Pathophysiology
The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.
Thalassemia produces a deficiency of α or β globin, unlike sickle-cell disease which produces a specific mutant form of β globin.
β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in Africans, but also in Greeks and Italians.
Alpha (α) thalassemias:
The α thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.
Beta (β) thalassemias:
Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (βo) if they prevent any formation of β chains (which is the most severe form of beta Thalassemia); they are characterized as (β+) if they allow some β chain formation to occur. In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.
Delta (δ) thalassemia:
As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains.
Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:
hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically similar to β thalassemia major or thalassemia intermedia.
hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
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