Sickle-cell disease (SCD) is a group of hereditary diseases, including sickle-cell anemia (SCA) and sickle B-thalassemia, in which the red blood cells contain an abnormal hemoglobin, termed hemoglobin S (HbS). HbS
FIGURE 5.19 Sickle cell anemia SOURCE: "Sickle Cell Anemia," in Genes and Disease, National Institutes of Health, National Center for Biotechnology Information, 2004, http://www.ncbi.nlm.nih.gov/disease/sickle.html (accessed February 8, 2005)
is responsible for the premature destruction of red blood cells, or hemolysis. In addition, it causes the red cells to become deformed, actually taking on a sickle shape, particularly in parts of the body where the amount of oxygen is relatively low. These abnormally shaped cells cannot travel smoothly through the smaller blood vessels and capillaries. They tend to clog the vessels and prevent blood from reaching vital tissues. This blockage produces anoxia (lack of oxygen), which in turn causes more sickling and more damage. (See Figure 5.19.)
Sickle-cell anemia is an autosomal recessive disease caused by a point mutation in the hemoglobin beta gene (HBB) found on chromosome 11p15.4. (See Figure 5.20.) A mutation in HBB results in the production of hemoglobin with an abnormal structure. Figure 5.19 shows how in SCA a point mutation
FIGURE 5.20 The sickle cell anemia gene SOURCE: "HBB: The Gene Associated with Sickle Cell Anemia," in Gene Gateway—Exploring Genes and Genetic Disorders, U.S. Department of Energy, Office of Biological and Environmental Research, Human Genome Project, http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml (accessed February 9, 2005)
causes the amino acid glutamine to be replaced by valine to produce abnormal hemoglobin called HbS. It also shows how when red blood cells with HbS are oxygen-deprived they become sickle shaped and may cause blockages that result in tissue death.
Symptoms of SCA
People with SCA have the symptoms of anemia, including fatigue, weakness, fainting, and palpitations or an increased awareness of their heartbeat. These palpitations result from the heart's attempts to compensate for the anemia by pumping blood faster than normal.
In addition, patients experience occasional sickle-cell crises—attacks of pain in the bones and abdomen. Blood clots may also develop in the lungs, kidneys, brain, and other organs. A severe crisis or several acute crises can permanently damage various organs of the body. This damage can lead to death from heart failure, kidney failure, or stroke. The frequency of these crises varies from patient to patient. A sickle-cell crisis, however, occurs more often during infections and after an accident or an injury.
Who Contracts SCD?
Both the sickle-cell trait and the disease exist almost exclusively in people of African, Native American, and Hispanic descent and in those from parts of Italy, Greece, Middle Eastern countries, and India. When one parent has the sickle-cell gene, a couple's offspring will carry the trait but only if both the mother and the father have the trait can they produce a child with sickle-cell anemia. This trait is relatively common among African-Americans, and about six in 1,000 black couples carry the risk of having a child with the disease. People of African descent are advised to seek genetic counseling and testing for the trait before starting a family. The sickle-cell trait is present in one in twelve African-Americans, or about two million people. According to the National Heart Lung and Blood Institute (NHLBI), in the United States the disease afflicts approximately 72,000 people, most of whose ancestors come from Africa. SCA occurs in approximately one in 500 African-American births and in one in 1,000 to 1,400 Hispanic-American births. Numbers are much lower for other groups.
A CALL FOR UNIVERSAL SCREENING.
In 1993 a federal panel of researchers, clinicians, and policy makers called for sickle-cell screening of all newborns because early diagnosis and treatment significantly improve future health. Because of intermarriage, it is becoming more difficult to be certain of a person's racial or ethnic background based on physical appearance, surname, or self-reporting. Many sickle-cell sufferers could possibly be missed by exclusively screening a target population such as African-Americans.
By 1993 thirty-four states and jurisdictions had already instituted the universal screening of infants recommended by an earlier study group of the National Institutes of Health in 1988. Another ten states had targeted screening aimed at groups traditionally considered at higher risk, and eight states and jurisdictions had no sickle-cell screening program. As of 2005, according to the NHLBI, forty-four states, the District of Columbia, Puerto Rico, and the Virgin Islands screened all newborns for sickle-cell disease, and the remaining six states provided screening at the request of parents.
Early diagnosis (soon after birth) could save the lives of children born with SCD. Studies have found wide differences in the mortality rates of children with SCD. To improve survival rates for children with SCD living in
high mortality areas, public health advocates recommend further study of the accessibility and quality of available screening and medical care, and the duplication of successful treatment programs. In addition, they emphasize the importance of educating parents about the disease and its treatments ("Mortality among Children with Sickle Cell Disease Identified by Newborn Screening during 1990–1994—California, Illinois, and New York," Mortality and Morbidity Weekly Report, vol. 46, no. 9, March 13, 1998; "Geographic Differences in Mortality of Young Children with Sickle Cell Disease in the United States," Public Health Reports, vol. 112, no. 1, January–February 1997).
Treatment of SCD
There is no universal cure for SCD, but the symptoms can be treated. Crises accompanied by extreme pain are the most common problems and can usually be treated with painkillers. Maintaining healthy eating and behavior and prompt treatment for any type of infection or injury is important. Special precautions are often necessary before any type of surgery, and for major surgery some patients receive transfusions to boost their levels of hemoglobin (the oxygen-bearing, iron-containing protein in red blood cells). In early 1995 a medication that prevented the cells from clogging vessels and cutting off oxygen was approved.
The 1993 federal panel of experts on SCD recommended that all infants diagnosed with the disease receive daily doses of penicillin to prevent infections. Parents are urged to make sure that these children receive the scheduled childhood immunizations and are vaccinated against influenza, meningitis, pneumonia, and hepatitis B. In the mid-1980s, 20% of children with SCD died before their first birthday; by 1993, primarily because of preventive antibiotics, that proportion had dropped to less than 3%. Although there is neither uniform SCD reporting nor national reports of incidence or prevalence, public health professionals believe that the antibiotic prophylaxis (prevention) has further reduced SCD mortality.
Many adults with SCD now take hydroxyurea, an anticancer drug that causes the body to produce red blood cells that resist sickling. In 1995 a multicenter study showed that among adults with three or more painful crises per year, hydroxyurea lowered the median number of crises requiring hospitalization by 58%. In 2003 an extension of that study showed that not only do patients on hydroxyurea have fewer crises but they also have a significant survival advantage when compared to SCD patients who do not take the medication. Subjects treated with it overall showed 40% lower mortality than others. (Martin H. Steinberg et al., "Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia: Risks and Benefits Up to 9 Years of Treatment," Journal of the American Medical Association, April 2, 2003).
An international study conducted in 1996 found that bone marrow transplants were successful in curing SCD in sixteen out of twenty-two patients, or 72.7% of the patients in the five-year study. All of the participants in the study were under age fourteen, had advanced symptoms, and had siblings who were compatible bone marrow donors. Of the remaining six patients, four (18%) rejected the donor marrow, and their sickle-cell symptoms returned, while two (9%) died.
Because of the risks associated with bone marrow transplants and the difficulties of finding matching donors, transplants are not appropriate for most patients. Further studies are needed to test the procedure for older patients and to reduce the proportion of transplant rejects. Blood harvested from umbilical cords and placentas has been found to be less likely to trigger rejection or graft-versus-host disease, in which the transplanted cells attack the cells of the bone marrow recipient, causing organ damage.
FIGURE 5.21 Chromosome 15, where HEXA gene mutations can cause Tay-Sachs disease SOURCE: "Where is the HEXA Gene Located?" in Genetics Home Reference: Your Guide to Understanding Genetic Conditions, U.S. National Library of Medicine, May 2004, http://ghr.nlm.nih.gov/gene=hexa (accessed February 9, 2005)
FIGURE 5.22 Molecular basis for Tay-Sachs disease SOURCE: "GM2 Ganglioside," in Genetics, volume 4, Q–Z, Macmillan Reference USA, Gale Group, 2002
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