Thalassemia, hemoglobin abnormalities

Abnormal hemoglobulins can be detected by electrophoresis, as shown in Figure 7.4, which includes a pattern observed in /3+-thalassemia and one in a newborn with a-thalassemia (possibly HbH disease). It should also be mentioned that, unless there is a coexisting hemoglobin abnormality resulting from a point mutation or crossover problem, the globin chains of classic a- and /3-thalassemia are perfectly normal. It is usually the quantities of either the a or the /3 chains that are decreased. Some frameshifts have been found near the terminus of the /3 chain that lead to frameshift mutations in certain areas. 

Alternatively, sites adjacent to an abnormal gene may differ from those on normal chromosomes. Such linked polymorphisms have been found for the sickle cell gene and for several -thalassemias. Because different individuals having a particular hemoglobin abnormality will not... 

A search for Heinz bodies Is helpful In the detection of an unstable hemoglobin, of a-thalassemia, homozygous 3-thalas-semla and related abnormalities, because hemoglobin often precipitates In the red cells of patients with one of these disorders. Inclusion bodies may consist of precipitated unstable hemoglobin, of 3 chalns (In a-thalassemia), or of a chains (In thalassemia) ... 

An Attempt to Unify Some Observations In Thalassemia and In Related Conditions". Proc. Third Cooley s Anemia Conf. April, 1973. Ann. N. Y. Acad. Scl., (1974), 232 107. Hulsman, T. H. J. "Normal and Abnormal Hemoglobins". 

Summary Thalassemias as a group are the most common genetic diseases in the world. Beta thalassemia is an inherited blood disorder in which the body produces an abnormal form of hemoglobin. The disorder results in excessive destruction of red blood cells, which in a severe form manifests as life-shortening anemia shortly after birth. Short-chain fatty acids had previously been shown to be useful in the... 

Hemoglobinopathies have traditionally been defined as a family of dis orders caused by production of a structurally abnormal hemoglobin molecule, synthesis of insufficient quantities of normal hemoglobin, or, rarely, both. Sickle-cell anemia (HbS), hemoglobin C disease (HbC), and the thalassemia syndromes are representative hemoglobinopathies that can have severe clinical consequences. The first two conditions result from production of hemoglobin with an altered amino acid sequence, whereas the thalassemias are caused by decreased produc tion of normal hemoglobin. 

Under normal circumstances, transferrin is one-fourth to one-third saturated with iron. The level of saturation may decrease in systemic infection or cancer and in iron deficiency anemia, the most common nutritional deficiency in the United States. In individuals with iron deficiency anemia, transferrin levels are increased. The level of saturation with iron increases in iron overload syndromes such as hereditary hemochromatosis or as a result of repeated blood transfusions, as is the case in thalassemia patients. Determinations of total plasma iron (TI) and plasma total iron binding capacity (TIBC) are routinely performed in the clinical biochemistry laboratory. The TIBC value reflects transferrin levels in plasma the amount of iron that can be bound by transferrin is equal to TIBC x 0.7. Total plasma iron levels in iron deficiency anemia become abnormal before hemoglobin levels show any change. 

Abnormal mRNA splicing can be one cause of /3+-thalassemia in which the production of /3-hemoglobin chains is greatly reduced. The defect appears to be caused by mutations that interfere with the correct removal of introns from the globin pre-mRNAs. 

There is a possible relationship between thalassemia (abnormal hemoglobins) and exposure to benzene. Aksoy (1989) presented a series of 44 pancytopenic patients, 4 of which had P-thalassemia heterozygotes. Two of these four patients had high levels of fetal hemoglobin, while a third patient had pseudo-Pelger-Huet anomaly. Thus, some forms of P-thalassemia may increase the deleterious effects of benzene on the hematopoietic system. 

Reports describing patients with Hb-S-/3-thalassemia or with Hb-C-)3-thalasseraia are numerous [ (A5, A6, B28, C22, K21, K23, N12, R38, S50, S51, S63) and many others]. The patients suffer from a mild to rather severe anemia (Hb levels between 7.5 and 12 g/100 ml) which is usually microcytic and hypochromic. Hemoglobin analysis shows a high percentage of the abnormal variant (60-80%), elevated Hb-A2 levels (4-7%), variable amounts of Hb-F (1-20%) and of Hb-A (0-20%). Patients who produce notable amounts of Hb-A are usually less severely affected than patients in which the normal Hb-A production is completely suppressed. 

Singer, K., Josephson, A. M., Singer, L., Heller, P., and Zimmerman, H. J., Studies on abnormal hemoglobins. XIII. Hemoglobin S-thalassemia disease and hemoglobin C-thalassemia disease in siblings. Blood 12, 593-602 (1957). 

Huisman THJ. Combination of P chain abnormal hemoglobins with each other or with P thalassemia determinants with known mutations influence of phenotype. Clin Chem 1997 43 1850-6,... 

Characteristics of the more common /3-thalassemia syndromes are summarized in Table 28-4. Not included are two different abnormal heterozygotes. Anemia results from precipitation of excess a-globin chains, premature red cell destruction in bone marrow and the circulation, and deficiency of functional hemoglobin tetramer. /S-Thalassemia major, or Cooley s anemia, occurs when /3-globin synthesis is markedly depressed or absent. The ineffective erythropoiesis causes massive erythroid proliferation, skeletal deformities, and extramedullary erythropoiesis. The usual treatment is frequent blood transfusion. 

Figure 29,35 A splicing mutation that causes thalassemia. An A to-G miutation within the first intron of the gene for tlie human hemoglobin (3 chain creates a new 5 splice site (GU). Both 5 splice sites are recognized by the U1 srtRNP so splicing may sometimes create a normal mature mRNA and an abnormal mature mRNA that contains intron sequences. The normal mature mRNA is translated into a fiemoglobin (3 chain. Because it includes intron sequences, the abnormal mature mRNA now has a premature stop codon and is degraded.

Anemia is the abnormally low level of hemoglobin or red blood cell mass, which has the potential of limiting the delivery of oxygen to tissue. By far, the most common cause of anemia is iron deficiency, leading to small volume of red blood cells (microcytic). Another common cause of microcytic anemia is thalassemia. Certain ethnicities have higher incidences of thalassemia, for example, Mediterranean or East Asian descent. 

The demand for folate is increased in people with thalassemia because of a more rapid cell turnover due to ineffective erythropoiesis. Where this demand cannot be met, a megaloblastic anemia may be superimposed on the thalassemia (R14, G8). This may be difficult to recognize because the abnormal synthesis of the globin moiety of hemoglobin may prevent the development of characteristic megaloblasts. A similar situation may occur in iron-deficiency anemia where characteristic megaloblasts will not develop until... 

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