Sickle Cell Disease

SICKLE CELL DISEASE

The sickle cell diseases are a group of disorders that have in common the propensity of the red blood cells to become deformed when oxygen tension in the blood is lowered, causing anemia, occlusion of blood vessels by misshapen cells, and various associated clinical consequences, including death. In sickle cell disease, a mutation of the beta-globin gene results in the substitution of valine for glutamic acid in the sixth amino acid of the chain, producing a hemoglobin, designated hemoglobin S, that has less solubility than does normal hemoglobin A. Inheriting one gene for hemoglobin S, together with a normal gene, results in the formation of red cells that contain approximately 40 percent of the abnormal hemoglobin and 60 percent of the normal hemoglobin, an essentially harmless state that is designated as sickle cell trait. But if the gene inherited together with the sickle gene is not normal, then the sickle cell disease may develop. The most common hemoglobin that interacts with sickle hemoglobin is hemoglobin C, and the ß-thalassemia (beta-thalassemia) mutation also interacts with the sickle gene by restricting the formation of normal hemoglobin.

The sickle gene, and genes that interact with it, are common in a number of different populations, but the highest gene frequencies are observed in Africa. The gene is also found in southern Europe, the Middle East, and India. A single dose of the sickle gene provides protection against malaria. Since malaria was a major cause of death in Africa, persons who carried the sickle gene had a survival advantage over those who did not. Thus, the number of persons carrying this mutation has tended to increase generation after generation in areas where malaria was a major killer. Among African Americans, approximately 7.8 percent are carriers of the sickle mutation, that is, they have sickle cell trait; while 2.3 percent have hemoglobin C trait (one copy of the hemoglobin C gene); and0.8 percent have ß-thalassemia trait.

Although a single copy of the hemoglobin S gene is quite harmless, if a person inherits two copies of the hemoglobin S genes, he or she will have sickle cell disease. If one hemoglobin S gene and one hemoglobin C gene are inherited, the patient has hemoglobin S-C disease. Coinheritance of the beta-thalassemia and sickle hemoglobin result in sickle cell thalassemia. Patients with these three disorders have a similar clinical disease. Anemia occurs as a result of the rapid destruction of red blood cells. The red cells may have the shape of sickles, hence the term "sickle cell disease." However, the cells may assume may other forms. The misshapen red cells occlude blood vessels and cause pain and even tissue death.

In small children, one of the great problems incident to sickle cell disease is infections. If these are treated promptly, most children with sickle cell disease survive into adult life. One of the most characteristic manifestations of the disease in adults and older children is "pain crises." These occur at regular intervals, often at a time of stress, and may cause frequent hospitalizations and varying degrees of dependence upon pain-killing drugs. As patients with the sickle cell disease grow older they begin to suffer from the results of accumulated damage in small blood vessels all through the body. Dysfunction of the lungs, kidneys, and heart are common. Strokes may occur. Interruption of the blood supply to bones may result in areas of bone death, particularly in the hips.

Although sickle cell disease is a disorder that has been better understood and studied in more detail than most other disorders, treatment is still very unsatisfactory. Prenatal diagnosis can be carried out quite easily and very reliably, and parents are provided with the option of terminating the pregnancy. Antibiotics and immunization programs have drastically reduced the mortality rate among young children. Transfusion of red blood cells improves the flow properties of blood and may ameliorate the symptoms. Hydroxyurea has been administered to increase the amount of fetal hemoglobin, a hemoglobin that does not interact with sickle hemoglobin. This treatment has met with some success.

The disease is cured by bone marrow transplantation, a procedure with a relatively high risk, even in those patients in whom a match can be found. Ultimately the disease may be treated by putting a normal beta-globin gene into a stem cell of the patient, and then transplanting that patient with his or her own transduced cells, but there are many barriers to implementing such a strategy. Because stem cells do not divide often, they are relatively resistant to many gene-transfer methods. It is not enough to put a normal globin gene in the cell; the abnormal globin gene needs to be inactivated. There is also a tendency for normal human cells to shut off the function of foreign genes that are implanted in them. It is likely that these technical obstacles to gene therapy will be overcome eventually, and that the treatment of this group of diseases will give better results in the future.

Ernest Beutler

(see also: Genes; Genetic Disorders; Hemoglobin; Hemoglobinopathies; Malaria; Medical Genetics )