14.

Compare and Contrast Alpha & Beta Thalassaemias The thalassaemias are among the most common single gene disorders in the world. The thalassaemias are characterized by reduced, or absent synthesis of one or more globin chain types. The resultant imbalance of globin chain synthesis leads to formation of A or B tetramers rather than exclusively - dimers, which causes ineffective erythropoiesis and a shortened red cell lifespan. The thalassaemias are classified according to three criteria: the affected globin gene(s), e.g. , , gamma-, whether the reduction in the rate of synthesis of the affected globin is partial (designated by a +) or absolute (designated by a 0 after the affected gene), and the genotype, e.g. homozygous, heterozygous or compound heterozygous (e.g. 0). The clinical consequence of the genotype (being homozygous or heterozygous) differs between and thalassaemia. thalassaemia, the heterozygous state with a single gene for thalassaemia, causes no symptoms or merely mild anaemia because there is another gene still able to make chains. But the homozygous state with both genes for thalassaemia is lethal before birth (Hb Barts Hydrops) because no chains can be made and without chains there can be no Hb F or Hb A and without them there can be no life. In thalassaemia, the heterozygous state (called thalassaemia minor) is accompanied by no symptoms or at most by very mild anaemia. In comparison to thalassaemia, the homozygous form of thalassaemia (thalassaemia major) is not immediately lethal because there is some production of Hb F, which does not contain chains. However, there is severe anaemia with complications including progressive enlargement of the liver, spleen and heart and malformation of bones. In thalassaemia, when only one of the four globin chains genes is defective, the patient has little clinical disease and the condition can only be detected at birth from the presence of a small amount of Bart's haemoglobin, a haemoglobin made up of four gamma globin chains. Heterozygous 0, and homozygous + patients show microcytosis, hypochromia, and a mild anaemia, suggesting thalassaemia minor. In contrast to those with B-thalassaemia minor, however, they have normal haemoglobin F and A2 levels. Depending on the genetic mutation, thalassaemia can present as an incidental laboratory finding in an otherwise asymptomatic patient or as a moderate to severe anaemia. One unifying feature is the presence of microcytosis and hypochromia, which reflects the decreased synthesis of globin chains. The genetic mutation that causes thalassaemia can be caused by different molecular mechanisms, such as point mutations or deletions. Normal individuals carry four globin genes, two tandem pairs on the short arm of each chromosome 16. More that 95% of -thalassaemias result from the deletion of one or both of the tandem -globin genes, which gives rise to six possible genotypes. The frequencies of the different deletions that give rise to thalassaemia vary widely in different races. Deletion of both -globin genes on one chromosome 16 is relatively common in SE Asia and the Philippines, leading to a high incidence of haemoglobin H disease and haemoglobin Barts Hydrops fetalis. Conversely, the most common deletion in African-Americans is of only one -globin gene, meaning that haemoglobin H and haemoglobin Barts hydrops fetalis are very rare. In comparison, normal individuals carry two -globin genes, one on the short arm of each chromosome 11. Most -thalassaemias result from a point mutation within or close to the -globin gene complex. Each mutation can result in a reduction or abolition of -globin gene function and so to + or 0 thalassaemia. The classification of thalassaemia is similar to that for thalassaemia.

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The classification of thalassaemias underestimates the complex nature of the relationship between genotype and phenotype. More than 100 different gene defects that cause thalassaemia have been described. Most thalassaemias result from gross deletions within the -globin gene complex. At least nine deletions that result in complete abolition of -globin synthesis have been described, and each is closely associated with a particular population, such as Philippines and Thailand, and Mediterranean. All of these deletions remove both -globin genes on one chromosome and so result in a 0 haplotype. Deletions of only one -globin gene have been described in many populations are the most common deletions in thalassaemia. Such deletions are denoted according to the size of the deleted region, which arise from unequal crossing over of two chromosome 16s within the -globin complex. Several deletions that affect only the -globin gene and result in thalassaemia have been described, but all except one are extremely rare. In contrast to thalassaemia, most cases of thalassaemia result from point mutations within or close to the globin gene. More than 200 different mutations have been described, and the distribution of these mutations is linked to certain geographical locations. Mutations can occur in the exons that code directly for -globin, in the promoter region, mRNA cap site, intron splice sites and in the introns. Mutations that do not lay within the globin introns can cause thalassaemia by impairing gene transcription, which reduces -globin synthesis. Mutations in the intron splice sites mean that function -globin cannot be synthesized. Thalassaemias are most common in parts of the world where malaria is endemic because the heterozygous state affords some protection against malaria. This phenomenon, where an apparently severely detrimental genetic abnormality persists because it confers a survival advantage, is known as a balanced polymorphism. The incidence is also high in immigrant populations that originate from these parts of the world. The incidence of thalassaemia is not uniform. + thalassaemia is most common in African-Americans and in people from Indonesia, SE Asia, the Middle East, India and the south Pacific islands. 30% of African-Americans are 'silent carriers' of the + thalassaemia, while about 3% are homozygous. 0 thalassaemia is most common in people from the Philippines, SE Asia and southern China. The population incidence of 0 reaches 25% in some parts of Thailand. thalassaemia has a slightly different incidence to thalassaemia, affects people from the Mediterranean, Africa, India, SE Asia and Indonesia. The incidence of B thalassaemia mutations is almost 10% in some parts of Greece. and thalassaemia are distinct and different disorders since they diminish the production of distinct and different globin polypeptide chains and particularly in the homozygous state they have distinct and different consequences.

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