The thalassemia syndromes: Biochemical, genetic and clinical considerations

Abstract Dr. Nicholas P. Christy: The thalassemia syndromes are a heterogenous group of entities. They are hereditary diseases most commonly found in, but not restricted to, Mediterranean countries. The two main clinical forms are thalassemia minor and thalassemia major: in the former, subjects are heterozygous for a thalassemia gene; in the latter, homozygous. The salient metabolic defect in thalassemia is a decreased capacity of erythroid cells to synthesize normal adult hemoglobin, hemoglobin A. Over 95 per cent of the total hemoglobin in red cells of patients with thalassemia major may be fetal hemoglobin, hemoglobin F. This exercise has dealt with attempts to elucidate the mechanism of disordered synthesis of hemoglobin in thalassemia, and with recent studies of the genetic mechanisms which underlie this abnormal biosynthetic process. The defect in synthesis of hemoglobin A in thalassemia is probably not due to an altered amino acid sequence of the globin moiety; amino acid analysis has yielded normal findings, so there is no evidence to support this hypothesis. Deficient synthesis of heme probably does not account for the defect because in certain patients the rate of synthesis of hemoglobin A 2 or of fetal hemoglobin may be normal or even greater than normal. A reduced rate of heme synthesis, if present, should result in a diminished rate of synthesis of all hemoglobins. Recent investigations have suggested the possibility of a third mechanism: that the defect may reside in one of the factors which control the over-all rate of hemoglobin A synthesis, not involving the structure of the protein. It has been observed that polyribosomes of reticulocytes from patients with thalassemia major have a strikingly reduced capacity to incorporate isotopically-labeled leucine. In contrast, thalassemic polyribosomes are capable of carrying out a normal or greater than normal rate of incorporation of isoleucine, an amino acid present in fetal hemoglobin (hemoglobin F), but not in hemoglobin A. The selective deficiency in leucine incorporation may well explain the observed defect in hemoglobin A synthesis; it is not yet known whether this deficiency derives from an altered messenger RNA or from a decreased amount of messenger RNA for hemoglobin A formed. In either case, the defect is likely to be due to a defective gene. The genetic information now available concerning some of the thalassemia syndromes is most consistent with the concept of abnormalities in "regulatory" genes. It seems probable that these hemoglobinopathies are best interpreted by assuming more than one pair of involved genes, i.e., more than one genetic locus. Studies of patients possessing two or four abnormal hemoglobins have tended to support the Itano scheme of independent synthesis of the alpha and beta chains of hemoglobin, with random combination of the chains following their synthesis. Such an assumption appears to account most reasonably for the augmented synthesis of hemoglobin S in some patients with hemoglobin S-thalassemia disease (genetic interaction), and the nonaugmented synthesis of hemoglobin S-synthesis in others. In the first instance, the defect most probably lies in one of the hemoglobin-synthesizing genes, the betachain gene, and in the second, in another gene, the alpha-chain gene. Thalassemia major may be regarded as an example of a chemically defined developmental process which goes awry, i.e., as a failure of the normal substitution of beta chain synthesis for synthesis of the gamma chains which characterize hemoglobin F. An example of an abnormality in a "structural gene" is observed in the so-called "Lepore" trait in which there is coexistence in a single person of beta thalassemia and of an abnormal hemoglobin (Lepore hemoglobin) which contains a chain made up of both the delta and beta chains. An abnormal "regulatory gene" is assumed to determine the rate of synthesis of these altered beta chains. The thalassemia syndromes are currently interpreted as a biochemical defect in ribosomal synthesis of hemoglobin A. This defect and other abnormalities appear to be dependent upon intrinsic abnormalities in the gene or genes which control the synthesis of hemoglobin.