Thalassemia is a genetic defect that results in production of an abnormally low quantity of a given hemoglobin chain or chains. This condition along with other hemoglobinopathies are life threatening and can cause the physician a lot of frustration trying to identify the vague and sometimes elusive symptoms that commonly accompany just such diseases. It should also be kept in mind that there are literally hundreds of diseases associated with hemoglobin in one form or an other, and so this paper will concentrate on the hemoglobin defects associated with Thalassemia and its chemical make up and break down.

Hemoglobin is one of many molecules that comprise erythrocytes (red blood cells) and give them their ability to bind and transport oxygen to and from the many different tissues of the body not to mention other animals. Hemoglobin is an tetrameric heme-protein comprised of 2 Alpha subunits and 2 Beta subunits noncovalently bound to each other. Each subunit of a hemoglobin tetramer has a heme prosthetic group identical to that described for myoglobin. The subunits together make up the quaternary structure of hemoglobin. Each of the subunits holds a heme group containing one Fe++ atom. It=s these heme-iron complexes that give hemoglobin it=s red color. A histidine nitrogen binds the iron to the heme subunit, helping to anchor its position. (1) The hydrophilic propanoate groups of heme face the water at the surface of the protein, while the hydrophobic portions of the heme are buried among the hydrophobic amino acids of the protein, much like the properties seen with cell membrane proteins.(2) Most of the amino acids in hemoglobin form alpha helices, connected by short non-helical segments. Hemoglobin has no beta strands and no disulfide bonds as seen with Deoxyribonucleic acid.

When oxygen binds to the first subunit of deoxyhemoglobin it increases the affinity of the remaining subunits for oxygen. As additional oxygen is bound to the second and third subunits oxygen binding is further, strengthened , so that at the oxygen tension of the lung alveoli, hemoglobin is fully saturated with oxygen. Its these properties that make chemistry so important to the body=s physiology. As oxyhemoglobin, as it=s now called, circulates to deoxygenated tissues, oxygen is reduced. Thus at the lowest oxygen tensions found in very active tissues the binding affinity of hemoglobin for oxygen is very low allowing maximal delivery of oxygen to the tissue. The oxygen binding properties of hemoglobin arise directly from the interaction of oxygen with the iron atom of the heme prosthetic group (described earlier) and the resultant effects of these interactions on the quaternary structure of the protein. When oxygen binds to an iron atom of deoxyhemoglobin it pulls the iron atom into the plane of the heme. Since the iron is also bound to histidine F8, this residue is also pulled toward the plane of the heme ring. The conformational change at histidine F8 is transmitted throughout the peptide backbone resulting in a significant change in tertiary structure of the entire subunit. Conformational changes at the subunit surface lead to a new set of binding interactions between adjacent subunits. The latter changes include disruption of salt bridges and formation of new hydrogen bonds and new hydrophobic interactions, all of which contribute to the new quaternary structure.(3),(5)

The latter changes in subunit interaction are transmitted, from the surface, to the heme binding pocket of a second deoxy subunit and thus results a greater affinity of the hemoglobin molecule for a second oxygen molecule. The tertiary configuration of low affinity, deoxygenated hemoglobin is known as the taut (T) state. Conversely, the quaternary structure of the fully oxygenated high affinity form of hemoglobin is known as the relaxed (R) state. In addition to oxygen transportation, hemoglobin plays a part in transporting CO2. N-terminal amino groups of the T form of hemoglobin are available for reaction with CO2 and about 15% of the CO2 formed in tissues is carried to the lung covalently bound to the N-terminal nitrogens as carbamate(5)

In the lung the high oxygen partial pressure favors formation of the R form resulting in the reversal of the carbamate with release and exhalation of the CO2.(5)

Distortions or deletions of the sequences of amino acids that make up the hemoglobin molecule is the main reason that someone develops Thalassemia. While some of these amino acid sequence positions on the peptide chain can tolerate substitutions without compromising the physiologic integrity of hemoglobin, other positions are very sensitive to the changes. For instance

substitution of valine or lysine for glutamate at position 6 of the b chain produces hemoglobins S and C, respectively, which form intraerythrocytic tactoids and crystals that cause premature destruction of the RBC and cause some anemia by hemolysis.(7)

Chromosome 16 contains the genes for all-important a chain. The genes for all of the other important globin chains are on chromosome 11, where they are closely linked. The linkage means that the genes tend to be inherited as a group, as opposed to non-linked genes which assort independently due to crossing over during gametogenesis. Because of the linkage, a mutation that affects the rate of production of the b chain not uncommonly affects rate of production of adjacent a chain. An individual carrying such a mutation would then have a gene for Adb Thalassemia@. He or she could pass a db gene to offspring but would essentially never, say, pass a d thalassemia gene to one child and a b thalassemia gene to another.

The clinical problem in Thalassemia is the inability to maintain a balance between the synthesis rate of one type of globin chain and its mate. Even though thalassemia have been described for all four classes of globin chains (a,b,g,d), we will consider only the b chain thalassemias and the a chain thalassemias.

Beta thalassemia is the classical form, but not the most common. Known as ACooley=s anemia@ after Dr. Thomas Cooley who first described it in 1925. The term Cooley=s anemia has been used synonymously with clinically severe forms of b thalassemia. It is a fatal microcytic anemia of children of Mediterranean descent. The name Athalassemia@ was coined to reflect the original geographic home of the target population (thalassa is Greek for Mediterranean sea). Over the years, it became clear that many other groups (Africans, Arabs, Indians, and southeast Asians) are affected as well. Clinical symptoms range from asymptomatic expression to classical deadly Cooley=s anemia. The beat thalassemias are grouped by amount of b globin chain production, into two groups b0 and b+. bO thalassemia gene allows no production of b chains. Patients usually only live to six months of age.(7) The b+ thalassemias gene allows some, but still subnormal, production of beta chains. These patients make a subnormal amount of hemoglobin, but still have trouble with the destructive effects of a tetramers on the erythrocytes in the marrow. This form is seen mostly with Mediterranean Caucasians and has it=s highest population in Liberia.

The a thalassemias include the most common of all hemoglobinopathies and thalassemias. One form of a thalassemia is very common in African-Americans. Fortunately this form is so mild that it=s very detection is almost impossible in adult heterozygotes, and even homozygotes are asymptomatic with mild laboratory abnormalities. Yet another form of a thalassemia, fortunately uncommon, produces the most severe disease of all the hemoglobinopathies and thalassemias and usually takes the life of its victim even before birth. Surely a thalassemia is a disease of extremes.

1.) Hemoglobin: red and ready

2.)THCME Medical Biochemistry Page

3.) Hemoglobin and myoglobin

4.) Hemoglobin: Iron in the blood

5.)Hemoglobin and myoglobin oxygen binding

6.) Erythrocytes

7.) Anemia