Type of paper: Essay

Topic: Blood, Hemoglobin, Genetics, Nursing, Condition, Medicine, Shape, Acid

Pages: 6

Words: 1650

Published: 2021/02/05

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Sickle cell anemia (SCA) is the form sickle cell disease (SCD) that is most widely known. In this condition, the body makes red blood cells that are sickle-shaped. Sickle cells have abnormal hemoglobin which causes them to have a sickle-shape. These cells are sticky and stiff, blocking blood vessels, which damages organs and causes pain. This discussion will be based on the genetic predisposition of sickle cell anemia as well as the biochemical processes that occur in the normal and diseased condition.

Different processes in the normal and diseased state

Linus Pauling and associates in 1949 described sickle cell anemia (SCA) as the first “molecular disease” coining the phrase “molecular medicine” (Gabriel & Przybylski, 2010). They were able to prove that the physical properties of hemoglobin from SCA patients were different from those of the hemoglobin found in normal individuals. They also discovered that the hemoglobin from people with the sickle cell trait had characteristics similar to those of the hemoglobin found in both SCA patients and in normal individuals (Gabriel & Przybylski, 2010). The hemoglobin of adults contains two chains of α-globin and two chains of β-globin. The gene that codes for the β-subunit of a hemoglobin molecule is located on chromosome 11, and sickle cell anemia patients have a mutation on this gene (Gabriel & Przybylski, 2010). Vernon Ingram in the 1950s showed that the structure of adult SCA hemoglobin was only different from that of normal adult hemoglobin by having valine replacing glutamic acid in the amino acid chain of β-globin (Gabriel & Przybylski, 2010). This relates to a change in a single base whereby the normal adenine is replaced by thymine in the sixth codon (Gabriel & Przybylski, 2010). Since glutamic acid is negatively charged, its loss leads to an alteration in electrophoretic mobility.
In vivo, this substitution of an amino acid has its consequences becoming obvious when there is a dissociation of oxygen from hemoglobin (Gabriel & Przybylski, 2010). Specifically, there is a conformational change in the deoxygenated hemoglobin whereby the exposed mutant valine adheres to a hydrophobic patch present on an adjacent hemoglobin molecule (Gabriel & Przybylski, 2010). This valine can form hydrophobic bonds with phenylalanine and leucine residues in positions 88 and 85 respectively in the β-chain of a neighboring molecule (Gabriel & Przybylski, 2010). The linkage in the polymer is facilitated by only the mutant valine residue of one of the two aforementioned β-chains on each molecule of HbS (sickle cell hemoglobin). The consequence of this is that hemoglobin stacks up into long polymers which alter the formation of the cell membrane into a sickle cell shape, characteristic of this condition (Gabriel & Przybylski, 2010). Surprisingly, the misshapen RBCs return the proper shape when oxygen binds again to their hemoglobin. However, these repeated transitions gradually irreversibly distort the membranes of these RBCs into a sickle cell form (Gabriel & Przybylski, 2010). In normal individuals however, RBCs always have a round shape and are flexible to allow their free movement through narrow blood vessels (Utah.edu, 2015). The round shape and flexibility of normal RBCs are constant in both the oxygenated and deoxygenated state of their hemoglobin (Utah.edu, 2015). In normal individuals, hemoglobin does not form long inflexible chains characteristic of sickle cell anemia since adhering of mutant valine to adjacent hemoglobin molecules does not occur (Utah.edu, 2015).
In the capillary beds of tissues, where deoxygenated conditions exist, the distorted RBCs cause all the complications linked to SCA. The misshapen cells can accumulate in veins and capillaries, hindering blood flow, and causing great pain and damage of tissues in almost any body organ (Utah.edu, 2015). Since the cells have a sickle cell shape and are fragile, the body of the patient destroys its own RBCs (Gabriel & Przybylski, 2010). This results to anemia, jaundice, gall stones, congestion, and spleen fibrosis at a young age (Gabriel & Przybylski, 2010).

Inheritance of the condition and population genetics

The kind of hemoglobin made in an individual’s RBCs is dependent on the hemoglobin genes he/she inherited from the parents. Genes for hemoglobin are pairs, whereby each parent contributes one the offspring. The inheritance pattern of SCA is autosomal recessive (Gabriel & Przybylski, 2010). This means that a child can only inherit the condition if he/she inherits the genes for the condition in the homozygous state, whereby the genes for the β-subunit of hemoglobin inherited from both parents have the aforementioned mutation that leads to the condition (Gabriel & Przybylski, 2010). In case one of the parents has the sickle cell trait and the other has sickle cell anemia, there is a 50 percent probability of having a child with either the sickle cell trait or the sickle cell condition with each pregnancy (Sicklecelldisease.org, 2015). On the other hand, when only the sickle cell trait is present in both parents, there is a 25 percent chance that the child their child will have the sickle cell condition with each pregnancy (Sicklecelldisease.org, 2015).
Humans who are not related have differences in their DNA at about 1000-2000 bases per chromosome (Gabriel & Przybylski, 2010). Long sections of the DNA that have such polymorphisms in large numbers are called haplotype blocks (Gabriel & Przybylski, 2010). People with similar polymorphisms have a common ancestor. This is because polymorphisms are inherited (Gabriel & Przybylski, 2010). This enables investigators to identify how related individuals are through haplotype analysis. Geneticists, using fragment length polymorphism analysis, have discovered many different haplotypes in and near the tens of kilobases of the gene cluster of β-globin (Gabriel & Przybylski, 2010). Pagnier et al. in 1984 found from studies on four African populations that were significantly affected by sickle-cell trait that there were three different haplotypes among the patients, and these haplotypes matched greatly with geographic origin (Gabriel & Przybylski, 2010). Beninese and Algerian patients were homozygous for a particular haplotype (Benin type) while more than 80 percent of patients from Senegal and from the Central African Republic were homozygous for other two haplotypes (Senegal and Bantu types respectively) (Gabriel & Przybylski, 2010). This study showed that the mutation for sickle cell developed at least three times distinctly in Africa and occurred among populations that were reproductively and geographically isolated (Gabriel & Przybylski, 2010). This makes it not to be surprising that African Americans who have SCA have haplotypes that correspond to their origins in Africa, where they were forced to emigrate from. A study of 98 patients from Georgia showed that 54%, 27%, and 15% had the Benin, Bantu, and Senegal haplotypes respectively (Gabriel & Przybylski, 2010). In the US, one African American child in every 500 born has SCA (Gabriel & Przybylski, 2010). Sickle cell anemia’s historical spread has also been seen in SCA patients of Portuguese, Sicilian, Greek, and various Southern European origins (Gabriel & Przybylski, 2010). Studies on patients from the central India and Saudi Arabia and have shown another distinct haplotype thought to originate from a region with a history of malarial epidemics (Gabriel & Przybylski, 2010).
I short SCA is common among persons from Africa, the Caribbean, India, the Mediterranean, and the Middle East. This is due to the fact that a mutation in the β-subunit of hemoglobin confers malarial resistance. People with SCA, have origins in places historically affected by malaria (Gabriel & Przybylski, 2010).
Population genetics of SCA show that the severity of the disease varies across populations. Fetal hemoglobin (HbF) which has two alpha chains and two gamma chains is the major type of hemoglobin during the fetal life of a human, but it is replaced by hemoglobin A (α2β2) after birth (Gabriel & Przybylski, 2010). Saudi Arabs who have SCA (homozygous for Hbs) produce HbF even in adult life, having it at a concentration of 10-25% (Gabriel & Przybylski, 2010). Their high production of HbF is genetically determined. Their heterozygous parents interestingly have a HbF concentration of 1-2% (Gabriel & Przybylski, 2010). It has been known for a while that HbF and HbS cannot copolymerize, which dilutes out the concentration of HbS, inhibiting the sickling of RBCs (Gabriel & Przybylski, 2010). This reduces the severity of SCA.

Diagnosis, Prognosis, and Treatment

Diagnosis can be done on newborns through a blood test which checks for the shape of RBCs. If this test is not accurate at birth, hemoglobin electrophoresis, which can identify different types of hemoglobin, can be used (Sicklecelldisease.org, 2015). When a voltage is applied through a hemoglobin solution, different hemoglobins migrate to different distances based on their composition (like their charge) (Sicklecelldisease.org, 2015). This can differentiate between normal and sickle hemoglobin.
There is a reduction in the life expectancy of SCA patients. However, proper management of the condition can enable patients to live beyond the age of forty (Gabriel & Przybylski, 2010). Bacterial infections, tissue and organ damage, fatigue, and intermittent pain are expected in most sufferers. Causes of death include stroke, organ (liver, heart, or kidney) failure, or bacterial infections (most common cause). The risk of Bacterial infections decreases after the age of three (Sicklecelldisease.org, 2015.
One treatment for SCA is by the administration of hydroxyurea. SCA patients maintain detectable levels of fetal hemoglobin in their RBC’s in their entire childhood (Gabriel & Przybylski, 2010). This protects them from the severity of SCA by preventing the formation of long polymers of HbS. The rationale for administration of hydroxyurea is to increase and reactivate the production of fetal hemoglobin (Gabriel & Przybylski, 2010). Folic acid is also given to patients to help in the formation of new RBCs (Sicklecelldisease.org, 2015). Infants and young children are given daily doses of penicillin to prevent infections (Sicklecelldisease.org, 2015).

Currently available genetic testing

Genetic testing for SCA involves the use of restriction fragment length polymorphisms (RFLP). This test requires a restriction enzyme that cleaves the DNA in a way that is informative with regard to the condition (McClean, 2015). The second requirement is a probe for nucleic acids that detects that region (McClean, 2015). The DNA is analyzed through Southern hybridization (McClean, 2015). In SCA, a replacement of glutamic acid by valine in the sixth position of hemoglobin’s β- globin chain is due to a replacement of adenine by thymine in the coding region of its gene. This results in the loss of a site that the restriction enzyme Ddel recognizes leading to identification of the condition (McClean, 2015). The following figure shows how the sickle cell trait can be identified using a restriction enzyme and Southern hybridization.

Site Eliminated

Normal ß-Globin | 175 bp | 201 bp |

Allele ____________________________

Probe XXXXXXXXXXXXXXXXXXX
Sickled ß-Globin | 376 bp |

Allele ____________________________

Probe XXXXXXXXXXXXXXXXXXX
Normal Sickled
ß-Globin ß-Globin
------------------
376 bp ___
201 bp ___
175 bp ___

Source (McClean, 2015)

"|” in the figure denotes a cleavage site for the restriction enzyme.
In summary, sickle cell anemia is a genetic disorder that is inherited in the recessive homozygous form from parents. Individuals who are heterozygous are only carriers of the trait. In this condition, hemoglobin is defective due to a mutation in the amino acid sequence of its β-globin chain. Through various biochemical processes, the defective hemoglobin leads to the RBCs of SCA patients having a distorted form, which leads to various body disorders including organ damage and anemia.

References

Gabriel, A., & Przybylski, J. (2015). Sickle-Cell Anemia: Haplotype | Learn Science at Scitable.Nature.com. Retrieved 8 April 2015, from http://www.nature.com/scitable/topicpage/sickle-cell-anemia-a-look-at-global-8756219
McClean, P. (2015). Molecular Markers. Ndsu.edu. Retrieved 8 April 2015, from http://www.ndsu.edu/pubweb/~mcclean/plsc431/markers/marker1.htm
Sicklecelldisease.org,. (2015). Sickle Cell Disease Association of America, Inc. - What is Sickle Cell Disease (SCD)?. Retrieved 8 April 2015, from http://www.sicklecelldisease.org/index.cfm?page=about-scd
Utah.edu,. (2015). Sickle Cell Disease. Learn.genetics.utah.edu. Retrieved 8 April 2015, from http://learn.genetics.utah.edu/content/disorders/singlegene/sicklecell/

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