Rose Farrington and Rachel Nash BIOL 362 Lab M. Bulgarella Genetic Diseases 10/14/2008 Sickle Cell Anemia Introduction Sickle cell anemia is an inherited disorder of the blood which occurs when just one base pair substitution leads to the creation of mutant hemoglobin, which ultimately leads to the formation of abnormal sickle shaped red blood cells that impair blood flow. Carriers of the sickle cell trait may experience mild symptoms during long periods of low blood oxygen levels, while individuals who are homozygous for the mutant allele suffer extreme bouts of sickle crisis during which sickle shaped cells clog small blood vessels, leading to multiple painful and damaging effects. Affected individuals as well as carriers of the sickle cell allele are identifiable early in life where finances and access to modern medical facilities allow. Current treatments for sickle cell anemia include regular blood transfusions and medication. The sickle cell allele has a higher frequency than other alleles coding for comparable genetic diseases. It is especially high in areas of the globe where malaria is widespread, probably due to the heterozygote advantage conferred to carriers of the sickle cell allele who are infected with the malaria parasite (Campbell and Reece, 2005). Current research suggests that the spread of malaria probably resulted in sickle cell disease (Converse J.P. et al, 2008 August 21). Point Mutation Mutant hemoglobin leading to the symptoms of sickle cell anemia forms when a base pair substitution occurs in the affected individual s hemoglobin DNA. Wild type hemoglobin DNA has the sequence cytosine, thymine, thymine, while adenine replaces the second thymine in mutant hemoglobin DNA. The mrna created from the mutant hemoglobin template thus differs in one nucleotide as well. Where normal hemoglobin mrna has a codon made up of guanine, adenine, adenine, the mrna codon that translates to abnormal hemoglobin 1
has a uracil base in place of the adenine base, due to the original substitution in the template hemoglobin DNA. This base pair substitution allows for a missense mutation, in which the altered codon of the mrna codes for valine instead of the glutamic acid that is present in regular hemoglobin. Hemoglobin molecules manufactured with glutamic acid rather than valine crystallize when blood oxygen is low, creating the deformed sickle shaped cells which give sickle cell anemia its name (Campbell and Reece, 2005). Effects of Mutant Hemoglobin Symptoms can range from mild to quite severe and scientists do not yet understand why some patients with sickle cell anemia seem much more affected than others. Tiredness, a symptom of all anemias, is the most common symptom, but others include headache, dizziness, shortness of breath, cold hands and feet, and chest pain (National Heart Lung and Blood Institute, 2008). If sickle cells form clumps in the kidney, lungs, or other organs, a crisis can result. A sickle cell crisis can be relatively mild, or can be quite severe sending a sufferer to the emergency room. Nearly everyone with sickle cell anemia will suffer an acute sickle cell crisis at least once a year, and some suffer such episodes more than once a month. In some cases the affected organ suffers permanent damage caused by reduced blood flow. Acute chest syndrome is the most common cause of death, but other potential life threatening symptoms include splenic sequestration, renal failure, hepatic failure, stroke, and pulmonary or thrombosis emboli (Converse J.P. et. Al, 2008, August 21). Treatment Currently there is no cure for sickle cell anemia, but there are treatments available to treat the symptoms. Dehydration increases the chance of experiencing symptoms, so increasing fluid intake can help prevent and control mild pain associated with sickle shaped blood cells blocking blood flow. Over the counter pain medicines such as ibuprofen can also be used, but chronic pain and acute pain resulting from sickle cell crisis are typically treated with a combination of narcotics and anti inflammatory drugs (National Heart Lung and Blood Institute). Hydroxyurea is used to prevent crises and recurring bouts of acute chest syndrome. However, the long term 2
effects of this drug are not well known and currently this drug is only prescribed for severe cases of sickle cell anemia. Many patients also require frequent blood transfusions which can cost as much as $25,000 per year for children, and more for adults (Medical College of Georgia, 2003). Medicare will not cover the first three transfusions, but will usually cover at least 80% of subsequent transfusions (Medicare Reimbursement, 2004). These transfusions reduce the probability of having a stroke because the goal is to keep the percentage of blood cells with abnormal hemoglobin to less than 30% of the total red blood cells. While frequent blood transfusions appear to be an expensive option, it reduces the need for hospitalization and in the long run is less expensive. Individuals with sickle cell anemia need regular medical care, and may require a specialist in blood disorders. Many will need occasional hospitalization and some will be in and out of the hospital quite frequently. Children under the age of five are often prescribed daily doses of penicillin to reduce the possibility of getting infections such as pneumonia, one of the largest causes of mortality in children with sickle cell anemia. Heterozygote Advantage A heterozygote advantage exists for carriers of the sickle cell allele who live in areas of the world where malaria is common. During the second phase of the infection in humans, the malaria parasite inhabits red blood cells. In Individuals who are heterozygous for the sickle cell allele the infected red blood cells do not stick as effectively to the endothelial cells that form blood vessels. This reduction in stickiness of the blood cells reduces the ability of the parasite to kill infected individuals (Converse J.P., et. Al, 2008, March 13). Though homozygous individuals who have the sickle cell disease suffer a range of negative symptoms, these disadvantages caused by the allele are outweighed by the advantages conferred on carriers of the sickle cell trait who are also infected with malaria. Individuals with the heterozygote genotype are ten times less likely to contract the fatal strain of malaria and also experience some protection from the severity of deadly malaria attacks, particularly in the young (Converse J.P. et al., 2008). In parts of the world where many people die annually from malaria, heterozygous carriers of the sickle cell allele have a higher fitness than both dominant and recessive homozygous 3
individuals. This has allowed the sickle cell allele to persist and thrive in human populations where malaria is common, leading to higher than usual frequencies for an allele with such possible detrimental effects. The allele has the highest frequency in Africa, where malaria is most widespread. In some tribes as many as 20% of the population are carriers of the sickle cell allele. In fact, sickle cell anemia is the most common genetic disease among individuals of African descent (Campbell and Reece, 2005). One in every five hundred African Americans suffer from the disorder, and one in twelve is a carrier for the sickle cell trait (National Diabetes Information Clearinghouse, 2007). Although sickle cell anemia is most commonly found in individuals of African descent, it is estimated that this mutation has occurred at least five separate times; four of which occurred in distinct locations in Africa and one which appears in India and Saudi Arabia (Converse J.P., et. Al, 2008, March 13). This distinction may explain why some individuals seem to exhibit a much more severe sickle cell disease than others. This record of multiple mutation events also indicates that protection against malaria increases the fitness of an individual. Other places where both the malaria parasite and the sickle cell allele are present in high frequencies are Southeast Asia, and the nations bordering the Mediterranean Sea (Campbell and Reece, 2005) Conclusion Sickle cell anemia is one of the most common inherited disorders of the blood, and is particularly prevalent in those of African and South American descent. The disease is caused by a point mutation which alters one amino acid in hemoglobin proteins. Mutant hemoglobin leads to sickle shaped blood cells which can block blood flow throughout the body. Common symptoms range from fatigue and tiredness to strokes. Individuals who are homozygous for the mutation are particularly sensitive to infection, and must constantly be under close supervision by medical professionals. The financial and social burdens on families of those with sickle cell anemia are very severe as frequent costly trips to the hospital are common, making it difficult to lead a normal lifestyle. 4
References Campbell, N. A., & Reece, J. B. (2005). Biology. (7 th ed.). San Francisco, CA: Pearson Education, Inc. Converse J.P., et. Al (2008, March 13). Hemoglobin Beta Locus; HBB. [Online]. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=141900&a=141900_allelicvariant0243 Converse J.P., Hamosh A., Tiller G. E (2008, August 21). Maleria, Susceptablity to. [Online]. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=611162 Medical College of Georgia. (2003). Stroke Prevention using Transcranial Doppler and Blood Transfusion. [Online]. http://www.mcg.edu/neurology/research/sicklecell/descstrokeprev.htm National Diabetes Information Clearinghouse. (2007, November) Sickle Cell Trait and Other Hemoglobinopathies and Diabetes: Important Information for Physicians. [Online]. http://diabetes.niddk.nih.gov/dm/pubs/hemovari A1C/index.htm National Heart Lung and Blood Institute. (2008, August). Diseases and Conditions Index: Sickle Cell Anemia. [Online]. http://www.nhlbi.nih.gov/health/dci/diseases/sca/sca_signsandsymptoms.html Medicare Reimbursement of Blood Transfusion. (2004, November 10). [Online]. http://www.bloodbook.com/medicare.html 5