Alpha-thalassemia

Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the genes HBA1 and HBA2. Alpha-thalassemia is due to impaired production of 1,2,3, or 4 alpha globin chains, leading to a relative excess of beta globin chains. The degree of impairment is based on which clinical phenotype is present (how many chains are affected).

Epidemiology

The worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure, suggesting a protective role for alpha-thalassemia against the more severe manifestations of malaria. Thus, alpha-thalassemia is common in sub-Saharan Africa, the Mediterranean Basin, the Middle East, South Asia, and Southeast Asia, and different genetic subtypes have variable frequencies in each of these areas. The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. The most common form of alpha(+) thalassemia seen in the US is due to the -alpha(3.7) deletion, a single alpha-globin gene deletion, and is present in approximately 30% of African Americans. However, even in the homozygous state this disorder will result only in a mild microcytic anemia. The more serious clinical disorders of Hb H and Hb Bart hydrops fetalis syndrome, although found throughout the US today, are more common in the Western US and have dramatically increased in prevalence in the past 2 decades due to increased Asian immigration.

Causes

It is most commonly inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome.

It can also be acquired, under rare circumstances. Due to the low occurrence of alpha-thalassemia, the disease can be mistaken for iron deficiency anemia.

Pathophysiology

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. The excess γ chains form tetramers which are poor carriers of O₂ since their affinity for O₂ is too high so it is not dissociated in the periphery. Homozygote α⁰ thalassaemias, where there is lots of γ₄ but no α-globins at all (referred to as Hb Barts), often result in still birth.

Types

There are two genetic loci for α globin, and thus four genes in diploid cells. Two genes are maternal in origin and two genes are paternal in origin. The severity of the α thalassemias is correlated with the number of affected α globin genes: the greater, the more severe will be the manifestations of the disease.

When noting the genotype, a "-" indicates an absence of function, and a "α" indications a functional alpha chain. (In contrast to the "β^o" and "β⁺" notation used in beta-thalassemia, in alpha-thalassemia a distinction between absent and reduced function is not usually noted.)

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