Sickle cell disease and genetics

ALSO KNOWN AS: Sickle cell anemia; hemoglobin S/S disease; sickle-hemoglobin C disease; sickle-beta thalassemia

DEFINITION: Sickle cell disease (SCD), also known as sickle cell anemia, is a hereditary blood disorder that affects red blood cells. Red blood cells undergo hemolysis (breakage) and change shape, which causes vascular occlusive crises (small blood-vessel blockages). This results in acute and chronic pain, as well as multi-organ dysfunction.

Risk Factors

Individuals of African, Mediterranean, Middle Eastern, Indian, Central American, and Caribbean ancestry have the greatest chance of having a mutation in the hemoglobin beta gene (HBB). According to the Centers for Disease Control and Prevention (CDC), approximately one in twelve African Americans has a single copy of the mutated HBB allele—a condition known as the sickle-cell trait—while approximately one in five hundred African Americans has two mutated alleles, causing full-blown sickle cell disease.

Etiology and Genetics

Sickle cell disease was the very first example of a genetic disease being traced to its precise origin at the molecular level. The HBB gene, located on chromosome 11, encodes the main type of adult (hemoglobin A). Hemoglobin is the major protein in red blood cells that allows them to bind with oxygen in the lungs and transport it to other parts of the body.

Sickle cell anemia occurs when there is a single point mutation in the HBB gene that causes the nucleotide thymine to be substituted for adenine. This causes a corresponding substitution of amino acids, replacing glutamic acid in the sixth codon with valine. The change of amino acids causes an absence of normal hemoglobin A production. Consequently, structurally abnormal hemoglobin S is produced. For individuals with sickle cell anemia, the mutation causes the hemoglobin molecules to stick to one another and changes the normally smooth, flexible, doughnut-shaped appearance of the red blood cell to a characteristic sickled crescent-moon shape. This prevents red blood cells from traveling through tiny capillaries, especially under conditions of oxygen deprivation. On average, the life span of red blood cells of healthy individuals is 120 days, after which they are replaced by new cells. In individuals with sickle cell disease, the red blood cells have a reduced life span of only 16 days.

Sickle cell disease is inherited in an autosomal recessive manner. One mutation in the HBB gene means that a person is a carrier for sickle cell disease, which is also known as having sickle-cell trait (hemoglobin A/S). If both parents have sickle cell trait, then there is a 25 percent risk for each child to have sickle cell disease (hemoglobin S/S), a 50 percent risk for each child to have sickle cell trait, and a 25 percent chance that neither parent will pass on the sickle cell trait and the child will be unaffected (hemoglobin A/A). If only one parent has sickle cell trait and the other parent does not, then there is zero chance of the child having sickle cell disease but a 50 percent risk that the child may inherit sickle cell trait.

Sickle cell disease may occur in classical form, as described above for sickle cell anemia, or may occur as other forms of the blood disorder. Hemoglobin S/S occurs in 60 to 70 percent of affected individuals. There are many mutations that have been reported in the HBB gene that can interact with sickle-cell trait and cause various hemoglobinopathies (conditions in which abnormal hemoglobin is produced), such as mutations for hemoglobin C trait or beta thalassemia trait. If an individual inherits a sickle cell trait from one parent and a hemoglobin C trait from another, for example, then the child has a 25 percent risk of having sickle-hemoglobin C disease, which is often less severe than classical sickle cell anemia but may show similar symptoms. HbVar, a database of hemoglobin variants, lists more than a thousand entries for globin gene mutations that may lead to hundreds of clinically significant blood disorders.

Sickle cell disease is one of the best-documented examples of an evolutionary process known as heterozygote advantage, in which carriers have a greater probability of surviving or reproducing than either an affected or an unaffected noncarrier individual. In most cases, hereditary diseases with such significant symptoms as those associated with sickle cell disease are kept at low frequencies in populations by natural selection. However, having sickle-cell trait provides an advantage in environments, such as Africa, where malaria is prevalent. Malaria is a deadly, mosquito-borne disease that uses human red blood cells as hosts for part of its life cycle. Individuals who have hemoglobin A/A are vulnerable to the disease, and people who have sickle cell disease have an increased risk for early death because of anemia and other complications. However, when the red blood cells of individuals with sickle cell trait are invaded by the malarial parasite, they adhere to blood vessel walls, become deoxygenated, and assume a sickle shape, prompting both their destruction and that of their parasitic invaders. This provides a sickle cell carrier with a natural resistance to malaria and explains the relatively high frequency of the sickle cell gene in such environments. This is an important phenomenon from an evolutionary standpoint because it provides a mechanism by which genetic diversity in a population may be preserved.

Symptoms

Individuals with sickle cell trait typically display no symptoms, although some have been known to become ill under extreme circumstances, such as high altitudes with decreased oxygen supply. Symptoms of sickle cell disease typically appear about six to twelve months after birth, when the last of fetal hemoglobin (hemoglobin F), a type of hemoglobin that increases the oxygen supply of blood in pregnancy, decreases and hemoglobin S increases. The severity of the illness varies widely among individuals.

Individuals have varying degrees of red-cell breakdown, which may cause a decrease in the amount of red blood cells (hemolytic anemia), jaundice, physical weakness, and delayed growth and puberty. The change in the red blood cell shape leads to a vaso-occlusive crisis (sickle cell crisis), which causes a lack of oxygen to be delivered to the body’s tissues. Subsequently, this causes organ dysfunction and may cause significant pain in joints and bones. The organs that are most often involved include the spleen, lungs, brain, kidneys, and genitalia. Individuals typically have an enlarged spleen, and the compromised function predisposes mostly children but also adults to infections. The lungs may have significant life-threatening complications such as damage or changes to the lungs (acute chest syndrome), as well as a constriction of blood supply to the lungs (pulmonary hypertension). Other significant complications include the possibility of a stroke or blindness. Male individuals may have priapism, a long and painful erection. Despite the many treatments that exist, there remains an increased risk for medical problems and mortality. The mean age of death is forty-two years for males and forty-eight years for females.

Screening and Diagnosis

A diagnosis of sickle cell disease may be made by several different laboratory techniques. High-performance liquid chromatography (HPLC), isoelectric focusing (IEF), hemoglobin electrophoresis, and peripheral blood smears are all available testing options. Almost all cases of sickle cell disease are diagnosed at birth. All fifty states provide newborn screening for sickle cell disease by one of these methods. Molecular genetic testing is available to detect mutations in the HBB gene associated with sickle cell disease. Mutation analysis is typically reserved for when a sickle cell trait is suspected to be inherited with another hemoglobin variant or for purposes of diagnosing a fetus in pregnancy.

Any individual planning a pregnancy or who is currently pregnant who is from the aforementioned ethnic backgrounds should be offered screening for sickle cell disease. If a pregnancy is found to be at 25 percent risk for sickle cell disease, then prenatal diagnosis is available. Prenatal diagnosis includes testing options of chorionic villus sampling (CVS) at ten to twelve weeks of gestation or amniocentesis at approximately fifteen to twenty weeks of gestation. In CVS, a sample from the placenta is obtained, and in amniocentesis, a sample of fetal cells from amniotic fluid is withdrawn. Both diagnostic testing options provide a greater than 99 percent detection rate of sickle cell disease.

Genetic counseling is available for individuals at risk for having a child with sickle cell disease or for individuals who are diagnosed by newborn screening with sickle cell disease. Genetic counselors may review testing options and participate in the multidisciplinary management and education of children or adults with the diagnosis.

Prevention and Outcomes

Despite advancing treatments, there still exists no cure for sickle cell disease. Stem cell transplantation, whereby an individual receives stem cells from the bone marrow of an unaffected individual, has the potential to cure symptoms of sickle cell disease, but it is highly risky and is limited to individuals with a sibling donor who has identical human leukocyte antigens. Bone marrow transplantation is another option, with similar restrictions on potential donors. There are significant risks with this procedure, including complications such as bone-marrow rejection, infection, bleeding, and possible death.

It may be possible to prevent the onset of symptoms by proper fluid hydration, avoiding high altitudes with poor oxygenation and climates with extreme temperatures, and taking preventive medications. Antibiotics are administered to all children to reduce infections, and vaccinations are recommended to reduce the chance of other illnesses. A folic acid supplement may also be prescribed.

Treatments for symptoms include oral medication and fluid hydration for vaso-occlusive pain and crises. The oral medication Voxelotor has been approved for treatment of patients older than four years of age. Crizanlizumab-tmca, a medication administered through an intravenous line, can aid patients sixteen and older in preventing blockages, inflammation, and reducing pain. Typically, over-the-counter pain medications, such as acetaminophen or ibuprofen, can be used to manage the pain crisis at home. However, more severe pain crises may require stronger medications, such as opioids, and hospitalization for intravenous fluids. Blood transfusions may be performed during severe pain episodes or in an attempt to prevent a further complication, such as a stroke. Hydroxyurea, a chemotherapy agent used to increase the amount of fetal hemoglobin and break down sickled cells, has proven successful at reducing the number of pain episodes and the need for blood transfusions and hospitalizations. The drawbacks of this treatment are that it does not prevent the brain complications of sickle cell disease and that the treated individual is at a higher risk for infection and other possible complications, such as leukemia.

The results of a clinical trial conducted in 2024 suggested that gene therapy might be an effective form of treatment for patients with sickle cell disease. The process, which involves the use of chemotherapy and stem cell infusion, was shown to alter the method through which red blood cells are produced in such a way that they are no longer sickle and cannot become trapped in organs or bones. This ultimately led to a near normalization of blood counts and functioning, as well as a reduction in pain and overall improved health, in patients who participated in the trial.

Prevention of sickle cell disease itself may be possible during pregnancy via the technology of preimplantation genetic diagnosis (PGD), a method of testing embryos or egg cells (oocytes) prior to fertilization. Only unaffected embryos or oocytes, with or without sickle cell trait, would be implanted in the uterus for pregnancy by in vitro fertilization. The main advantage of PGD technology is that parents who would not end a pregnancy with sickle-cell disease diagnosed by prenatal diagnosis have a high probability of not having an affected child.

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