Sickle+Cell+Enemia


 * //Sickle Cell Anemia //**

**Historical Background **
It is important to understand the historical findings of sickle cell anemia because this information is helpful in learning what the disease is and how it affects a species. Below is a timeline that takes you step-by-step through the genetic findings of various scientists.
 * 1910**- The first description of sickle cell anemia was described by Herrick when he observed the blood cells of a dental student to be “sickle-shaped”.
 * 1910-1925-** Many other similar cases were found supporting the idea that this is a new disease that needs further research.
 * 1927-**Hahn and Gillespie link the sickle shape of red blood cells with a lack of oxygen by filling cells with carbon dioxide.
 * 1940-** Sherman found that the sickling of red blood cells without oxygen is caused by a change in the hemoglobin molecule structure.
 * 1948-**Watson finds that if fetal hemoglobin is present at birth babies will not show symptoms of sickle cell anemia even if they are affected.
 * 1956-**Vernon Ingram, J.A. Hunt, and colleagues show that the mutant sickle hemoglobin (Hb S) is caused by only a change of a single amino acid in the protein. This was followed by many studies analyzing the structure of the mutant hemoglobin.
 * 1995**- Charache reports a drug, hydroxyurea, that is the first to reduce the pain of sickle cell anemia.

**What is Sickle Cell Anemia? **
Sickle cell anemia (SCA) is a monogenic, autosomal recessive disorder caused by a single missense mutation in the beta-globin gene. SCA is the most common type of sickle cell disease and is characterized by the HbS mutation, although there are several possible mutations (Kempińska-Podhorodecka et al 2011). This disease occurs when a person inherits the affected gene from each parent and produces hemoglobin S instead of normal hemoglobin A (See Inheritance Pattern Involved in Genes). However, before continuing any further, a brief explanation of the beta-globin gene needs to be addressed.

The beta-globin gene is one component of a larger protein known as hemoglobin. Hemoglobin is the red-pigmented protein found in erythrocytes that is responsible for providing arterial blood with its bright red color. Hemoglobin is also responsible for the transportation of oxygen and carbon dioxide within the body. As aforementioned, beta-globin is only a partial contributor to the overall structure of hemoglobin. Hemoglobin actually consists of two beta-chains and two alpha-chains. All globin chains contain a nonprotein (or heme) group that is in the shape of a ring, with an iron ion (Fe2+) in its center (McKinely, O’Loughlin, 2008). These iron ions allow oxygen (O2) to bind to them so that oxygen can be transported in the blood (figure A).

Figure A
 * Molecular Structure of Hemoglobin. **

Under conditions of oxygen deprivation, when hemoglobin is deoxygenated, hemoglobin S polymerizes into long fibers (Fox, 2011). This causes the red blood cells to lose their natural concave structure and become sickle shaped (figure B). Flexibility of the red blood cells becomes greatly reduced, which hinders their ability to pass through narrow vessels and thereby reduces blood flow through the blood vessels, body tissues, and organs. The long fibers of hemoglobin S also damage the plasma membrane of red blood cells and promote destruction of red blood cells by rupture, a process termed //hemolysis// (McKinely, O'Loughlin, 2008).




 * Figure B **
 * Structure features of Sickle-cell anemia. The image on the left portrays a normal erythrocyte. The image on the right displays a sickled erythrocyte. **

**Inheritance Pattern Involved in Genes **
Sickle cell anemia (SCA) is inherited as an autosomal recessive disorder, but technically the gene is not completely dominant or recessive because it was later found that it exhibits intermediate penetrance (Tchuenche, J. M. 2005). This means that not everyone with the genotype for the disease actually has the disease, although many do. Nevertheless, only those who are homozygous recessive for any of the variant alleles have SCA.


 * Mutation**

The mutant allele responsible for producing hemoglobin S is found at the end (position 15.5) of the short arm (p) of chromosome 11 (HBB: The Gene Associated with Sickle Cell Anemia 2003). In the figure of chromosome 11 the gene is labeled as HBB, although it should be noted that the mutation is called HbS.



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The figure below illustrates the single base pair mutation responsible for creating hemoglobin S. The A to T substitution is a common variant of the normal allele, although other mutant alleles exist.

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As shown, the most common mutation replaces the amino acid glutamine with valine. Glutamine is hydrophillic, meaning that it is prone to interact with water. Valine is hydrophobic, meaning it is prone to repel water. Chemically, molecules that produce similar intermolecular forces are more likely to interact. In the normal protein, hemoglobin A contains the glutamine and is folded next to one of the beta sheets. Beta sheets are hydrophobic, so these two molecules do not form a strong interaction, and this loose interaction is partly responsible for the rounded shape of the normal protein. However, when valine is present in hemoglobin S, it experiences strong attraction to the beta sheet because both are hydrophobic. The abnormal interaction creates a tight and inflexible protein structure that results in the rigidity of the sickled erythrocytes. (HBB: The Gene Associated with Sickle Cell Anemia 2003)

**Inheritance of the mutant allele follows racial lines**
Although found in the Middle East and Mediterranean region, Africa is the region most widely affected by SCA. The presence of malaria, a protozoan pathogen, in Africa is what created the selection for the mutant alleles causing the sickle cells. Malaria infects and destroys normal red blood cells, but for some reason the sickle cells are resistant to it. Thus, individuals who had one copy of the mutant allele and one copy of the normal allele have both normal and sickled erythrocytes. The presence of the sickle cells makes the heterozygote resistant to malaria, and because of the heterozygote advantage the allele still occurs with a high frequency in Africans. The problem is, of course, when individuals are born who are homozygous for both mutant alleles. It is estimated that in a year anywhere from 150,000 to 300,000 Africans are born with both mutant alleles. (Kempińska-Podhorodecka et al, 2011)


 * Symptoms **

Due to the physical changes to the RBC's in the body from SCA, there are many physiological symptoms that develop in the patient. The misshaped blood cells do not properly flow through the tiny arterioles and veinioles of the body. Circulation and cardiovascular health are directly affected. Many of the symptoms relate to anemia, which is the low amount of healthy blood cells. Anemic symptoms are shortness of breath, dizziness, headaches, coldness of extremities, pale skin, and jaundice. Body pain is a major symptom that arises from lack of blood circulation to organs, bones, abdomen, and joints. Acute forms of the pain are most common rather than chronic pain. Hand-foot syndrome typically affects children under the age of 4 where swellling and pain is experienced from the blockage of the small blood vessels. Patients with SCA are much more susceptible to infections due to damage to the spleen, which filters the blood cells from infections. Damage to the spleen also cause pain in the abdomen. Patients can experience pulmonary hypertension and acute chest syndrome, which is similar to pneumonia. With lack of blood flow to the body, some children experience delayed growth or puberty. Stroke, eye problems, gallstones, leg ulcers, and multiple organ failures are other possible symptoms of the disease. Below is chart describing the damage sickle cell anemia inflicts on our body. blood in the urine kidney failure || Splenic sequestration (large amount of body's blood pooled in the spleen) || Acute chest syndrome || Bone damage || Headache || Gallstones Gives yellow color to eyes and skin || []
 * **Organ/Tissue Involved** || **Problem Caused** ||
 * **Kidney** || bed-wetting
 * **Hands & Feet** || Swelling and pain ||
 * **Spleen** || increased risk for serious infections
 * **Lungs** || Pneumonia
 * **Bones** || Infection
 * **Brain** || Stroke
 * **Skin** || Slow - healing sores on legs and ankles ||
 * **Penis** || Painful unexpected erection ||
 * **Eyes** || Vision problems ||
 * **Liver** || Increased size
 * Not all of these symptoms occur in everyone with sickle cell anemia: all, one, or a combination can be present.

**Diagnosis **
Diagnosis of sickle cell anemia and the sickle cell trait is usually performed by blood testing at birth. However, testing can be performed at any age and even before birth. There are three main tests done to see if hemoglobin S is being produced instead of normal hemoglobin A.

Amniocentesis is a test that can be performed before birth. In this test, an ultrasound is used to localize the fetus and find a pocket of amniotic fluid. Then, a long, thin needle is used to safely remove a small amount of amniotic fluid. This is then sent to the laboratory for further testing to see if hemoglobin S is present. Amniocentesis is used to test for other genetic diseases, chromosome abnormalities, and neural tube defects (Cunningham, 2010).

Another test performed is the Sickledex Test, which can also be completed at any age. In the Sickledex test a deoxygenating agent is added to the drawn blood; if 25% or more of the hemoglobin is hemoglobin S, then the test is positive for sickle cell trait or sickle cell disease (Weiner, 2008). Hemoglobin electrophoresis is then performed to distinguish between sickle cell trait and sickle cell disease. This test separates different types of hemoglobin based on electrical charge. Hemoglobin S can be differentiated from Hemoglobin A and other types of hemoglobin (Cecil textbook of, 2003).


 * Treatments **

Sickle cell anemia does not a have a widely available cure that works for everyone ill with the disease. However, after many years of research scientists have treated both children and adults using bone morrow transplants. If bone morrow transplants are not advised for the patient then treatment focuses on preventing infections, relieving pain, and controlling complications.


 * Bone Marrow Transplants**

A bone marrow transplant, also called a stem cell transplant, involves replacing bone marrow affected by sickle cell anemia with healthy bone marrow from a donor. A bone marrow transplant is recommended only for people who have substantial symptoms and problems from sickle cell anemia. This procedure carries risk and there is a chance that the patient’s body could reject the transplant, which could lead to death. Also not every patient is able to find a proper donor (Mayo Clinic Staff, 2011).

If a donor is found, the diseased bone marrow in the person with sickle cell anemia is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are then taken from their blood and injected intravenously into the bloodstream of the person with sickle cell anemia. The healthy stem cells them move to the bone marrow cavities and begin making new blood cells (Mayo Clinic Staff 2011).

This bone marrow transplant procedure used to be considered too harsh for adults and was only used with children. This changed in 2009 when a team from the National Institutes of Health and Johns Hopkins University reported that they had developed a much-less-toxic transplant procedure and used it to cure nine of the first 10 adult patients studied (Maugh, 2009).

** Other Treatment Methods **
Pain is one of the leading symptoms with SCA and throught a two year experiment with hydroxyurea, it was found that intaking the medication hydroxyurea helped lower pain intensity quickly and consistently. It was also suggested that hydroxyurea may play a part in reducing organ damage, especially in younger patients (Smith, Ballas, McCarthy 2011.) For episodic treatment of severe pain that has overcome any homecare treatments, opiods such as morphine may be administered in an emergency room setting. Codein, Hydrocodone, and oxycodone are some medications that are used in tandem with opiods in severe pain situations. Antideppressants are common in SCA cases due to the deppression atributed to having chronic or acute pain (Smith, Ballas, McCarthy 2011.)

In order to prevent circulatory problems such as stroke or heart attack, chronic blood transfusions and constant hydration will be a treatment in order to thin the blood and alleviate the body from the sickled RBC's that have developed. This treatment may only be advised if the patient has had a transcranial ultrasound machine that assesses stroke risk (Adams, Ataga, Ballard 2012.) Blood transfusions will reduce the symptoms of anemia as well. Supplementary oxygen is also used as a treatment for patients that have poor blood oxygen content. Oxygen masks help the patient breath with less effort as well, especially when the patients has acute chest syndrome or sickle cell crisis, which is associated with SCA (Mayo Clinic Staff, 2011.)

Patients with SCA are prone to infections. Therefore, medications and immunizations need to be prescribed to SCA sufferers. Children with SCA are usually placed on penicillin from 2 months of age until 5 years of age to prevent infections, especially in the lungs. Vaccinations are highly suggested for patients with SCA to better prepare their immune systems (Mayo Clinic Staff, 2011.)

A very promising and important experimental treatment is gene therapy.

**__References for timeline:__**
Frenette, P. S., & Atweh, G. F. (2007). Sickle cell disease: old discoveries, new concepts, and future promise. //American Society for Clinical Investigation//, //117//(4), 850-858.

The U.S. Department of Energy Biological and Environmental Research program (2005, May). //Genetic disease profile: Sickle cell anemia//. Retrieved from []

__**References:**__
Adams, Robert, Ataga, Kenneth, Ballard, Harold. "National Institutes of Health." //The Managment of Sickle Cell Disease//. Version 4th Edition. NIH Publication, n.d. Web. 4 Apr. 2012. [|www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf]

Brooker, R. J. (2009). Extensions of Mendelian Inheritance. //Genetics: Analysis &// //Principles// (3rd ed., pp. 77-78). New York, N.Y.: McGraw-Hill.

(2003). //Cecil textbook of medicine//. (22 ed.). W.B Saunders Company.


 * Chang, Judy, Lin Ye, and Yuet Kan. "Correction of the sickle cell mutation in embryonic stem cells." //Jstor.org//. Version Vol. 103 No. 4. Departments of Labratory Medicine and Medicine, Cardiovascular Research Institute and Center of Human Genetics, n.d. Web. 4 Apr. 2012. http://www.jstor.org/stable/pdfplus/30049125.pdf?acceptTC=true

Coghlan, A. (2009, December 10). Stem cell transplants treat 'incurable' blood disorder. //NewScientist//, Retrieved from []

Frenette, P. S., & Atweh, G. F. (2007). Sickle cell disease: old discoveries, new concepts, and future promise. //American Society for Clinical Investigation//, //117//(4), 850-858.

Fox, S. I. (2011). Respiratory Physiology. //Human Physiology// (12th ed., pp. 556-557). New York, N.Y.: McGraw-Hill.

HBB: The Gene Associated with Sickle Cell Anemia (2003, September 12). In genomics.energy.gov. Retrieved April 3, 2012, from []

Ciechanowicz, A. (2011). Sickle Cell Anemia-Associated Beta-Globin Mutation in Shagia and Manasir Tribes from Sudan. Polish Journal Of Environmental Studies, 20(6), 1525-1530. []
 * Kempińska-Podhorodecka, A., Knap, O. M., Parczewski, M., Bińczak-Kuleta, A., &

Maugh, T. H. (2009, December 10). Bone marrow transplant 'gets rid of' sickle cell anemia. //Los Angeles Times//, Retrieved from []

Mayo Clinic Staff. (2011, March 26). //Sickle cell anemia treatments & drugs//. Retrieved from []

McKinley, M., & O'Louglin, V. D. (2008). Blood. //Human Anatomy// (2nd ed., pp. 640-642). New York, N.Y.: McGraw-Hill.

NHLBI. (2011, August). //National heart lung and blood institute//. Retrieved from http://www.nhlbi.nih.gov/new/sicklecell.htm

Philippe, J., PondarreÂ´, C., Bardel, C., Francina, A., & Martin, C. (2011). The alpha-globin genotype does not influence sickle cell disease severity in a retrospective cross-validation study of the pediatric severity score. //European Journal of Haematology//, //88//(1), 61-67. Retrieved March 23, 2012, from the EBSCOhost database. Tchuenche, J. M. (2005). REALISTIC PATTERNS OF INHERITANCE OF SICKLE-CELL ANEMIA GENE:: A THEORETICAL APPROACH. Journal Of Biological Systems, 13(1), 13-22.


 * Smith, W. R., Ballas, S. K., McCarthy, W. F., Bauserman, R. L., Swerdlow, P. S., Steinberg, M. H., et al. (2011). The Association Between Hydroxyurea Treatment and Pain Intensity, Analgesic Use,. //Pain Medicine//, //12//(5), 697-705. Retrieved April 3, 2012, from the EBSCOhost database.

The U.S. Department of Energy Biological and Environmental Research program (2005, May). //Genetic disease profile: Sickle cell anemia//. Retrieved from []

What Are the Signs and Symptoms of Sickle Cell Anemia? - NHLBI, NIH. (2011, February 1). //NIH Heart, Lung and Blood Institute//. Retrieved April 3, 2012, from []