A thalassemia

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) ... 

The thalassemias are the most common disorders caused by mutations of a single gene worldwide both a-thalassemia and -thalassemia occur, depending on which subunit is deficient. 

Haploinsufficiency, or when 50% of normal gene activity is inadequate a-Thalassemia trait and the a-globin gene P-Thalassemia trait and the P-globin gene... 

A. a-Globin gene deletions in the a-thalassemias. B. Hemoglobin tetramers formed in a-thalassemias. 

Thalassemias are hereditary hemolytic diseases in which an imbalance occurs in the synthesis of either a or 3 globin chains. Each thalassemia can be classified as either a disorder in which no globin chains are produced (a0- or p°-thalassemia), or in which some chains are synthesized but at a reduced rate (a+- or p+-thalassemia). [Note In p-thalassemias, synthe sis of p globin chains is decreased or absent, whereas in a-thalassemias, synthesis of a globin chains is decreased or absent.]... 

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. 

Mediterranean, a-thalassemia and hemoglobin C in Africa, and hereditary persistence of fetal hemoglobin in North Africa and India. These combinations have created diverse presentations of this disease, the most severe being hemoglobin SS and hemoglobin S(3 zero thalassemia. 

The continued absorption of iron causes its deposition in various tissues starting with liver and spleen and followed by myocardium. Deposition of iron in the myocardium usually results in death by intractable cardiac failure. Patients suffer from hypoparathyroidism and hypogonadism. Patients with the severe form of thalassemia are more susceptible to bacterial infection, possibly due to the increase in serum iron, which may favor bacterial growth. Iron overload is less common in the adult forms of Q -thalassemia. This is most likely the result of a fundamental difference between a and -thalassemia. As mentioned, the excess of Q -globin chains cannot form viable tetramers and causes red-cell destruction. The excess jS-chains present in a-thalassemia are able to form solnble homodimers and do not precipitate in the bone marrow. This is paralleled in the fetal state when excess y-chains form solnble homodimers. Hence, a-thalassemia is characterized by a severe degree of inefficient erythropoiesis and a milder degree of anemia. 

In 1969 Schwartz (S29) described an Albanian family of two children with mild j8-thalassemia major. Their mother had a classical j8-thalassemia heterozygosity, but the father had a normal red cell morphology and normal levels of Hb-A, and Hb-F. The synthesis of /8 chains in this individual was impaired, although to a lesser extent than is usually observed in the classical jS-thalassemia. Interaction of this type of j8-thalassemia with the classical type results in a thalassemia major of reduced severity because the apparent homozygous children from this marriage are only mildly affected with levels of Hb-F of less than 12%. 

Basic information on a-thalassemias, i.e., defects with an impaired production of a polypeptide chains, is still limited because of difficulties in identifying the simple adult heterozygote. Detection of a-thalassemia can best be made by hemoglobin analysis of cord bloods and of subjects with Hb-H disease. 

Detailed hematological studies of several hundred obligatory adult heterozygotes for a-thalassemia suggest that this condition is often associated with a normal blood picture (P23). The hemoglobin concentration varies between 10 and 13 g/100 ml with MCV values of 60-80 and MCH of 22-30 pg per cell hypochromia is not prominent and reticulocytosis is hardly observed. Osmotic fragility of red cells is usually reduced. 

Fig. 13. Starch gel electrophoresis of hemoglobin of cord blood samples from newborns with various types of a-thalassemia. Tris-EDTA-boric acid buffer, pH 8.6. Stained with o-dianisidine. From Pootrakul et al. (P22) with permission of the authors and publisher.

The homozygous state of a-thalassemia type-1 (a-Thi) leads to a form of erythroblastosis fetalis and intrauterine death [ (K2, L18, L20, L21, L22, L23, L24, L26, P4, T6, T7, T8) and others]. This form of hydrops fetalis is found in Chinese from various countries, in Filippinos, and in Thais. All children are either stillborn or die within hours after birth. The hematological observations usually include anemia with reticulo-cytosis, hypochromia with macrocytosis, aniso- and poikilocytosis, and many erythroblasts. The red cells sickle rather easily. Most fetuses are hydropic (but not all). 

Homozygosity for the a-thalassemia of the incomplete type (a-Tha) does not seem to cause ill effects. It results in a phenotype which is more or less identical to the a-Thi heterozygosity (P22). 

Small quantities (less than 1%) of Hb-Bart s are often observed in blood from Negro newborns (HIO, H22, S3) the incidence approaches the 20%. In some babies a larger amount (up to 5%) is present. The -chain deficiency does not express itself beyond infancy. Because Hb-H disease and hydrops fetalis have not been found in the Negro, it seems that either the a-Th2 type or an additional type of a-thalassemia is present. The babies with the higher amounts of Hb-Bart s are considered to be homozygous for the deficiency and those with the minute amounts heterozygous. 

The combination of a-thalassemia with chain variants has frequently been observed w hen associated with Hb-E a well-defined clinical syndrome is present which is primarily found in Thailand (Til, T13, W5). The combination of two a-thalassemia genes (a-Thi and o-Thj) and a single Hb E gene results in a thalassemia intermedia with moderate anemia and hepatosplenomegaly. At time of birth these patients produce some 25% Hb-Bart s, Hb-A, Hb-F, and small amounts of Hb-E. At a later age the disease is characterized by the presence of an increased y chain production and a decreased chain production the hemoglobin phenotype shows some 15% Hb-E, 5-15% Hb-Bart s, and the remainder Hb-A. Hb-H i t) is hardly present as is the tetramer of the yS chain. 

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