The Genetic Disorder Which is Called Sickle Cell Anemia - Case Study Example

SICKLE CELL ANAEMIA [Pick the Sickle cell anaemia is a genetic disorder controlled by a recessive autosomal gene, HBB located onthe chromosome 11 short arm. The disease is characterized by sickling of red blood cells due to clumping of haemoglobin in its deoxygenated state resulting in anaemia and sharp pain specifically known as sickle cell crisis. The disease predominantly affects people of African origin where its occurrence was a key to survival against malarial parasite. But in the malaria free America today, where a huge population of Afro-Americans is affected by Sickle cell anaemia, the disease is hard to manage. Knowledge of the pathophysiology, symptoms, diagnosis and treatment of the disease is imperative in the fight against the disease and in order to find a permanent solution to the problem. This study aims to analyse the various aspects of SCA integrating information from the fields of genetics, cytology, human physiology and pharmacology. INTRODUCTION : Sickle cell anaemia, also known as HbS disease, Haemoglobin S disease, Haemoglobin SS disease, sickle cell disease (a group of related diseases including sickle cell anaemia), sickle cell disorder (a group of HbS gene disorders), sickling disorder due to haemoglobin S; is a severe genetic disease characterized by production of sickle shaped red blood cells (RBCs) (figure 1) in people of African origin. The disease is caused by the inheritance of an autosomal recessive trait, leading to a group of genetic disorders including production of haemoglobin S, blockage of blood flow due to abnormal shape of RBCs, followed by acute and chronic tissue damage (Steinberg, 2008). Sickle cell anemia was the first genetic disorder identified, linking disease phenotype to gene, and is today the most common type of sickle cell disease effecting 70,000 to 80,000 Americans (Herrick, 1910). The abnormal gene is found to be present in 375 live births in Afro-American population, and is also found to affect individuals of Mediterranean, Caribbean, South and Central American, Arabian and East Indian origin (NIH, 2002). Thus sickle cell disease, besides being an issue of great concern offers a perfect medical condition enabling the integration of various fields of study viz. biochemistry, genetics, cellular biology, human physiology and pharmacology, in developing an understanding of the various aspects of this disease. METHOD: Thorough literature search was done to gather and study all available material on sickle cell anaemia. All published material from peer reviewed journals, including both review and research articles, and also those available from authentic and reliable sources on internet; was studied, referenced and cross referenced. The relevant material was compiled concisely to prepare the document, presented under appropriate subheads. SYMPTOMS: Sickle cell anaemia is a genetic disease, yet infants affected by the disease usually exhibit signs after four months of age. The symptoms vary in nature and intensity and are usually related to anaemia and pain. The anaemia leads to extreme weakness and reduced working capacity, along with breathlessness, dizziness, headache, pale complexion and low temperature of extremities (Steinberg, 2008). Another major problem associated with SCA is excruciating pain, arising suddenly; and known as sickle cell crisis (Dunlop & Bennett, 2006). Small blood vessels in the circulatory system become clogged by clumping together of sickle shaped RBCs. This occlusion obstructs the blood flow in capillaries and is painful. The regions affected are bones including joints, lungs, spleen and abdomen. Pain, in the lungs, leads to severe chest crisis. Further symptoms of SCA arise due to complications arising as a result of these basic conditions. GENETICS: An understanding of the Genetics of SCA requires a basic understanding of the overall structure of haemoglobin molecule and its genetics. Haemoglobin is a 146 amino acid long protein with a molecular weight of 15,867 Daltons. It is located inside the RBCs and is the major oxygen carrier molecule in blood. It is a tetrameric protein made of four protein subunits: two alpha globins and two beta globins, each of which carries an iron containing molecule called heme, which is imperative for oxygen transport function of haemoglobin (Perutz, 1960). Each haemoglobin molecules binds to four molecules of oxygen (HbO4), which imparts the bright red colour to the blood. Of the subunits of haemoglobin, the beta globins are encoded by HBB gene, thus mutations in HBB results in altered structures of beta globins. The HBB gene or the haemoglobin beta gene is located in the 15.5 region on the short arm of chromosome 11 of humans (Steinberg, 2009). The normal allele of it is 1600 base pairs (bp) long and consists of three exons. The intron free mRNA formed as a consequence of HBB gene is 626bp long, of which 444bp code for the amino acid sequence of beta haemoglobin. The HBB gene is known to exhibit more than 250 mutations, most of which involve single nucleotide alterations within or in vicinity of gene locus. Few are addition and deletion mutations, resulting from addition of an extra nucleotide or removal of one within the gene locus. SCA is caused by a single nucleotide substitution (GAG to GTG) leading to formation of the variant of haemoglobin, haemoglobin S or Hb S, in which the hydrophilic amino acid glutamic acid (Glu) at the sixth position from N-terminus of HBB chain is replaced by the hydrophobic amino acid valine (Val) (Conran et al., 2009). Two similar hydrophobic regions created on the outer side of two beta chains of adjacent haemoglobin molecules clump together to form polymerized product. This polymerization of Hb S molecules results in the sickle cell formation of RBCs. The Hb S gene or s gene is an autosomal recessive gene and therefore follows the pattern of inheritance described in figure 2 and 3. For the expression of this gene or occurrence of SCA, both alleles of the gene should be altered (Barlow-Stuart, 2007). If only one of the allele is altered, the individual is a carrier of SCA gene and is said to have the sickle cell trait. The individual is not at a risk of SCA, since the Hb A is present at about 60%, and therefore no sickling occurs. However, there is risk of hematuria due to papillary necrosis and thus precaution is recommended during administration of anaesthesia to the carriers and during pregnancy. Further, the expression is gender independent, since the gene is not present on a sex chromosome. The abnormal Hb S gene is highly prevalent in tropical and sub tropical regions, since it protects the RBCs from malarial infection by Plasmodium falciparum (NIH, 2002). PATHOPHYSIOLOGYLOGY: The cells containing deoxygenated polymerized Hb S become rigid and their concave shape is altered to a characteristic sickle shape (Herrick, 1910), thus causing blockage of blood vessels. The clinical feature of SCA thus occurs due to preponderance of RBCs containing the ‘sickled’ haemoglobin (Conran et al., 2009). This polymerization occurs only in the deoxygenated state of haemoglobin that is after releasing oxygen in the tissues. Once they return to lungs for reoxygenation, and bind oxygen, the clumping is reversed and Hb S molecules are once again separate. Thus a cycle of polymerization occurs along with the cycle of oxygenation and deoxygenation, which leads to rigidity of RBC membranes. Finally these deformed and rigid RBCs are sequestered or isolated in the reticuloendothelial system causing hemolysis and therefore, anaemia. These rigid RBCs also come to occupy the microcirculation and cause occlusion. This blockage results in painful experiences, and causes damage to organs; further adding to discomfort (Dunlop & Bennett, 2006). DIAGNOSIS: Diagnosis of SCA based on the three pathological conditions involves blood film appearance, screening test for sickling, haemoglobin electrophoresis. In study of blood film appearance a low oxygen smear of blood (to induce Hb S, if present to sickle) is prepared and the abnormal cells are identified under a microscope. This is done along with (complete blood count) CBC and iron studies to detect anaemia in general. During screening tests for sickling Hb S solubility tests and sodium metabisulfite tests are performed on tube of sample blood for screening deoxygenated blood samples for the presence of haemoglobin S. In individuals with sickle cell trait the screening shows presence of some Hb S and therefore electrophoresis needs to be done to differentiate SCA from trait condition. Also infants below six months do not show the presence of Hb S, due to presence of Hb F in them and therefore a misinterpretation is highly probable. To avoid this haemoglobin electrophoresis is done. The different Hb species from a blood sample are separated on an electrophoretic gel based on their electric charges. Since the SCA affected blood sample does not contain Hb A, in the results the band for Hb A is absent, and instead there is a band for Hb S. Thus the assay helps in SCA diagnosis. Other methods of diagnosis are HPLC or high pressure liquid chromatography which is increasingly used to assay Hb S and isoelectric focussing, which is another technology making use of electric charges of molecules for their separation and assessment, and is highly sensitive. HPLC and isoelectric focussing are used for screening of new borns for Hb S. The number of Hb S in newborns varies, increasing with age as Hb F decreases; finally becoming stable at the age of two. Prenatal Screening is another preventive measure which can be done as early as 10week foetus, and involves use of amniocentesis or chorionic villus sampling. Here the sample is tested for the presence of Hb S gene and not the gene product (NIH, 2002). TREATMENT: The main issue in treatment of SCA is keeping pain in control. The treatment therefore mainly involves behavioural recommendations or advising the patient to avoid low temperatures, high altitude and exertion, in order to prevent breathlessness and hypoxia. High fluid intake particularly following vigorous physical activity or any other kind of fluid loss is essential. Another treatment procedure deals with medications involving daily dosage of folate and daily prophylactic penicillin. Low doses pf hydroxyurea, which is a cancer drug, has also been found to be effective in alleviating pain, reducing blood transfusion and increasing haemoglobin in blood (Charache et al., 1995). The mechanism of action is not known, but it could be by inducing the foetal haemoglobin. Pain management is possible through analgesics, alone or in combination with anti-inflammatory agents. Vaccinations against encapsulated bacteria such as Streptococcus pneumonia, Haemophilus influenzae, Neisseria meningitides (Ammann et al., 1977) is recommended. Oxygen administration is advised in cases of respiratory insufficiency. Bone marrow transplant from an optimally matched donor is the only available cure for SCA, and this too has many limitations such as toxicity (Walter et al., 1996). Hence only high risk people are recommended this operation. Gene therapy techniques are being developed to cure SCA, but these are still under study (Gaziev et al., 2010) . COMPLICATIONS AND PROGNOSIS: Besides the pain and anaemia, other problems of SCA arise due to the certain complications (Howard and Hamilton, 2002). The complications can be genitourinary complications involving lack of ability to concentrate urine, papillary necrosis with hematuria, nephritic syndrome and priapism; skin complications i.e. lower limb ulcerations; eye complications such as proliferative retinopathy, glaucoma; hepatobiliary complications involving liver damage and pigment gallstones and pulmonary hypertension (PHT). The physiology of PHT has recently been found to be determined by the availability of nitric oxide (NO) in sickle cell (Hagar and Vichinsky, 2008). Proper disease management and treatment leads to survival of 80-90% of SCA patients. Mortality is commonly due to infection in infancy, cerebrovascular accidents in teenage and respiratory complication in adults (Steinberg, 2008). CONCLUSION: SCA is a life threatening disease, involving a complex set of interactions between the various biological systems in human body. It enables an understanding of the various aspects of the functioning of the biological system such as, the cellular uniqueness of red blood cells compared to other cells in human body, the significance of oxygen carrying capacity of haemoglobin, the aspects of determination of protein structures by the genetic makeup of an individual and the remarkable changes in the phenotype as a consequence of a single nucleotide change in the DNA. This same disease condition although highly advantageous in malaria affected regions, is a menace for US, where there is no malaria. In US alone the SCA trait frequency is 1 in 12 and 1 in 600 children are born with SCA. Hence, it is imperative that carriers of sickle cell trait should be well aware of their condition and should be discrete in reproductive choices. Prenatal diagnosis must be done when both parents are with sickle cell trait. With increasing awareness and the choices as well as treatments, available the heterozygote frequency has been found to decrease in recent years. FIGURES Figure 1: Source NHLBI website (October 2010) Figure 2: Barlow-Stuart (2007) Figure 3: Barlow-Stuart (2007) References 1. Ammann, A. J., et al., (1977). , Polyvalent Pneumococcal polysaccharide immunisation of patient with sickle cell anaemia and patient with splenectomy. N Engl J Med, 297, 897-900 2. Barlow-Stuart , K. (2007). Autosomal recessive inheritance - Traditional Patterns of Inheritance 1, retrieved November 21, 2010 from Centre for Genetics education website. http://www.genetics.com.au/factsheet/fs8.asp 3. Charache S, Terrin ML, Moore RD, et al. (May 1995). "Effect of hydroxyurea on the frequency of painful crises in sickle cell anaemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anaemia". N. Engl. J. Med. 332 (20): 1317–22. 4. Conran, N., Franco-Panteado, C. F. And Costa, F. F. (2009). Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Haemoglobin, 33(1), 1-16. 5. Dunlop RJ, Bennett KC. (Apr 19 2006) Pain management for sickle cell disease. Cochrane Database Syst Rev. ;CD003350. 6. Farrel, K. Et al., (2010). Relationship of oxygen transport and cardiac index for prevention of sickle cell crises. J. Nat Med. Assoc. 102(11), 1000-7. 7. Gaziev J, Lucarelli G, (2010 Dec) Allergenic cellular gene therapy for hemoglobinopathies. Hematol Oncol Clin North Am; 24(6):1145-63. 8. Hagar, W. and Vichinsky, E. (2008). Advances in clinical research in sickle disease. British journal of hematology, 141, 346-56. 9. Herrick, J.B. (1910). "Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anaemia". Archives of Internal Medicine 6: 517–521. 10. Howard, M. R. And Hamilton, P. J. (2002), Hematology: an illustrated colour text. China: Elsevier Limited. 11. NHLBI, (October 2010) retrieved November 21, 2010 from http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html 12. NIH Publication, (Sep, 2002), Sickle cell research for treatment and cure, Retrieved 23 November 2010 from http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html 13. Perutz, M. F. (November 1960). "Structure of haemoglobin". Brookhaven symposia in biology 13, 165–83. 14. Retrieved November 21, 2010 from httpwww.nhlbi.nih.govhealthdciDiseasesScaSCA_WhatIs.html 15. Steinberg MH. (2008). Sickle cell anaemia, the first molecular disease: overview of molecular aetiology, pathophysiology, and therapeutic approaches. Scientific World Journal. 25(8), 1295-324. 16. Steinberg MH. (2009 Jan).Genetic aetiologies for phenotypic diversity in sickle cell anaemia. Scientific World Journal. 18(9), 46-67. 17. Walters MC, Patience M, Leisenring W, et al. (August 1996). "Bone marrow transplantation for sickle cell disease". N. Engl. J. 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