Pathogenesis and genetics of thalassemia.

The two main forms of the disease, α-thalassemia and β-thalassemia, result from mutations in genes encoding the respective globin chains (α-globin: genes HBA1 and HBA2; β-globin: gene HBB on chromosome [1]). Both forms are inherited as recessive alleles. Individuals with α-thalassemia have reduced production of α-globin chains, which leads to a relative excess of β-globin chains and, in turn, to the formation of unstable tetramers that have abnormal oxygen dissociation curves. In β-thalassemia, for which more than 200 gene mutations have been identified [2], a reduction in β-globin production occurs, which leads to a relative excess of α-globin chains. These chains do not, however, form tetramers. Instead, they bind to erythrocyte membranes causing membrane damage and, at higher concentrations, have the tendency to form toxic aggregates. The severity and required treatment regimen of both diseases depends upon the type of mutation and whether the carrier is heterozygous or homozygous to the disease.
Alpha Thalassemia
Alpha thalassemia occurs when one or more of the four alpha chain genes fails to function. Alpha chain protein production, for practical purposes, is evenly divided among the four genes. Alpha thalassemia has four manifestations that correlate with the number of defective genes. Since the gene defect is almost invariably a loss of the gene, there are no "shades of function" to obscure the matter as occurs in beta thalassemia.
(i) Silent carrier state. This is the one-gene deletion alpha thalassemia condition. People with this condition are hematologically normal. They are detected only by sophisticated laboratory methods. The loss of one gene diminishes the production of the alpha protein only slightly. A person with this condition is called a "silent carrier" because of the difficulty in detection.
(ii) The loss of two genes (two-gene deletion alpha thalassemia) produces a condition with small red blood cells, and at most a mild anemia. People with this condition look and feel normal. The condition can be detected by routine blood testing, however. It is called mild alpha-thalassemia. These patients have lost two alpha globin genes.
(iii) Patients with this condition have a severe anemia, and often require blood transfusions to survive. The severe imbalance between the alpha chain production (now powered by one gene, instead of four) and beta chain production (which is normal) causes an accumulation of beta chains inside the red blood cells. Normally, beta chains pair only with alpha chains. With three-gene deletion alpha thalassemia, however, beta chains begin to associate in groups of four (tetramers), producing an abnormal hemoglobin, called "hemoglobin H". The condition is called "hemoglobin H disease". Hemoglobin H has two problems. First it does not carry oxygen properly, making it functionally useless to the cell. Second, hemoglobin H protein damages the membrane that surrounds the red cell, accelerating cell destruction. The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia. Untreated, most patients die in childhood or early adolescence. The result is a severe anemia, with small, misshapen red cells and red cell fragments. These patients typically have enlarged spleens. Bony abnormalities particularly involving the cheeks and forehead are often striking. The bone marrow works at an extraordinary pace in an attempt to compensate for the anemia. As a result, the marrow cavity within the bones is stuffed with red cell precursors. These cells gradually cause the bone to "mold" and flair out. Patients with hemoglobin H disease also develop large spleens. The spleen has blood forming cells, the same as the bone marrow. These cells become hyperactive and overexpand, just as those of the bone marrow. The result is a spleen that is often ten-times larger than normal. Patients with hemoglobin H disease often are small and appear malnourished, despite good food intake. This feature results from the tremendous amount of energy that goes into the production of new red cells at an extremely accelerated pace. The constant burning of energy by these patients mimics intense aerobic exercise; exercise that goes on for every minute of every day.

(iv) Hydrops fetalis. The loss of all four alpha genes produces a condition that is incompatible with life. Hemoglobin Barts develops in fetuses with four-gene deletion alpha thalassemia. During normal embryonic development, the episilon gene of the alpha globin gene locus combines with genes from the beta globin locus to form functional hemoglobin molecules. The episolon gene turns off at about 12 weeks, and normally the alpha gene takes over. With four-gene deletion alpha thalassemia no alpha chain is produced. The gamma chains produced during fetal development combine to form gamma chain tetramers. These molecules transport oxygen poorly. Most individuals with four-gene deletion thalassemia and consequent hemoglobin Barts die in utero (hydrops fetalis). The abnormal hemoglobin seen during fetal development in individuals with four-gene deletion alpha thalassemia was characterized at St. Bartholomew's Hospital in London. The hospital has the fond sobriquet, St. Barts, and the hemoglobin was named "hemoglobin Barts."


Beta Thalassemia

The fact that there are only two genes for the beta chain of hemoglobin makes beta thalassemia a bit simpler to understand than alpha thalassemia. Unlike alpha thalassemia, beta thalassemia rarely arises from the complete loss of a beta globin gene. The beta globin gene is present, but produces little beta globin protein. The degree of suppression varies. Many causes of suppressed beta globin gene expression have been found. In some cases, the affected gene makes essentially no beta globin protein (beta-0-thalassemia). In other cases, the production of beta chain protein is lower than normal, but not zero (beta-(+)-thalassemia). The severity of beta thalassemia depends in part on the type of beta thalassemic genes that a person has inherited.
(i) one-gene beta thalassemia has one beta globin gene that is normal, and a second, affected gene with a variably reduced production of beta globin. The degree of imbalance with the alpha globin depends on the residual production capacity of the defective beta globin gene. Even when the affected gene produces no beta chain, the condition is mild since one beta gene functions normally. The red cells are small and a mild anemia may exist. People with the condition generally have no symptoms. The condition can be detected by a routine laboratory blood evaluation. (Note that in many ways, the one-gene beta thalassemia and the two-gene alpha thalassemia are very similar, from a clinical point of view. Each results in small red cells and a mild anemia).
(ii) two-gene beta thalassemia produces a severe anemia and a potentially life-threatening condition. The severity of the disorder depends in part on the combination of genes that have been inherited: beta-0-thal/ beta-0-thal; beta-0-thal/ beta-(+)-thal; beta-(+)-thal/ beta-(+)-thal. The beta-(+)-thalassemia genes vary greatly in their ability to produce normal hemoglobin. Consequently, the clinical picture is more complex than might otherwise be the case for three genetic possibilities outlined.
Features

(i) Thalassemia minor, or thalassemia trait. These terms are used interchangeably for people who have small red cells and mild (or no) anemia due to thalassemia. These patients are clinically well, and are usually only detected through routine blood testing. Physicians often mistakenly diagnose iron deficiency in people with thalassemia trait. Iron replacement does not correct the condition. The primary caution for people with beta-thalassemia trait involves the possible problems that their children could inherit if their partner also has beta-thalassemia trait. These more severe forms of beta-thalassemia trait are outlined below.
(ii) Thalassemia intermedia. Thalassemia intermedia is a confusing concept. The most important fact to remember is that thalassemia intermedia is a description, and not a pathological or genetic diagnosis. Patients with thalassemia intermedia have significant anemia, but are able to survive without blood transfusions. The factors that go into the diagnosis are:
• The degree to which the patient tolerates the anemia.
• The threshold of the physician to transfuse patients with thalassemia.
With regard to the tolerance of the anemia, most patients with thalassemia have substantial symptoms with a Hb of much below 7 or 8 gm/dl. With hemoglobins of this level, excess energy consumption due to the profound hemolysis can produce small stature, poor weight gain, poor energy levels, and susceptibility to infection. Further, the extreme activity of the bone marrow produces bone deformities of the face and other areas, along with enlargement of the spleen. The long bones of the arms and legs are weak and fracture easily. Patients with this clinical condition usually do better with regular transfusions. The need for regular transfusions would then place them under the heading of thalassemia major (see below). On the other hand, some patients with marked thalassemia can maintain a hemoglobin of about 9 to 10 gm/dl. The exercise tolerance of these patients is significantly better. The question then becomes whether the accelerated bone marrow activity needed to maintain this level of hemoglobin causes unacceptable side-effects such as bone abnormalities or enlarged spleen. This is a judgment decision. A given patient at the critical borderline would be transfused by some physicians to prevent these problems, even if they are slight. The patient then would be clinically classified as having thalassemia major. Another physician might choose to avoid the complications of chronic transfusion. The same patient then would be clinically classified as thalassemia intermedia. The patient has thalassemia that is more severe than thalassemia trait, but not so severe as to require chronic transfusion as do the patients with thalassemia major.
A patient can change status. The spleen is enlarged in these patients. The spleen plays a role in clearing damaged red cells from the blood stream. Since all of the red cells in patients with severe thalassemia have some degree of damage, clearance by the spleen accelerates the rate of cell loss. Therefore the bone marrow has to work harder to replace these cells. In some patients, removal of the spleen slows the rate of red cell destruction just enough, that they can manage without transfusion, and still not have the unacceptable side-effects. In this case, the patient converts clinically from thalassemia major to thalassemia intermedia.
(iii) Thalassemia major. (also known as Cooley's anemia) This is the condition of severe thalassemia in which chronic blood transfusions are needed (3). In some patients the anemia is so severe, that death occurs without transfusions. Other patients could survive without transfusions, for a while, but would have terrible deformities. While transfusions are life-saving in patients with thalassemia major, transfusions ultimately produce iron overload.Chelation therapy, usually with the iron-binding agent, desferrioxamine (Desferal), is needed to prevent death from iron-mediated organ injury.