Hemoglobinpathies

A large number of mutations have been described in the globin genes. These mutations can be divided into two distinct types: those that cause qualitative abnormalities (e.g. sickle cell anemia) and those that cause quantitative abnormalities (the thalassemias). Taken together these disorders are referred to as the hemoglobinopathies. A third group of hemoglobin disorders include those diseases in which there is a persistence of fetal hemoglobin expression. These latter diseases are known collectively as hereditary persistence of fetal hemoglobin (HPFH).

Of the mutations leading to qualitative alterations in hemoglobin, the missense mutation in the β-globin gene that causes sickle cell anemia is the most common. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of hemoglobin in persons with sickle cell anemia is referred to as HbS.

The underlying problem in sickle cell anemia is that the valine for glutamic acid substitution results in hemoglobin tetramers that aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and unable to traverse the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling. The end result is clogging of the fine capillaries. Because bones are particularly affected by the reduced blood flow, frequent and severe bone pain results. This is the typical symptom during a sickle cell "crisis". Long term the recurrent clogging of the capillary beds leads to damage to the internal organs, in particular the kidneys, heart and lungs. The continual destruction of the sickled red blood cells leads to chronic anemia and episodes of hyperbilirubinemia.

An additional relatively common mutation at codon 6 is the conversion to a lysine codon (AAG) which results in the generation of HbC.