The thalassemias are the result of quantitative abnormalities in hemoglobin synthesis. With the α-thalassemias the level of α-globin production can range from none to very nearly normal levels. This is due in part to the fact that there are 2 identical α-globin genes on chromosome 16. Thus, the α-thalassemias involve inactivation of 1 to all 4 α-globin genes. The two identical α-globin genes are identifed as HBA1 and HBA2. Both the HBA1 and the HBA2 genes are located at 16p13.3 and are both composed of 3 exons that encode a 142 amino acid protein.
If 3 of the 4 α-globin genes are functional, individuals are completely asymptomatic. This situation is identified as the "silent carrier" state or sometimes as α-thalassemia 2. Genotypically this situation is designated αα/α– (where the dash indicates a non-functional gene) or α–/αα.
If 2 of the 4 genes are inactivated individuals are designated as "α-thalassemia trait" or as α-thalassemia 1. Genotypically this situation is designated αα/– –. In individuals of African descent with α-thalassemia 1, the disorder usually results from the inactivation of 1 α-globin gene on each chromosome and is designated α–/α–. This means that these individuals are homozygous for the α-thalassemia 2 chromosome. The phenotype of α-thalassemia 1 is relatively benign. The mean red cell volume (designated MCV in clinical tests, for "mean corpuscular volume", a red blood cell is also referred to as a corpuscle) is reduced in α-thalassemia 1 but individuals are generally asymptomatic. Normal MCV is around 90 ± 5 femtoliters (fl) and in α-thalassemia trait it is usually found to be around 81 ± 7fl. In addition, the mean corpuscular hemoglobin content (MCH) is reduced. Normal MCH is around 30 ± 2 picograms (pg). and in α-thalassemia trait it is around 26 ± 2pg.
The clinical situation becomes more severe if only 1 of the 4 α-globin genes is functional. Because of the dramatic reduction in α-globin chain production in this latter situation, a high level of β4 tetramer is present. Clinically this is referred to as hemoglobin H disease (HbH). Afflicted individuals have moderate to marked anemia and their MCV is quite low, but the disease is not fatal. In HbH disease individuals have MCV of 65 ± 7fl and MCH of 19 ± 2pg.
The most severe situation results when no α-globin chains are made (genotypically designated – –/– –). This leads to prenatal lethality or early neonatal death. The predominant fetal hemoglobin in afflicted individuals is a tetramer of γ-chains and is referred to as hemoglobin Bart's. This tetrameric form of hemoglobin has very high affinity for oxygen resulting in poor oxygen release and thus, oxygen starvation in the fetal tissues. Heart failure results as the heart tries to pump more oxygenated blood to oxygen starved tissues leading to marked edema. This latter situation is called hydrops fetalis.