Structural Biochemistry/Protein function/Heme group/Hemoglobin/Thalassemia

General Info

Unlike sickle-cell anemia, which is a disorder that results in the synthesis of an incorrectly functioning globin chain, Thalassemia is a condition in which too few globin strands are synthesized. Thalassemia is generally caused by mutations in regulatory genes. This defect reduces the synthesis rate of one of the necessary globin chains needed to make hemoglobin which leads to the formation of abnormal hemoglobin and causes anemia.

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Strains of Thalassemia

There are three types of Thalassemia (bases on the globin strand affected), α-Thalassemia, β-Thalassemia and ɣ-Thalassemia.

α-Thalassemia: The effects and severity of α-Thalassemia depends on the number of α-globin loci affected, because α-globin chains are encoded by two genes, each containing 2 loci, affects of the disease can be minimal or even non-existent. If only one of the four loci is affected then the person usually doesn’t display any symptoms of the disorder, they are just a carrier. If two loci are affected then the person often has somewhat mild symptoms which mimic those of iron deficiency induced anemia (this condition is generally referred to as the α-Thalassemia trait). However, the effects of the disorder become more evident and severe when three loci are affected because now both genes that encode for the α-globin are defective (this condition is called Hemoglobin H disease), unstable hemoglobin is produced which acts as a much poorer oxygen transporter (because it has a higher than normal affinity for oxygen), which causes anemia and splenomegaly. If all four loci are affected than the fetus can’t survive and will either die in the womb resulting in a miscarriage or will be a stillbirth.

β-Thalassemia: Like α-Thalassemia the severity of β-Thalassemia depends on the nature of the mutation; the mutation can either completely prevent the production of β chains (referred to as βo) or allow limited β chain formation (known as β+). However, unlike α-globin, which is coded for by 4 loci, β-globin is only coded for by one gene with two loci, so the severity of the condition is very different based on whether one or two of the loci are affected. If only one of the loci is mutated then the symptoms are very mild and sometimes even unnoticeable, the only effect is a slight decrease in red blood cell size (this disorder is called β-Thalassemia minor). However, if both alleles are affected the person will experience severe anemia that could even cause death unless they receive periodic blood transfusion (called β-Thalassemia major). There also exists conditions which are intermediates between the two extremes, which often result in anemia but it can be managed with occasional blood transfusions (called Thalassemia intermedia). However, no matter the severity of the disorder (i.e.-the number of loci affected) there is still an excess of α chains produced in relation to the β strands which tend to bind to red blood cells and can cause membrane damage or even form toxic aggregates.

ɣ-Thalassemia: As with the other disorders, ɣ-Thalassemia exist as either a mutation that limits the production of ɣ-strands or completely eliminate the formation altogether. However, unlike the other disorders, ɣ-strands only make up about 2-3% of hemoglobin, so the effects of the condition are not severe even if no ɣ-strands are produced. The biggest risk associated with the disorder is that it counteracts the tested effects of β-Thalassemia (which is an increase in A2 hemoglobin) and can lead to a misdiagnosis. Such a misdiagnosis may lead to extreme sickness and, in some cases, death.

Sources

Berg, Jeremy M. John L. Tymoczko. Lubert Stryer. Biochemistry Sixth Edition. W.H. Freeman and Company. New York, 2007.