Genetic Diseases: Sickle Cell Anemia

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Abstract

Sickle cell anemia (SCA) is a hereditary disorder of the blood. In the SCA patients, the hemoglobin polymerizes in low oxygen conditions, causing erythrocytes to become sickle shaped. This affects the ability of erythrocytes to penetrate narrow vessels, which results in tissue damage, painful episodes, and other complications. The sickle cell trait is transmitted by a homozygous recessive allele that belongs to the beta-globin gene family located on chromosome 11. A normal beta-globin gene produces normal hemoglobin (HbA), which gives RBCs their oval and flexible shape. However, a point mutation involving this gene locus produces HbS, which, when in a homozygous state, causes SCA. This paper synthesizes various studies examining SCA symptoms, genetics, pathogenesis, and management interventions.

Introduction

Sickle cell anemia (SCA) is a condition that causes the erythrocytes to sickle. It is caused by a mutant globin gene, which produces a defective beta-globin protein that has Valine amino acid in place of glutamate in its sequence. This substitution causes hemoglobin to stiffen in the presence of low oxygen, making the RBCs to acquire an irregular shape instead of their usual oval shape.

SCA is a heritable recessive trait that has a high degree of morbidity and mortality among certain populations. It causes severe anemia because the sickle-shaped RBCs are easily entangled in the blood vessels, blocking blood circulation (Serjeant, 2001). Due to the obstruction of blood flow, patients experience pain in the joints, organ damage, and, in some cases, fatal strokes. Individuals with SCA require regular blood transfusions to live a normal life. The lifespan of SCA sufferers is normally less than 20 years. The SCA trait is prevalent in Africa, South Asia, and the Mediterranean region where the ‘carriers’ develop a natural resistance (a selective advantage) against Plasmodium (malaria). This research paper will review studies examining SCA’s genetic inheritance, causes, diagnosis, medical interventions, and frequency in certain populations. Based on the findings of the research, the paper will make viable recommendations.

Objectives

This genetic disorder research paper aims to elucidate the underlying molecular causes of SCA as well as its symptoms, inheritance, treatment, diagnosis, and prevalence in certain populations. Its objectives include:

To describe the symptoms and genetic causes of the sickle cell disorder
To analyze the inheritance of the recessive sickle cell trait that causes the sickle cell disease (SCA)
To review recent advances in the treatment and diagnosis of sickle cell anemia
To explain risk factors that predispose certain individuals to the disease

Methods

The paper aims to analyze current studies examining sickle cell anemia. The inclusion criteria used involved a search of peer-reviewed articles in medical databases, such as Medline and CINAHL, using key phrases like ‘sickle cell anemia’, ‘sickle cell disease’, and ‘genetic disorders’. The synthesis involved five recent scholarly publications (those published after 2000) examining areas pertinent to the topic. The following sections analyze the findings of the articles.

The Globin Gene and SCA

Studies indicate that blood hemoglobin is a conjugate of iron and globin protein chains (alpha and beta) produced by a gene cluster that occurs on chromosome 11 (Ashley, Yang & Olney, 2000). The alpha gene cluster encodes α-globin proteins, which form normal hemoglobin, HbA. The beta gene cluster synthesizes the β-globins that constitute hemoglobin in adults. In the fetal stage, a variant of the beta gene, the epsilon gene, and gamma gene synthesize the fetal hemoglobin, HbF (Ashley, Yang & Olney, 2000). In adults, normal hemoglobin consists of four subunits of two subtypes, namely, alpha and beta chains.

Studies have identified variants of hemoglobin that cause RBCs to become irregular in shape, hence, causing the sickle cell disease. The variants arise from a substitution mutation involving the globin gene locus on chromosome 11. According to Serjeant (2001), substitutions affecting the β-globin gene at position six involve an A→T point mutation, which result in the synthesis of abnormal hemoglobin, HbS. This mutation causes a replacement of glutamic acid with Valine on the globin polypeptide chain, which results in defective hemoglobin in sickle-shaped RBCs. The irregularly shaped cells clog capillaries causing sickle cell anemia.

Inheritance of the Sickle Cell Trait

The SCA trait does not occur on the sex chromosomes. It occurs on the autosomes where it is transmission to the offspring follows the normal Mendelian fashion of inheritance. The SCA condition occurs when a heterozygous individual (AS) bears a child with a homozygote (SS) or another heterozygote (AS) (Aidoo et al., 2002).

Since a person who is heterozygous for the sickle cell trait carries the defective gene, he or she is a carrier. Therefore, a marriage involving two heterozygous individuals (both AS) would produce children who are normal, carriers, and sick in the ratio of 1:2:1. On the other hand, a homozygote (SS) and a carrier have an equal chance of bearing either a child with SCA or a carrier. In contrast, a normal person and a partner with the sickle cell disease would only bear carriers. A heterozygote and a normal individual would bear normal children and carriers in the ratio of 1:1. Since SCA sufferers seldom reach adulthood, a marriage involving homozygous recessive individuals rarely happens. However, if they marry, they would only bear children with this condition.

Besides the HbS trait, SCA sufferers also inherit other globin variants. According to Ashley, Yang, and Olney (2000), hemoglobin subtypes like HbSD, HbSE, HbSα, and HbSβ thalassemia occur in association with the HbS trait. In this case, the SCA condition occurs when a child inherits one of these hemoglobin variants from the parents. As Diallo and Tchernia (2002) note, most of these hemoglobin subtypes do not lead to disease; however, some variants such as HbSβ and HbSα thalassemia cause anemic conditions comparable to SCA due to faulty synthesis of hemoglobin. SCA is the most widespread condition characterized by sickle-shaped RBCs.

SCA and Natural Selection

Although SCA is the most common condition of all the disorders caused by abnormal hemoglobin in the blood, its prevalence varies widely depending on race and region. In the US, SCA is prevalent among African Americans with one in every 375 people suffering from the disease (Diallo & Tchernia, 2002). Regionally, SCA is prevalent in Africa, where it occurs in one out of a hundred people. This disparity relates to natural selection forces against endemic P. falciparum infection. A study focusing on vulnerable populations predicts a correlation between SCA and malaria among people of the African descent (Diallo & Tchernia, 2002). The study postulates how natural selection causes genetic disorders in the native population. In the SCA, heterozygous individuals (carriers) are less prone to malarial infection compared to normal ones. While the homozygous condition causes SCA, natural selection favors carriers in the population.

Further evidence indicates that individuals who are heterozygous for the SCA allele have a relatively lower risk of contracting malaria because of the sickle-shaped configuration of their RBCs. Malaria is a disease caused by P. falciparum, a parasite that causes hemolysis of the RBCs in infected individuals. An insect vector, the mosquito, inoculates the parasites into the bloodstream when feeding. The symptoms of this disease, which has a high morbidity and mortality in Africa, include vomiting, fever, and chronic migraines (Aidoo et al., 2002). The Plasmodium parasite cannot thrive in the RBCs of a sufferer because their sickle-shape interferes with the microbe’s lifecycle, lowering its infectivity. However, homozygous recessive individuals die young due to the SCA condition and thus, do not transmit the resistance genes to the next generation.

In contrast, homozygous dominant people (AA) are prone to malarial infection because their hemoglobin is normal. Infection with malaria, especially in childhood, can lead to death. On the other hand, carriers (AS genotype) have both normal and sickle-shaped hemoglobin in their blood. As such, they have a lower risk of contracting malaria compared to their normal counterparts. Additionally, their heterozygous state protects them from the SCA condition (Aidoo et al., 2002). This allows them to inhabit malaria-endemic places and transmit the allele to their offspring. Since they are heterozygous, they have both allele ‘A’ (normal) and ‘S’ (mutant) in their genotype. Thus, the ‘S’ allele confers a selective advantage to carriers.

SCA Epidemiology and Pathophysiology

The actual prevalence of SCA is unknown, but it is estimated that the disorder affects a population of 100 million people globally (Diallo & Tchernia, 2002). SCA is more prevalent among people of the African and Mediterranean descent. About 5% of people have mutations on the globin gene that confer various hemoglobinopathies, including SCA (Diallo & Tchernia, 2002). In the US, the prevalence of the sickle cell disease stands at 0.2% with the African Americans being the worst affected.

The major clinical symptoms of SCA stem from the irregular structure of the RBCs. The erythrocytes assume the sickle shape through a process called polymerization, which is characterized by the inability of the globin molecule to conjugate with ferric iron, resulting in low oxygen tension in the RBCs (Aliyu et al., 2008). The reduced hemoglobin becomes insoluble and stiffens, distorting the shape of RBCs into sickle-like cells that block blood vessels. In this regard, the clinical symptoms of this disorder relate to the pain experienced due to the blockage of vessels. According to Serjeant (2001), the polymers interact with extracellular molecules and thus, adhere strongly to the endothelial lining of the vessels causing a painful ‘vasocclussion’ process in SCA sufferers. However, hemoglobin F has been found to reduce the effects of vessel blockage (Serjeant, 2001). It binds to oxygen and thus, inhibits the polymerization process in sickle-celled individuals.

In children, the disorder has been known to cause stroke because of the rise in the level of anticoagulants, such as protein S, in patients (Aliyu et al., 2008). Other symptoms include tissue damage due to the blockage of vessels by the sickle-shaped RBCs. This affects organs such as the lungs, spleen, and liver. SCA sufferers, especially children, are also prone to microbial infections, including hepatitis C virus (HCV) and pneumonia, due to impaired immunity. Patients with SCA also experience weight loss and fatal complications, such as hypoxia, microcytosis, low Hb, and renal malfunctioning (Aliyu et al., 2008).

SCA Management Interventions

Sickle cell screening is an essential intervention in the management of SCA. Neonatal screening involves genetic testing methods, like HPLC and PCR, which are highly sensitive and can detect point mutations involving the β-globin locus (Serjeant, 2001). PCR amplifies the DNA fragment from a patient (HbSS) to generate bands, which, when compared with those of a normal allele (HbAA), reveal the mutation. Another screening method involves the use of monoclonal antibodies to identify the variants of hemoglobin drawn from different samples.

Hb electrophoresis is also widely used as a laboratory tool for detecting the SCA allele. It entails the separation of the Hb proteins based on their charges and sizes in an electric field. The hemoglobin molecules migrate at different rates based on their charges and sizes. This produces distinct bands, which, when compared to healthy controls, reveals the sickle cell proteins. This technique can distinguish between HbA (normal), HbS (sickle), and other variants like HbC, HbD, and HbE with great accuracy (Aidoo et al., 2002). The screening methods vary in efficacy, cost, and availability in different regions.

The management of the sickle cell condition involves a number of interventions. First, community awareness can help at-risk populations learn how to care for SCA sufferers. Community-based clinic can also provide primary care to children born with the sickle cell condition. Another intervention involves the use of medications, such as penicillin prophylaxis, to reduce the effects of the disease (Aidoo et al., 2002). Sufferers also need to be immunized against pneumococcus bacteria to protect them from pneumonia. The management of SCA complications involves interventions such as antibiotic therapy, blood transfusion, and the use of IV fluids and analgesics to relieve pain.

Discussion of Results

The articles reviewed examine different aspects of sickle cell anemia, which is a common genetic disorder. Sickle cell anemia or disease is a disorder characterized by irregularly shaped erythrocytes that contain polymerized hemoglobin. The disorder generally affects blood circulation as the sickle-shaped cells block blood capillaries leading to various body organs. SCA sufferers become anemic because blood cannot nourish vital organs.

Besides anemia, the other symptoms of SCA include painful episodes due to the vaso-occlussion phenomenon, jaundice, and renal problems. In his article, Serjeant (2001) states that the irregularly shaped RBCs cause vessel blockage, which leads to insufficient blood flow to the body organs, causing tissue damage in the lungs, spleen, and kidneys. The impairment of the spleen, an organ involved in immune responses, predisposes patients to microbial infections from pneumococcus and hepatitis C virus. SCA patients also experience pain in the limbs and chest due to the blockage of vessels. The blockage of blood flow can also lead to priapism and sometime stroke in patients.

The disorder is caused by the sickle shape of the erythrocytes, which impairs their ability to penetrate tiny blood vessels. As a result, they block the vessels, preventing normal blood circulation in the tissues. This causes tissue damage, which is responsible for the various complications associated with the disease. Normal RBCs contain hemoglobin A while abnormal ones carry subtypes of hemoglobin such as HbC and HbS (sickle). The normal RBCs, unlike sickle-shaped ones, are soft and flexible, which allow them to pass through narrow vessels. Additionally, normal RBCs have a longer lifespan than sickle-shaped cells, which normally live for a period of less than 16 days (Aliyu et al., 2008).

SCA is inherited as an autosomal recessive trait located on chromosome 11. Individuals with SCA have a homozygous recessive genotype for this trait (HbS) while normal persons have a homozygous dominant allele (HbA). On the other hand, carriers contain both the recessive and the dominant allele in their genotype (HbAS). While the homozygous recessive state causes SCA, which leads to early death, the homozygous dominant genotype is protected from this condition. However, the HbA genotype is more prone to malarial infection compared to a homozygous recessive and a heterozygote. Thus, the heterozygote genotype confers a survival advantage to populations living in malaria-prone regions of Africa and Asia. This explains the high prevalence of SCA in these regions.

Early diagnosis of the condition facilitates the management of SCA. A number of clinical screening tools, such as PCR and Hb electrophoresis, are used to screen carriers and sufferers. Medications used to manage this condition include pneumonia vaccination and penicillin therapy. Patients also require regular blood transfusion.

Conclusion

Sickle cell anemia is a genetic condition with high mortality and morbidity outcomes among African Americans and Africans. Genetically, SCA patients have an autosomal recessive gene that produces defective hemoglobin, which causes a person’s RBCs to sickle. The sickle-shaped RBCs block blood flow in the tissues, leading to symptoms like anemia, pain, and organ damage. Based on the evidence reviewed in this paper, the writer recommends genetic counseling for at-risk populations to prevent them from passing the condition to their children. Additionally, since the gene locus is known, gene therapy should be used to treat SCA.

References

Aidoo, M., Terlouw, D. J., Kolczak, M.S., McElroy, P.D., Felko, O., Kariuki, S.,…Udhayakumar, V. (2002). Protective effect of the sickle cell gene against malaria morbidity and mortality. The Lancet, 359, 1311-1312.

Aliyu, Z.A., Kato, G.J., Taylor, J., Aliyu, B., Aisha, I., Mamman, V.,…Mark, T.G. (2008). Sickle cell disease and pulmonary hypertension in Africa: Global perspective and review of epidemiology pathophysiology and management. American Journal of Hematology, 83, 73-80.

Ashley, K.A., Yang, O., & Olney, R S. (2000). Sickle cell in heamoglobin (HbSS) allele and sickle cell disease. American Journal of Epidemiology, 151(9), 839-845.

Diallo D., & Tchernia G. (2002). Sickle Cell Disease in Africa: Current Opinion. Haematology, 9(2), 111-116.

Serjeant, G.R. (2001). The emerging understanding of sickle cell disease. British Journal of Haematology, 112, 3-18.

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