Thalassemia as an Inherited Genetic Disorder - Essay Example

THALASSEMIA Name Course Lecturer Word count 1810 Introduction Among the inherited genetic disorders is Thalassemia. This disorder is marked by abnormal lipid accumulations and abnormal appearance of the electrophoresis graph of the hemoglobin present. It is therefore important to analyze Thalassemia, its epidemiology, causes and the pathogenesis involved (Cheng, Lee & Lin, 2012). The essay would then focus on the diagnostic mechanism and focus on the major diagnosis criterion, analyze its principle, method and the procedure involved, the major reagents and the equipment used as well as the expected results. The discussion would then focus on the treatment modalities for thalassemia, the expected effect of the mechanisms, and the targets of the mechanisms. Hemoglobin is synthesized from globin (amino acids) and haem. Haem is produced from ion and bilirubin. All these processes take place in the reticulo-endothelial cells. Hemoglobin is essential for transport of oxygen to the tissues and carried by blood. Inadequate or defective hemoglobin synthesis would result into anemia. Improper incorporation of iron to form haem would lead to iron overload (Butt, 2013). The abnormalities of hemoglobin synthesis include thalassemia, hemoglobin C, sickle cell anemia and a rare group of hemoglobinopathy that lead to defective red blood cells production and abnormal structures. Normal hemoglobin levels range between 9-14 g/dL. In thalassemia, the hemoglobin levels are usually reduced below 9.0 g/dL. Disease and the Epidemiology The disease of concern is thalassemia which is an inherited disorder caused by a mutation of the genes essential for synthesis of globin chains. This condition has two major divisions; either as β-Thalassemia or α-Thalassemia. Β-Thalassemia majorly as a result of point mutation on chromosome 11 while or α-Thalassemia is usually due to deletions on chromosome 16 depending on the globin chain affected. The main classification is however, for β-thalassemia, Thalassemia major-, Thalassemia intermedia or Thalassemia minor. Beta-Thalassemia major is characterized by severely decreased hemoglobin levels around 3-4 g/dL, MCV of 50-70 fL (Duman, Arayici, Fettahoglu, Eryilmaz, Ozkaynak, Yesilipek & Hazar, 2011). There is also marked inclusions such as Howell-Jolly bodies and Pappenheimer bodies and basophilic stippling. Beta–Thalassemia intermedia patients have hemoglobin levels greater than 7 g/dL. It is distinguished from thalassemia minor as it does not require regular blood transfusion. Beta-Thalassemia minor is asymptomatic with hemoglobin levels ranging between 10.8-12.8g/dL. The red blood cells in this case are microcytic and hypochromic. The α-Thalassemia is classified as silent carrier (a deletion of just one α-globin gene), α-thalassemia trait (with two α-globin genes deleted), HbH (three of the α-globin genes deleted) disease, and hydrops fetalis (all the four α-globin genes deleted) commonly in the utero life. Epidemiologically, the disease poses a global threat. Several cases of the condition have been reported across world. However, it has specific areas in which the high percentage of cases has been reported from. This condition has a profound predilection for countries that lie within what is termed ‘the thalassemia belt’. This region extends from the Mediterranean east across the Middle East towards India and Southwards to Northern Africa (Cheng et al., 2012). Table 1 Population Per 100,000 births Hemoglobinopathies endocrine metabolic Cystic fibrosis Hispanic 20 70 25 30 Black 380 20 25 40 Southeast Asian 1075 75 25 0 Vietnamese 100 50 20 0 Multiple Asian 200 75 20 0 Middle Eastern 30 80 100 20 Filipino 75 50 20 20 Japanese 25 75 0 0 Quality in life in patients with Thalassemia (2016) Figure 1 showing incidence of Beta-Thalassemia Major The typical symptoms of the disease For beta-Thalassemia, clinical manifestations commence at around 6-12 months post-birth. This is the period marked by the replacement of the hemoglobin F of the fetus with the adult hemoglobin, hemoglobin A. It presents with the symptoms that are outlined below. Most of these symptoms cut across for the alpha thalassemia. The main clinical features of the condition include anemia that for thalassemia major would be microcytic hypochromic in presentation (International Journal of Research, 2016). Anemia in this case would be marked by its major presentation symptoms such pallor and jaundice. Another feature is skeletal deformities due to the expanded erythropoietic marrow that would then fill the intramedullary space of the skeleton. This leads top stunted growth and hypogonadism thus presenting as dwarfs. . Splenomegaly, hepatomegaly, and lymphadenopathy also occur due to hyperplasia and extramedullary hematopoiesis. Cachexia occurs due to increased nutrient consumption by the disordered erythropoiesis. There is a prevalent risk of hemochromatosis due to iron overload (Cheng et al., 2012). This would present with cardiac failure. Radiological changes occur as a result of expanded bone marrow cavity. The skull therefore has an appearance referred to as ‘hair-on-end’ appearance. The immunological/hematological mechanism(s) of the disease For β-Thalassemia, the mutation on chromosome 11, its pathogenesis follows the mutation and then inheritance of the abnormal alleles. Inheritance of one abnormal allele would lead to β-thalassemia minor which is usually mild and asymptomatic. If the child inherits two abnormal β alleles (β0 and β+), the condition would be termed β-Thalassemia major that is symptomatic. Inheritance two β+ alleles would cause a milder disease referred to as the β-Thalassemia intermedia (Sonakul, 1995). The effects of these mutations are as follows. They cause abnormal splicing of RNA depleting the number of maturely synthesized mRNA leading to decreased β globin synthesized. These mutated alleles also occupy the β-globin promoter region inhibiting the transcription of β-globin chain. Other alleles also target the coding regions of the β-globin gen reducing the translation rate of the β-globin mRNA thus preventing synthesis of β-globin chain (Saliba, Musallam, Cappellini, Graziadei, Daar, Viprakasit & Taher, 2017). The increased levels of α chain in comparison to the level of the β chains have a role. There follows precipitation of the α-chains in the developing red blood cells. This then results into inclusion bodies with an increased propensity to cause oxidative stress that would be exerted on the cell membranes triggering apoptosis and destruction of the precursor of erythrocytes. The reduced synthesis of the β-globin would then result into inadequate hemoglobin A production thus infective erythropoiesis occurs leading to anemia, iron overload due to ineffective binding of iron to haem which should then bind to globin to form a complete hemoglobin, hyperplasia of the mononuclear phagocytes leading to splenomegaly, hepatomegaly and lymphadenopathy (Livingstone, 1985). The α-Thalassemia occurs mainly due to deletions of a single or more α-chains. Loss of a single α-globin leads to silent carrier state as the milder with the deletions of all the four α-globin termed hydrops fetalis mainly in the utero life. Ineffective erythropoiesis is however not as pronounced as with the case in β-Thalassemia (Meloni, Borgna-Pignatti, Del Vecchio, Romeo, Gamberini, Bonetti, & Pepe, 2016). This is so due to the formation of β4 and γ4 from the increased β-globin. These are less oxidative hence less severe destruction of the erythrocytes (Forget, 2011). Diagnostic test for the disease The main diagnostic tool for thalassemia is the electrophoresis which is referred to as hemoglobin electrophoresis, cation-exchange high-performance liquid chromatography (HPLC) and capillary zone electrophoresis (CZE) (Livingstone, 1985). Other laboratory assessment methods include complete blood count with a consideration of the peripheral Blood Count (PBC), reticulocyte count, supravital staining and molecular genetic analysis. Principle This method involves the use of electric current to separate the normal hemoglobin from the abnormal hemoglobin (Thakur, Raw, Sharma & Mishra, 2016). The normal hemoglobin will be able to migrate to a support that is stained for easy identity of the bands that will appear on the support. The migration of the hemoglobin is based on the specific charges each of them has (Livingstone, 1985; Forget, 2011). Method i. The process begins with collection of blood. The patient’s arm is cleaned with a swab by rubbing using alcohol. ii. The needle is then inserted and blood collected iii. The blood sample is stoppered and sent to the laboratory. iv. The process of electrophoresis then begins. v. The patient’s blood is placed on a solid support, the most preferred in the agarose background. vi. The sample is then subjected to an electric current at an alkaline media. vii. The hemoglobin will then separate depending on their electronic charge into different bands. viii. The support is usually stained to allow the hemoglobin bands to able to be quantified through scanning densitometry to allow determination of their percentage distribution. ix. The bands are then compared with the normal range for each hemoglobin type present. Major Reagents (Sonakul, 1995). The major reagents used in the tests include: (Hematological Evaluation in Transfused beta-Thalassemia Major i. Hemoglobin A1c Reagents for HPLC-723G8 ii. Β-Thalassemia Reagents for HLC-723G8 iii. Blood sample is the main specimen iv. Electro photometer v. An alkaline medium Expected results Normally, the percentage distribution for the hemoglobin is as follows; Hemoglobin A (α) -:95% Hemoglobin: 2% -3% Hemoglobin F: 0.8%- 2% Hemoglobin S: 0% Hemoglobin C: 0% The results expected in that confirm the presence of thalassemia is increased hemoglobin, reduced hemoglobin A and increased hemoglobin F. These confirm the diagnosis of beta thalassemia (Butt, 2013). Alpha thalassemia is marked electrophoretically by normal electrophoresis in adults and newborns with hemoglobin H or hemoglobin Bart’s. Treatment The management of thalassemia involves the use of iron chelators such as deferoxamine, blood transfusion, bone marrow transplant, and the management of the specific conditions such as hypersplenism, endocrine abnormalities, pregnancy, cardiac failure, hypercoagulability, psychosocial withdrawal, and vitamin deficiencies (Sonakul, 1995). Fundamental mechanism Iron chelators Increased blood transfusion results into increased iron overload following poor mechanism of iron removal (Livingstone, 1985). The iron chelators (Deferoxamine) are given intravenously or subcutaneously thus depleting iron overload effects. Blood transfusion This is done to counter the effect of anemia as a result of poor erythropoiesis. This is done regularly to ensure that the hemoglobin level fall within the normal range (above 9.5g/dL). Bone marrow transplantation This is the surest curative mechanism that is deployed to counter beta-thalassemia. Through the transplantation of the erythropoietic progenitors, a response occurs that increases the volume of blood towards the normal range (Cheng, 2012). Table 2 Year Number of transplantation done 2006 238 2007 254 2008 233 2009 242 2010 258 2011 285 2012 243 2013 245 2014 229 2015 268 2016 297 Hematological evaluation in Transfused β-Thalassemia Major patients (2016) Management of specific symptoms of Thalassemia Splenomegaly is managed by splenectomy. This is however done to patients above four years of age considering the key role of spleen in preventing bacterial infections. After the fourth year vaccination can thenceforth play the role against sepsis. Other effects such as hypogonadism necessitate the use of growth hormone therapy. For pregnant patients, genetic counseling is recommended to limit the late presentation of defects of inherited genetic defects. Hypercoagulability o blood is managed by infusion of small doses of heparin to breakdown the clots. Psychosocial withdrawal is managed by education and proper counseling. Vitamin deficiencies such as folate deficiency can be managed through oral supplements of small doses of folate (Cheng, 2012). The expected results would be improvement of the clinical symptoms. Conclusion Thalassemia, a defect in the genes for the synthesis of globin, occurs due to mutation of these genes or their deletions. From the above analysis, thalassemia exists in main types as alpha or beta thalassemia. The main diagnosis method is hemoglobin electrophoresis whose principle is based on the charges of the individual hemoglobin. The percentage distribution of the individual hemoglobin is therefore assessed and the presence of the disease indicated. Thalassemia pose a great threat thus need to be controlled and managed and if possible completely eradicated. The use of the above treatment modalities including blood transfusion, bone marrow transplantation, use of iron chelators, and treatment of the clinical symptoms is therefore important and considered as management for the condition. References Butt, M. (2013). Professor Atifa Shuaib: A Divine Gift for Pakistani Thalassemia Major Patients. Middle East Journal of Business - 2013, Vol. 8, No. 4, pp. 24-27. Victoria: Medi+World International. Cheng, C., Lee, C., & Lin, C. (2012). Clinically significant red blood cell antibodies in chronically transfused patients: a survey of Chinese thalassemia major patients and literature review. Transfusion, 52(10), 2220-2224. doi:10.1111/j.1537-2995.2012.03570.x Duman, O., Arayici, S., Fettahoglu, C., Eryilmaz, N., Ozkaynak, S., Yesilipek, A., & Hazar, V. (2011). Neurocognitive function in patients with β-thalassemia major. Pediatrics International, 53(4), 519-523. doi:10.1111/j.1442-200x.2010.03279.x Forget, B. G. (2011). Thalassemia. Philadelphia, PA: Saunders. Transfusion, 52(10), 2220-2224. doi:10.1111/j.1537-2995.2012.03570.x Hematologic Evaluation in Transfused B - Thalassemia Major Patients. (2016). International Journal of Science and Research (IJSR), 5(7), 1534-1538. doi:10.21275/v5i7.art201648 Livingstone, F. B. (1985). Frequencies of hemoglobin variants: Thalassemia, the glucose-6-phosphate dehydrogenase deficiency, G6PD variants, and ovalocytosis in human populations. New York: Oxford University Press Meloni, A., Borgna-Pignatti, C., Del Vecchio, G. C., Romeo, M. A., Gamberini, M. R., Bonetti, F., ... & Pepe, A. (2016). Significant improvement of survival by T2* CMR in thalassemia major. Journal of Cardiovascular Magnetic Resonance, 18(1), P137. Quality of Life in Patients with Thalassemia Major. (2016). International Journal of Science and Research (IJSR), 5(5), 41-42. doi:10.21275/v5i5.nov163256 Saliba, A. N., Musallam, K. M., Cappellini, M. D., Graziadei, G., Daar, S., Viprakasit, V., & Taher, A. T. (2017). Serum ferritin values between 300 and 800 ng/mL in nontransfusion‐dependent thalassemia: A probability curve to guide clinical decision making when MRI is unavailable. American journal of hematology, 92(3). Sonakul, D. (1995). Endocrine Pathology in Thalassemia. Endocrine Disorders in Thalassemia, 75-82. doi:10.1007/978-88-470-2183-9_13 Thakur, S., Raw, S. N., SHARMA, R., & Mishra, P. (2016). Detection of type of thalassemia disease in patients: A fuzzy logic approach. International Journal of Applied Pharmaceutical Sciences and Research, 1(2), 88-95. Read More