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New Treatments for Thalassemias

Thalassemias are due to deletions or decreased transcription or synthesis of the globin genes. Typically alpha thalassemias are a deficiency of the production of alpha globin genes and typically they are due to a deletion or deletions of the alpha globin genes. You can have anywhere from a single deletion to all four deletions of the alpha globin genes, as we will discuss later. In the beta thalassemias typically it is rare to have a deletion, a gene deletion, that leads to the defect but usually there are point mutations. A large number of point mutations for  thalasemia.

Alpha thalassemias are caused by a decreased synthesis of the alpha globin chains and a relative excess of the beta-like globin chains. Now, in this setting we have the potential formation of certain abnormal hemoglobins. One is hemoglobin Bartís, which is gamma 4, four gamma globin chains bound to hemoglobin coming together, trying to form the normal hemoglobin molecule. But instead, this very abnormal gamma 4 hemoglobin molecule.

Now in the setting where you have two of the alpha globin genes deleted, either both of them deleted on one chromosome or the homozygous state for a single alpha gene deletion. At any rate, you only have half of the normal alpha globin genes functioning. This is the condition where we have alpha thalassemia trait. In this setting you tend to find 2-10% of the hemoglobin is hemoglobin Bartís instead of hemoglobin F in the newborn. In the adult there is no hemoglobin Bartís or hemoglobin H and this is a very mild hypochromic anemia that has very little clinical significance. If you have three of the alpha globin genes deleted, you only have one functioning alpha globin gene; this is called hemoglobin H disease. In the newborn there is 20-40%.

Finally, we have the possibility of having four alpha globin genes deleted and this setting is incompatible with life and it leads to fetal death and hydrops fetalis. In the cord blood of these infants, almost 100% of the hemoglobin is hemoglobin Bartís. These are stillborn, anemic,

A few more comments about the alpha thalassemia trait. The homozygosity for a single alpha gene deletion is present in about 7% of Africans throughout the African subcontinent and in about 7% of African-Americans. Itís important to note - and very fortunate - that the setting of two alpha gene deletions on one chromosome does not occur in Africa. That means that alpha thalassemia does not lead to severe disease in Africans. All we have is this alpha thalassemia trait-type picture. The main thing is to remember not to confuse this condition with iron

Hemoglobin H disease is the setting where you have only a single functional alpha globin gene and three of the alpha globin genes are deleted. This basically is almost always found only in Southeast Asia because this double deletion on a single chromosome is predominantly found in Southeast Asia. Hemoglobin H beta 4 stains with cresyl blue and so you can easily see

Iíd like now to turn to the beta thalassemias. The beta thalassemias are conditions in which there is a decreased synthesis of the beta globin chains. A correlation to this is that there is a relative excess of the alpha globin chains. An excess of alpha globin chains tend to be quite insoluble and they tend to aggregate and to form insoluble inclusions in the erythroid precursors. Now in the setting of the alpha thalassemias the abnormal hemoglobins, Bartís, gamma 4 and H beta 4 tend to be soluble and they tend to remain in solution in these cells and not be nearly so prone to precipitate out. So that is one of the reasons why the beta thalassemias tend to be more

We keep coming up with this term, ineffective erythropoiesis, and I think itís important to pause a little bit to make sure we define this and understand what ineffective erythropoiesis is. We donít mean in this condition merely that there is inadequate erythropoiesis which occurs with so many things, ranging from aplastic anemia to iron deficiency. We are speaking specifically in a setting where there is a high degree of erythropoietic activity in the bone marrow, but there is a death of these erythroid precursors in the bone marrow. So before they have a chance to come out into the periphery. And in ineffective erythropoiesis the blood tests tend to look like hemolysis, except for one thing. The reticulocytes are not increased or they are not

This is the distribution of the beta thalassemias globally. Again, it stretches from Southeast Asia through the Middle East to the African continent. It looks very much like the distribution of alpha thalassemias and again, pretty much exactly parallels the distribution of malaria.

Iíd like to go through the beta thalassemias, correlating the genotype with the phenotype in the hematologic findings, similar to how we did with the alpha thalassemias. Now Iíd like to point out that the beta thalassemias are extremely complex and that there are all kinds of gradations between the genotypes and between the phenotypes. But for us to get a handle on it, Iíd like to give you the simplified viewpoint of it. First of all, we have the heterozygote in which there is one normal beta globin gene and one abnormal beta globin gene in which the synthesis is

Third, we have the homozygote or compound heterozygote form in which both of the beta globin genes are affected by mutations but the synthesis is not completely shut off. There is merely a reduced production of the beta globin from these genes. This leads to the picture of thalassemia intermedia in which there is a moderate hemolytic anemia, a moderate degree of

Finally, we have the homozygote or compound heterozygote form in which both beta globin genes have mutations that lead to the absent synthesis of beta globin. This leads to thalassemia major and a severe hemolytic anemia, and very marked ineffective erythropoiesis.

There are literally dozens and dozens of point mutations that have been identified that cause beta thalassemia. This is a picture of the beta thalassemia molecule with the exons and the introns and the flanking sequences and showing that these mutations can effect transcription, RNA splicing, RNA cleavage, frame shift, nonsense codon, initiator codon, the development of non-stable globin or in certain circumstances, small deletions. But this picture is a very very

In the setting of thalassemia intermedia, some hemoglobin A is present because in this condition there is not complete shut off of effective transcription and translation of the beta globin genes, so some is present. But you tend to see to a varying extent increases in hemoglobin A2 and distinct increases in hemoglobin F. So if you keep this in mind this should help to

Okay, letís talk about beta thalassemia major in a little bit more detail. What are the clinical features? First of all there is, in addition to the severe microcytic anemia and splenomegaly, there is - if this condition is untreated - there are very very marked skeletal changes that occur. And these include osteopenia, marked expansion of the bone marrow cavity, thinning of the bone cortex, and these thalassemic facies where there is marked frontal bossing and marked overgrowth of the forehead and cheek bones to produce the typical thalassemic 

The prognosis of beta thalassemia major was very very grim before there was any treatment available for it. So with no treatment of it at all, the natural history is for death by age five from infections and cachexia. The first advance in treatment that was made was the initiation of episodic blood transfusions when the patient was having a particularly bad time. With the advent of this type of therapy, the survival was prolonged into the second decade, but death

So now the accepted treatment of beta thalassemia major is to begin a hypertransfusion program beginning around the second or third year of age, with a goal of maintaining the hemoglobin of 10 gm/dl. You monitor the spleen and you still do a splenectomy if it appears to be contributing to an increase in transfusion requirement. Then this very major advance in therapy has been the initiation of iron chelation therapy with desferrioxamine starting after the age of three years, given as described in the previous lecture. Other approaches that are effective are bone marrow transplantation. The condition can be cured by bone marrow transplantation,