Thalassemia

=Thalassemia= Thalassemia is a group of genetic blood disorders in which causes a significant deficiency in red blood cells (Fung et al., 2012).

Root Cause:
Root causes of the disease include point mutations or deletions in the alpha or beta globin gene located on the chromosome band 16p13.3 and 11p15.5 respectively. Alpha and beta globin genes are necessary for synthesis of the alpha and beta chains of hemoglobin. A defect or deletion of the gene results in highly unstable polypeptide globin chains. Consequently, thalassemia patients suffer from a deficiency in red blood cells (Shawky & Kamal, 2012). Thalassemia is inherited as an autosomal recessive disease so an individual must have two copies of the abnormal gene in their genotype in order to develop the disease. Children born to parents with the recessive mutation have a 25% chance of inheriting both of the defective genes, one from each parent. The child has a 50% chance of inheriting one of the abnormal genes in which will make him or her a carrier of the trait. If only one parent carries the recessive mutation, the child is exempt from developing the disease (Kaneshiro, 2012). There are more than 200 alpha and beta globin gene mutations (Fung et al., 2012). These mutations can be passed on in a homozygous or heterozygous manner in which will determine if the form of thalassemia that develops is of the major, minor, or intermediate form (Hershkovitz, & Edelson, 1991).

Affected cell types/tissues/organs/systems:
Thalassemia patients suffer from a decrease in red blood cells, which is most commonly associated with chronic anemia. Thalassemia major causes poor growth, inadequate immune functions, and oxidative stress. These associated symptoms are related to the lack of proper absorption of necessary nutrients from a well balanced diet (Fung et al., 2012). Complications due to the decrease in red blood cells of patients include masses of erythropoeitic tissue in which effects the spleen, liver, and lymph nodes. Skeletal abnormalities such as chest, spine, and facial deformities are common because of the expansion in erythroid bone marrow activity (Shawky & Kamal, 2012). A possible decrease in bone mineral density may result in early onset osteoporosis with a corresponding short stature, delayed puberty, or hypogonadism. Various endocrine complications and diabetes mellitus can be complications associated with thalassemia as well (Aslan et al., 2012).

Historical Background:
Thalassemia originated among the populations of the central and eastern Mediterranean region but was not limited to this location as the affected area was dependent upon the type of thalassemia. The classical beta type was commonly found in the Mediterranean but both beta and alpha thalassemia were found in southeast and East Asia. The first prevalence of the disease in these regions is thought to be in the prehistoric time period (Hershkovitz, & Edelson, 1991). The diagnosis of thalassemia during the Paleolithic time period was based upon long bone remains. It was known that thalassemia caused skeletal changes, however the understanding of the disease did not become its own entity until 1925 (Weatherall & Clegg, 2008). Between 1925 and 1940, it was obvious that there were various forms of the disorder. After 1940, Europeans and Americans studied how thalassemia is inherited. Their research clarified that thalassemia was a group of genetic blood disorders that result in hemoglobin deficiencies by 1960 (Weatherall & Clegg, 2008). American pediatrician, Thomas B. Cooley was the first to make a clinical diagnosis of a severe case of Thalassemia in the 1920s. People at the time did not understand how an American diagnosis this disease was possible as thalassemia was so much more prevalent in the Mediterranean. However, the controversy was settled once people realized the immigration patterns of Mediterranean people to the United States during this time period. Cooley was able to recognize the fatal major form of thalassemia because Mediterranean children were suffering from anemia and splenomegaly. Cooley knew these abnormalities would not be caused by an infection and therefore diagnosed them with a blood disorder. Italian clinicians identified the disorder around the same time period but could not make the connection that Cooley did because only milder forms were presented where subjects were surviving into their early adult years (Weatherall & Clegg, 2008).

Common Symptoms:
Intermediate forms of thalassemia are often asymptomatic and require extensive laboratory blood testing for diagnosis. Other phenotypes may present severe splenomegaly with hypersplenism complications, jaundice, and growth retardation. Symptoms of heterozygote patients vary greatly depending on the molecular basis of the particular point mutations (Harteveld & Higgs, 2010). Homozygous thalassemia major is very fatal. Patients rarely survive past childhood with major forms of the disease. Survivors will suffer from chronic hemolytic anemia and will be blood transfusion dependent (Hershkovitz, & Edelson, 1991). Thalassemia major can cause decreased bone mineral density in which results in early onset osteoporosis, short stature, skeletal abnormalities, delayed puberty, and hypogonadism (Aslan et al., 2012).

Standard Treatments:
Thalassemia major patients usually rely on blood transfusion therapy for survival and proper growth (Hershkovitz, & Edelson, 1991). Intermediate forms may only require blood transfusions with old age, times of infection, pregnancy, or development of hypersplenism (Shawky & Kamal, 2012). Management treatments for thalassemia intermediate patients vary depending on the patient. Transfusion therapy, splenectomy procedures, iron chelation therapy, modulation of fetal hemoglobin with pharmaceutical drugs, and nutrient supplementation are often beneficial in combination or alone depending on the genotype (Shawky & Kamal, 2012).

Current Research:
Current research has shown that reduced growth, decreased bone mineral density, inadequate immune function, and increased oxidative stress related to thalassemia disorders are associated with poor nutrition status. Background information for this study stated that thalassemia patients have low circulating levels of many key nutrients. Blood transfused patients have a significant deficiency in vitamins A, C, D, and selenium. This study was the first research performed that investigated the dietary intake patterns of thalassemia subjects. The results showed that thalassemia patients living in United States and Canada have health problems linked to an inadequate intake of essential nutrients. Limited consumption of dairy products increases the development of osteoporosis as thalassemia patients already lack key nutrients found in such foods. Iron overload is common in transfused and nontransfused patients and is the most common cause of death in patients. Chelation iron management techniques reduce the chances of iron overloads for transfused patients but a Vitamin C deficiency in subjects has been found to hinder these effects. The results form the research found that both types of patients would benefit from a diet low in iron. However, a set back was found when iron rich foods are avoided because this results in a reduction of zinc. Zinc is essential for improved immune status, bone health, and growth, which would be very beneficial to thalassemia patients. Other foods recommended for thalassemia patients include fruits, vegetable, and whole grains. These foods will increase their intake of antioxidants, fiber, and folate, which help red blood cell metabolism (Fung et al., 2012).

In Figure 1 below, the chromosome bands 16p13.3 and 11p15.5, which control alpha and non-alpha, or beta chain synthesis of hemoglobin respectively, are displayed. The genes in both globin clusters are arranged from the 5’ to 3’ on their coding strands for synthesis of DNA and RNA. The five functional genes are shown for the beta-like globin genes. 53 kb of the 60 kb region of DNA is missing specific regulatory sequences such as the locus control region, enhancer sequences, and promotor regions. The β-locus control region (LCR-β) is found in regions of the DNA sequence, which are sensitive to ε-globin gene. Erythroid-specific transcription factors have speicifc binding sites at the locus control regions and in the promotors. The beta-globin promotor restricts the expression of the erythroid cell genes. Mutation in the promotor sequences such as the TATA box and the CAT box are present in beta thalassemia major patients. The deletion of the enhancer or LCR sequences prevents the expression of the β-globin gene needed for beta chain synthesis. γ-globin in the diagram is the prenatal form of the major β-like globin. A mutation in the beta globin gene may cause an absence or decrease in β-globin, which results in a lack of HbA(hemoglobin), or decreased HbA respectively. Inadequate prenatal forms, γ-globin, with absent β-globin causes severe anemia. Due to the absence of β-globin, there is an excess of α-globin, which causes itself to precipitate, and ROS damage (Shawky & Kamal, 2012).

Figure 2 represents recessive autosomal hereditary involved with thalassemia.

Figure 1: Figure 2:

References:
Aslan, I., Canatan, D., Balta, N., Kacar, G., Dorak, C., Ozsancak, A., Oguz, N, & Cosan, R. (2012). Bone Mineral Density in Thalassemia Major Patients form Antalya, Turkey.//International Journal of Endocrinology Volume,// Article ID: 573298//.// doi:10.1155/2012/573298

Fung, E., Xu, Y., Trachtenberg, F., Odame, I., Kwiatkowski, J., Neufeld, E., Thompson, A., Bourdreaux, J., Quinn, C., & Vichinsky, E. (2012). Inadequate Dietary Intake in Patients with Thalassemia. //Journal of the Academy of Nutrition and Diabetics ,112//(7), 980-990. Retrieved from http://www.sciencedirect.com/science/article/pii/S22122672 12001293?np=y

Harteveld, C. & Higgs, D. (2010). α-thalassaemia. //Orphanet Journal of Rare Diseases, 5//(13). Doi: 10.1186/1750-1172-5-13

Hershkovitz, I. & Edelson, G. (1991). The first identified case of thalassemia? //Human Evolution, 6//(1), 49-54. Retrieved from http://link.springer.com/article/10.1007/BF02435606#page-2

Kaneshiro, N. (2012). Autosomal recessive. //MedlinePlus.// Retreived from http://www.nlm.nih.gov/medlineplus/ency/article/002052.ht

Neufeld, E. (2010). Thalassemia. //Boston Children’s Hospital.// Retrieved from http://www.childrenshospital.org/az/Site1707/mainpageS1707P0.html

Weatherall, D. & Clegg, J. (2001). //The Thalassemia Syndromes.// Oxford: Blackwell Science Ltd.

Shawky, R. & Kamal, T. (2012). Thalassemia intermedia: An overview. //Egyptian Journal of// //Medical Human Genetics, 13//(3), 245-255. Retrieved from http://www.sciencedirect.co m/science/article/pii/S1110863012000274