Summary: This paper deals with sickle-cell disease (SCD, also known as sickle cell anemia) from a genetic point of view. The disease and its genetic trait do not conform well to the traditional model of genetic inheritance, which required that the medical establishment rethink its ideas about genetic concepts like “dominant” and “recessive”. It often occurs in areas rife with malaria, and may be linked to an increased protection from severe malaria. Also discussed: symptoms of SCD, treatments and gene therapies, and demographics.
The study of human genetics has always involved the blood. Even in premicroscopic history, titles as well as traits were inherited through ‘bloodlines’. Mendel’s experiments with pea plants, however, were not a sufficient description of many human genetic patterns. Inherited blood-cell deformities such as sickle-cell disease (SCD) behave in a more complex way than traditional mendelian dominance/recessiveness patterns (Williams et al., 415). Many other aspects of SCD are of interest to the scientific community – its distinctive demographics, its responsiveness to genetic therapies, and the peculiar structure of hemoglobin S’s fibers, which will be discussed below. But from a genetic perspective, it is the unusual inheritance patterns that are interesting, and it is an explanation of these patterns and the theories about their existence which will form the bulk of the discussion.
The inherited condition of SCD affects the human circulatory system in a number of ways. The most well-known, and the symptom that gives the condition its name, is the strange “sickling” of erythrocytes, which causes them to have an irregular curvature that severely limits their usefulness as part of the circulatory system. This deformity is caused by a lack of elasticity in the cell structure due to weak proteins (Mohandas and Hebbel, 209). In their journey through the circulatory system, erythrocytes must pass through capillaries that are often smaller than the diameter of the cell. Normal erythrocytes bounce back into shape after being pushed through such a space. SCD-affected erythrocytes, however, retain the deformities caused by such spaces. Cellular breakage can result in a higher level of hemoglobin in the plasma, raising plasma viscosity to unsafe levels (Mohandas and Hebbel, 205). Sickle cells are particularly at risk for damage after deoxygenation, when hemoglobin-S is molecularly weakest.
Sickle cell anemia and sickle cell trait are the two main forms of SCD, but they differ greatly in the pattern of their genetic transmission. Sickling traits appear in those who exhibit hemoglobin-S in electrophoresis tests. The trait can develop into mild anemias during flight in unpressurized aircraft, hypoxia during anesthesia, and severe pneumonia. These individuals may also develop mild hyposthenuria and only rarely develop the hematuria commonly associated with sickle-cell anemia (Williams et al., 417). The gene for hemoglobin-S is a classically dominant one, propagating through generations in the same way other classically dominant traits do. However, the phenotype of SCD as a severe anemia is only present in those with homozygous sicklecell trait parents, and then also to varying degrees of severity.
The inheritance patterns are simple: If both parents carry one abnormal gene, there is a 1-in-4 chance that a child will have sickle-cell disease. The risk, of course, remains the same for each pregnancy regardless of the outcome of the previous one. If both parents have sickle-cell trait, there is a 75% chance of a healthy child at each pregnancy. If one parent has sickle-cell disease and their partner has the trait, then the risk of an affected child is doubled but if the partner is normal, the couple cannot have an affected child (Lancet 2000, 1170). This pattern corresponds to the ‘autosomal codominant’ definition.
The evolution of SCD and the natural selection of SCD carriers is empirically related to the transmission of malaria in central Africa. Significant work has been done on this subject, with as much anthropological and philosophical value as medical. The appearance of potentially deadly deformities simultaneously with traits that prevent disabling malarial symptoms flies in the face of a key dogma of natural selection, this being that every naturally selected development has a purpose. The interlaced fate of genes defies any developmental logic that strict Darwinians may be inclined to impose. However, the development of cerebral malaria in SCD trait individuals, especially children, with Plasmodium falciparum is rare in large part because of the preventative effect hemoglobin-S has on trophozoites associated with malaria. Anthropologically speaking, traditions concerning the yam harvest in Nigeria, especially among the Igbo people, have particularly anti-malarial tendencies. Prohibitions against eating the first yams of the season coincide with the yearly peak of malarial infestation (Edelstein, 60). Nigeria is one of the areas most severely affected by SCD. It is interesting to note that beta-thalassemia, another hematopathy, is commonly found in the malarial Mediterranean basin (ibid.).
The demographics of SCD are directly related to its prevalence in malarial areas. For some years after its discovery, it was believed to be a condition related to “racial traits” of African people and their descendants. We now know that hematological disorders have nothing at all to do, genetically speaking, with traits like pigmentation and facial features; on the contrary, traits that allow people to classify human beings along racial lines developed accidentally in a location that has a high incidence of malaria, and that more than anything else has brought SCD to a statistically significant portion of the world’s population. Currently, sickle-cell trait affects about 9.5% of the US population, and sickle-cell anemia 1-2% (Lancet 2000, 1175). Distribution of SCD is concentrated on the east and west coasts of central Africa, prevailing more often in wet, rainy areas, and along the Indian coast of the Arabian Peninsula. There are also high concentrations in population centers of India and Pakistan (Williams et al., 422).
The symptoms of sickle-cell anemia can be so mild as to go unnoticed and undiagnosed. However, for the majority of homozygous SCD births, this is not true. The liver, spleen, and kidneys are the most affected organs, displaying calcifications, necrosis, and enlargement. The effect on the entire renal system can be profound and drastic, but even in mild cases, the renal medulla usually exhibits some sort of damage, the most common being papillary necrosis (Williams et al., 418). SCD anemics can exhibit symptoms of pale mucous membranes, asthenia, malnourishment or underdevelopment, leg ulcers, dactylitis (swelling of the hands and feet, often known as hand-foot syndrome), retinal vessel tortuosity, various neurological complaints from drowsiness to aphasia, pulmonary infarction, jaundice, and ‘crises’.
These crises usually take one of three forms: aplastic crisis, in which the patient experiences a marked decrease in the rate of erythrocyte production (erythropoiesis) precipitated by infection or stress; pain crises, in which the patient experiences migratory, joint, or abdominal pain in conjunction with a fever; and sickle-cell crises, a term that represents any rapid onset symptom in a homozygous SCD patient that cannot be explained by anything other than sickle-cell anemia (Lancet 1997, 729). Episodic vascular occlusion, which limits oxygenated blood flow to the tissues, is another description of the pain crises that plague many sickle-cell anemia patients. Extreme erythrocyte dehydration can cause cells in the bloodstream to stick together, blocking vascular pathways, causing an accumulation of deoxygenated cells in the affected area, and often results in a painful swelling (Embury et al., 311).
Treatments for SCD, particularly in its severe anemic form, have advanced tremendously since the discovery of gene therapies. It is now possible for sickle-cell trait parents to have a child with no trace of SCD (JAMA, 1702). By far the most effective means for preventing sickle-cell anemia, however, is prenatal or infant screening. Instituted in many major hospitals, and part of some new state health mandates, this screening for sickle-cell trait and anemia can help parents as well as children deal with the restrictions that SCD may impose on their future. As parents, sickle-cell trait individuals have only a 25% chance of producing an SC-anemic child, if their partner is also a trait carrier. The large probability of having a healthy baby convinces some SCtrait couples to try for a pregnancy anyway, and wait for an in utero diagnosis before deciding to complete the pregnancy. Infant screening programs instituted by private hospitals can have race-specific guidelines, but most state screening programs require obstetricians to screen every baby because racial distinctions are often blurry and vague, resulting in a large proportion of unscreened infants whose doctors did not recognize them as members of an at-risk group (Wertz, 49). Traditional therapies for sickle-cell crises involve hydration, paracetamol, analgesics, and in more pronounced pain crises, oxygen, along with monitoring of fever and/or pulmonary activity. Find more papers at PhDify.com
Sickle cell anemia affects one out of every hundred Americans, but with advances in genetics and medical technology, it may be possible that some day that figure will approach zero. This hematopathy causes no few children’s deaths worldwide, especially in central Africa (Edelstein, 19). The symptoms of recurring pain and poorly functioning organs cause children to be “old before their time,” to take fewer risks, and to lead sheltered lives punctuated by lengthy hospital visits (Britto et al., 2). The study of this major genetic disease has sparked interest in genetics as well as bringing us a greater understanding of genetic transmission of hemoglobin mutations. Hemoglobin-S and hemoglobin-C, the two causes of erythrocyte sickling behavior, are interesting substances themselves, displaying a peculiar fibrous helix-structure that can cause the red cell to contract, dehydrate, and become brittle when deprived of oxygen.
Further studies of sickle-cell anemia could include isolating its antimalarial aspects. More effective means of cellular rehydration would also be useful, as would gene therapies that directly affect the erythrocyte-producing bone marrow, stimulating the production of red cells devoid of hemoglobin-S or C. This research could also prove useful in the study of alpha and betathalassemia, which produce symptoms similar to sickle cell anemia; bone marrow regeneration research done in the study of leukemia might also prove useful. The sicklecell phenomenon raises questions about evolution, ethics, reproductive freedom, cellular chemistry, and of course genetics. With time and diligent research, these questions may be answered.
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