Molecular pathology and diagnosis of beta-thalassemia intermedia

Beta-thalassemia intermedia is the clinical definition for markedly heterogeneous group of thalassemia like conditions ranging in severity from the clinically silent heterozygous beta-thalassemia to the severe transfusion-dependent thalassemia major. The molecular pathology for this group of disorders is to date only partially defined. The most common genotype is homozygosity or compound heterozygosity for mild beta-thalassemia, i.e. beta-thalassemia mutations associated with a high residual output of beta-chains from the affected beta locus. A very interesting group of mutations are those completely silent in the heterozygous state and thereby indicated as silent beta-thalassemia. In addition to the well know C a T mutation at position -101, we have recently defined two new silent mutations, i.e. beta -92 (Ca T) and beta IVSII -844 (Ca G). Another relatively common mechanism for a mild clinical course is the coinheritance with homozygous beta-thalassemia of genetic determinants able to substain a continuous production of gamma chains in the adult life (-158 Ggamma (Aa T) and –196 Ag (Ca T)].Thirdly coinheritance of alpha-thalassemia (-alpha/-alpha ou alpha-thal(non del) alpha/alpha alpha) is certainly able to ameliorate the clinical picture of beta° or beta+-thalassemia. However, there are a consistent number of homozygotes for beta°-thalassemia, for which modifying factors have not to date been reported. Most commonly, patients with thalassemia intermedia have both beta-globin genes affected. We know however several conditions in which heterozygous beta-thalassemia may lead to the development of thalassemia intermedia. The most common of these genotypes are double heterozygotes for beta-thalassemia and the triple alpha-globin gene arrangement or the presence of a hyperunstable Hb molecule, which most often results from mutations in the third exon of the globin gene. We have however observed several cases of heterozygous beta-thalassemia presenting a thalassemia intermedia clinical picture for which no cause for the unusual phenotype severity for a beta-thalassemia carrier state has been defined and for which we postulated a double heterozygosity for beta-thalassemia and a defect affecting a beta-globin gene transcription factor.