Beta thalassemia: molecular pathogenesis and clinical variability

Clinically, homozygous beta-thalassaemia is characterised by a severe anaemia requiring regular transfusion therapy in most patients. However, there is a marked clinical variability ranging from this severe picture to the virtual absence of symptoms and haematological abnormalities. Biochemically, beta-globin synthesis in the erythroid precursors of the bone marrow is reduced or absent resulting in a relative excess of insoluble alpha-globin chains and dyserythropoiesis. The molecular genetics of this disorder is highly variable involving a multitude of different mutations of the beta-globin gene. These mutations can inactivate gene expression at all levels on its way from DNA to mature haemoglobin. The clinical picture is largely determined by the type of mutations inherited. Additionally the degree of alpha-globin chain excess can be influenced by the co-inheritance of alpha-thalassaemia or mutations resulting in the hereditary persistence of fetal globin synthesis (HPFH). This review discusses the relationship between the molecular defect and the clinical picture of patients with beta-thalassaemia.