Beta Thalassaemia Major - Essay Example

Beta thalassaemia major. The most common 'single gene defect' in man comprises primarily of the inherited hemoglobin disorders. These hemoglobinopathies (blood or hemoglobin disorders) together, also have the highest incidence of prevalence worldwide in terms of incidence of single gene disorders. The thalassaemias belong to a category of these hemoglobinopathies. It refers to an inherited disorder that affects the production of hemoglobin by a decrease in globin chain synthesis and hence causes anemia (Rund D, Rachmilewitz E., 2005).There are two main classifications for the thalassaemias in terms of clinical relevance, i.e the a and the b-thalassaemia. This classification is based on the type of globin chain (alpha or beta) which is affected. This clearly indicates that hemoglobin structure is central to the pathology of thalassaemia. Beta thalassaemia or Cooley's anemia as it is called refers to decreased beta chain production and hence deficits in hemoglobin due to defects in the gene forming the chain Hemoglobin (Hb) is protein responsible for oxygen carrying in the body. It is made of four peptide chains, two alpha or a chains and two beta or b chains. Hemoglobin synthesis is controlled by genes which are switched on and off at different phases in the human life (beginning at the embryonic stage). Gamma genes regulate formation of fetal hemoglobin, which is switched to beta genes postnatally. It is about the 9th gestational week that the transcription switch from g chain to b chain production starts. Normally fetal hemoglobin synthesis declines gradually during this time but continues until 9 months of age. It is at about the 9th month after birth that the switch is completed.(Sarnaik 2005). This beta gene therein controls beta chain production in adults. In patients suffering from beta thalassaemia, there is a switch from a normal gamma-globin gene, in the fetus to an abnormal beta-globin gene, in the adult. (Blau 1994). Classical symptoms of anemia start once the gamma chain production is switched off and the b chains fail to form in adequate numbers. The abnormality of the beta globin gene in the adult has been attributed to mutation in the gene responsible for beta-globin formation. (More than 100 different forms mutations have been described so far) Beta-thalassaemia major is hence a result of transmission of the mutated form of beta-globin gene from both parents, to the offspring. This results in inheritance of both defected form of the gene and has severe clinical manifestations for the patient. Clinical features and abnormalities As has been described above, beta thalassemia major refers to a decreased production of beta globin chains which are required for formation of normal haemoglobin in the blood. This results in decreased levels of normal haemoglobin(A) in the body. Interestingly there are evidences of increased levels of fetal (F) and abnormal haemoglobin (A2). Recent studies established that this abnormal increase in other Hb forms was due to production of excess of alpha chains, some of which are consequently utilized to synthesize hemoglobins which do not require beta chains, such as hemoglobin F (a2 g2) or hemoglobin A2 (a2 d2) and hence the elevated levels of such hemoglobins! (Perrimond 2001). Clinically this is very relevant as it leads to excessively reduced RBC life, this is primarily due to precipitation of free alpha chains on the RBCs. Other clinical features are is extremely severe hypochromic anemia as a result of ineffective erythropoesis. There is also significant decrease in hemoglobin content per cell and microcytosis. In order to compensate for this the body attempts to increase the red cellproduction. This results in increase marrow cavities and 'extramedullary erythropoeisis' in the liver and spleen. The consequences of such endeavours may result in hepatosplenomegaly, bone defects and much discomfort (pain) in patients. In children, there is high incidence of growth deficit, cardiac problems and jaundice (due to excessive break down of red cells as described above). The symptomatic manifestations hence are retarded development, skin pallor, jaundice, enlarged spleen or liver, cirrhosis in many cases or deformed bones or pathologic fractures. Such abnormalities are indicative of beta thalassaemia major in clinics, however there are specific diagnostic tests to determine the illness. Methods used to investigate this illness Over the years several important insights into the etiology and pathophysiology of beta thalassaemia major has increased the techniques that are now available in the laboratory nd the clinic to investigate and diagnose the illness. While prenatal diagnosis and genetic counselling is still the most recommended as it is the most effective means to reduce the incidence of this life threatening disorder for which no cure is known so far, other diagnostic procedures are also available. Carrier detection is the first step and also common prestep to genetic counseling; haematological studies and mutation detection by DNA analysis for the basis of such detection. Prenatal diagnosis on the other hand included a study on PCR-amplified DNA from chorionic villi in order to test for muations (Cao 2002). After birth in thalassemia major, elevated levels of Hb A2, F, or both which are detected by Hb electrophoresis are most commonly used in confirming the diagnosis. However in cases of codominace of the alpha and beta forms of this disorder such techniques are ineffective. Peripheral blood film examination is another common method. It reveals marked hypochromia and microcytosis (and is useful in detecting differences from iron deficiency anemia since it is not accompanied by the anisocytosis usually encountered in the latter. Additionally imaging studies on bones reveal classic changes in bone patterns and cotical structures, while even plain radiographs of the long bones may reveal a differential trabecular pattern. These tests are al used in combination to investigate the various phenotypic expressions associated with the occurrence of the disorder. Treatment To a large extent the characteristic which is extensively used to differentiate Thallasemia minor and thallasemia minor is the need for transfusion dependency. Hypertransfusion and chelation therapy which are the most common forms of treatments used in cases of the disorder have indeed allowed a much improved survival curve in patients with thalassemia major. Blood transfusion has been the main stay of treatment regimes for patients since the 1990's. There have however been considerable problems associated with it in terms of the minimal required level of hemoglobin that should be transfused and the possibility of infection during the process. Nonetheless depending on the severity of the problem, transfusion is considered unavoidable in many cases. Chelation as mentioned previously is the other extensively used treatment modality. Both intravenous and oral chelating agents are present in the market and are very effective in decreasing harmful tissue iron stores and consequently preventing iron overload in the body (Hershko 1998). Given that administration of oral chelation is a more practical approach, several studies are now attempting to assess the efficacy and toxicity of new oral chelators. This is a major advancement since previously most drugs had to be administered parenterally and resulted in serious compliance issues. While iron overload is a major complication associated with transfusion although the cause underlying it remains elusive, significant dose-related side effects like neutropenia, and agranulocytosis are observed with some common chelating agents. (Franchini 2004) Only recently, combination therapies using various types of chelating agents have been studied preclinically and its potential benefits have now been advanced to clinical study stages. Hematopoietic stem cell transplantation is another therapeutic mode. Although this is recommended only in specific patients, and is proposed to be one of the only curative treatment for thalassaemia. A recent advancement which is now coming up as a cure for thalassaemia is gene therapy. This is presently being investigated both preclinically and clinically to establish the efficacy of this mode of treatment and may have far reaching consequences in terms of treatment of the disorder. Since the first successful "cure" of beta-thalassaemia in 1981 which was marked by bone marrow transplantation, there has been a remarkable improvement in the life expectancy of patients suffering from beta thalassaemia. Further advancements in terms of transfusion techniques, molecular genetics (i.e. prenatal diagnosis and genetic counseling) are now being promoted to improve the diagnosis, prognosis and treatment modalities of beta thalassaemia major. The widespread occurrence of this disease occurring across the Mediterranean countries, North Africa, the Middle East, India, and southeast Asia fostered initial interest in the study of this disease, and a search on medline gives a clear picture of the widespread interest ion the subject. It is surprising that such a debilitating disorder, still persists in the environment and selective pressures are not working against them. It is vital to understand why this occurs and geographical barriers are notwithstanding. There have been speculations that the distribution pattern of this disorder is quite similar to that of the endemic Plasmodium falciparum, the pathogen for malaria (Flint et al 1998). Further evidence is required to establish the possible link between the two in terms of natural selection. Is there a role for the old Darwinian mechanism in this order Could natural selection be playing a role How effective is the novel genetic therapy These questions remain unanswered , however the increased and persistent interest in the disorder gives much positive indications in terms of the possibility of answering these questions and also shows the scientific community the way to go! Sources Blau CA, Stamatoyannopoulos G. Hemoglobin switching and its clinical implications. Curr Opin Hematol. 1994 Mar;1(2):136-42. Cao . A. Carrier screening and genetic counselling in beta-thalassemia. Int J Hematol. 2002 Aug;76 Suppl 2:105-13. http://www.bookrags.com/other/health/thalassemia-woh.html Flint J, Harding RM, Boyce AJ, Clegg JB (1998) The population genetics of the haemoglobinopathies. Bailliere's Clinical Hematology. Vol 11, pp 1-50 Franchini M, Veneri D. Iron-chelation therapy: an update. Hematol J 2004; 5: 287-292 Harrison's Principles of Internal Medicine, McGraw-Hill, edited by Eugene Braunwald, et. al., 2001. Hershko, AM Konijn and G Link, Iron chelators for thalassemia. Br. J. Haematol. 101 (1998), pp. 399-406. Perrimond H. (Beta-thalassemia: clinical manifestations) Bull Soc Pathol Exot. 2001 May;94(2):92-4. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005 Sep 15;353(11):1135-46. Sarnaik S. A. 2005 Thalassemia and Related Hemoglobinopathies 72:4 ;319-324 Read More