Beta-thalassemia: from genotype to phenotype.

B eta-thalassemias are heterogeneous autosomal recessive hereditary anemias characterized by reduced or absent b globin chain synthesis. The resulting relative excess of unbound a globin chains precipitate in erythroid precursors in the bone marrow, leading to their premature death and, hence, to ineffective erythropoiesis. b-thalassemia phenotypes are variable, ranging from the severe transfusion dependent tha-lassemia major to the mild form of thalassemia interme-dia. Patients with the major form of the disease have severe anemia, microcytic and hypochromic anemia, hepatosplenomegaly, and usually come to medical attention within the first two years of life. Without treatment, affected children have severely compromised growth and development and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusional iron overload, allows for normal growth and development and extends life expectancy into the third to fifth decade. 1 Individuals with thalassemia intermedia present later in life, have milder anemia (that never or only rarely requires transfusion), liver and spleen enlargement, typical bone modifications , and mild to moderate jaundice. 2 Occasionally patients with thalassemia intermedia are completely asymptomatic until adult life with only mild anemia. The major and intermedia forms of the disease are the two extremes of a wide range of clinical variability. Each group includes a continuous scale of severity, as demonstrated by the variability in age at which thalassemia major patients need transfusion; from months to years of life. Beta-thalassemias are also very heterogeneous at the molecular level, with more than 200 disease-causing mutations so far identified; a complete updated list is available at the Globin Gene Server Web Site-http://glo-bin.cse.psu.edu/. In most cases, mutations are single nucleotide substitutions, deletions or insertions of single nucleotides or small oligonucleotides leading to frameshift. Their diversity and the consequent variable degree of globin chain imbalance are the main determinants for milder phenotypes, the coinheritance of homozygosity or compound heterozygosity for mild b-thalassemia alleles being responsible for a consistent residual output of b chains from the affected b globin locus. However, much of the phenotypic variability is also explained by other genetic determinants capable of reducing the a/non-a chain imbalance thereby resulting in a lesser degree of a chain precipitation. 3 One of the first discovered mechanisms able to reduce this imbalance is the coinheritance with homozygous b-thalassemia of a-thalassemia determinant. In this case, the severity of the clinical phenotype correlates with the a globin chain deficiency and with the improved a/non-a …