of the many hemoglobinopathies.

In general, hemoglobinopathies are divided into those in which the gene abnormality results in a qualitative change in the hemoglobin molecule and those in which the change is quantitative. Sickle cell anemia (sickle cell disease) is the prime example of the former, and the group of disorders known as the thalassemias constitute the latter. It has been estimated that one third of a million people worldwide are seriously affected by one of these genetic disorders.

Sickle cell anemia (SSA), an autosomal recessive disorder more common in the Black population, is caused by a single mutation in the gene that codes for the beta polypeptide. Approximately 1/400 to 1/600 African-Americans are born with the disorder, and, one in ten is a carrier of one copy of the mutation. In certain parts of the African continent, the prevalence of the disease reaches one in fifty individuals.

The sickle cell mutation results in the substitution of the amino acid valine for glutamic acid in the sixth position of the beta polypeptide. In turn, this alters the conformation of the hemoglobin molecule and causes the red blood cells to assume a characteristic sickle shape under certain conditions. These sickle-shaped cells, no longer able to pass smoothly through small capillaries, can block the flow of blood. This obstruction results in symptoms including growth retardation, severe pain crises, tissue and organ damage, splenomegaly, and strokes. Individuals with SSA are anemic and prone to infections, particularly pneumonia, a significant cause of death in this group. Some or all of these symptoms are found in individuals who have the sickle mutation in both copies of their beta-globin gene. Persons with one abnormal gene and one normal gene are said to be carriers of the sickle cell trait. Carriers are unaffected because of the remaining normal copy of the gene.

The thalassemias are a diverse group of disorders characterized by the fact that the causative mutations result in a decrease in the amount of normal hemoglobin. Thalassemias are common in Mediterranean populations as well as in Africa, India, the Mideast, and Southeast Asia. The two main types of thalassemias are alpha-thalassemia due to mutations in the alpha polypeptide and beta-thalassemia resulting from beta chain mutations.

Since individuals possess a total of four genes for the alpha polypeptide (two genes on each of their two chromosomes 16), disease severity depends on how many of the four genes are abnormal. A defect in one or two of the genes has no clinical effect. Abnormalities of three results in a mild to moderately severe anemia (hemoglobin H disease) and splenomegaly. Loss of function of all four genes usually causes such severe oxygen deprivation that the affected fetus does not survive. A massive accumulation of fluid in the fetus (hydrops fetalis) results in stillbirth or neonatal death.

Beta thalassemias can range from mild and clinically insignificant (beta thalassemia minor) to severe and life-threatening (beta thalassemia major, also known as Cooley's anemia), depending on the exact nature of the gene mutation and whether one or both copies of the beta gene are affected. While the milder forms may only cause slight anemia, the more severe types result in growth retardation, skeletal changes, splenomegaly, vulnerability to infections, and death as early as the first decade of life.

Many countries, including the United States, have made concerted efforts to screen for sickle cell anemia at birth because of the potential for beginning early treatment and counseling parents about their carrier status. Diagnosis is traditionally made by blood tests including hemoglobin electrophoresis. Similar tests are used to determine whether an individual is a sickle cell or thalassemia carrier. In certain populations with a high prevalence of one of the mutations, carrier testing is common. If both members of a couple are carriers of one of these conditions, it is possible through prenatal genetic testing to determine if the fetus will be affected, although the severity of the disease cannot always be predicted.

Treatment of SSA has improved greatly in recent years with a resulting increase in life expectancy. The use of prophylactic (preventative) antibiotic therapy has been particularly successful. Other treatments include fluid therapy to prevent dehydration, oxygen supplementation, pain relievers, blood transfusions, and several different types of medications. Recent interest has focused on bone marrow transplantation, which has been successful in selected patients.

Since the clinically important thalassemias are characterized by severe anemia, the traditional treatment has been blood transfusion, but the multiple transfusions needed to sustain life lead to an iron overload throughout the tissues of the body and eventual destruction of the heart and other organs. For this reason, transfusion therapy must also include infusions of medications such as deferoxamine (desferroxamine) to rid the body of excess iron. Phlebotomy is another technique that has been used with some success to lower the concentration of iron in the patient's blood. As with sickle cell anemia, bone marrow therapy has been successful in some cases.

Until very recently, patients being treated with bone marrow transplants had to find a sibling or other closely related donor in order to avoid rejection of the transplant. Advances in the preparation of the transplanted cells, however, have made the use of bone marrow from unrelated donors (URD) an option for patients with hemoglobinopathies. As of 2003, the National Marrow Donor Program reports that about 40% of bone marrow transplants involve a patient in the United States receiving marrow from an international donor or an international patient receiving marrow from a donor in the United States.

Emphasis is also being placed on developing drugs that treat sickle cell anemia directly. The most promising of these drugs in the late 1990s is hydroxyurea, a drug that was originally designed for anticancer treatment. Hydroxyurea has been shown to reduce the frequency of painful crises and acute chest syndrome in adults, and to lessen the need for blood transfusions. Hydroxyurea seems to work by inducing a higher production of fetal hemoglobin. The major side effects of the drug include decreased production of platelets, red blood cells, and certain white blood cells. The effects of long-term hydroxyurea treatment are unknown; however, a nine-year follow-up study of 299 adults with frequent painful crises reported in 2003 that taking hydroxyurea was associated with a 40% reduction in mortality.

Another promising development for the treatment of hemoglobinopathies is gene therapy, which has interested researchers since the early 1990s. In late 2001, genetic scientists reported that they had designed a gene that might lead to a future treatment of sickle cell anemia. Although the gene had not been tested in humans, early results showed that the injected gene protected cells from sickling. As of 2003, experiments in gene therapy for sickle cell disease have been carried out in mice, using lentiviral vectors to transfer the corrective gene into the mouse's stem cells. This technique, however, has not yet been attempted in human subjects as of late 2003.

Hemoglobinopathies are life-long disorders. The prognosis depends upon the exact nature of the mutation, the availability of effective treatment, as well as the individual's compliance with therapies. Hemoglobinopathies significantly complicate pregnancy, and increase the risk of infant mortality.

Because the hemoglobinopathies are inherited diseases, primary prevention involves carriers making reproductive decisions to prevent passage of the abnormal gene to their offspring. At present, most prevention is targeted toward the symptoms using treatments such as those described above.