DOMINANT β THALASSAEMIA: MOLECULAR BASIS AND PATHOPHYSIOLOGY

The thalassaemias are a group of inherited haemoglobin disorders characterized by reduced synthesis of 8 globin chains and primarily affecting peoples of Mediterranean. Asian and African ancestry in the malaria-endemic regions. More than 80 mutations causing p thalassaemia have now been characterized (Kazazian, 1990); these result in a deficit of [j chain production that ranges from minimal (mild /I+ thalassaemia alleles) to a complete absence ($ thalassaemia alleles). Typically, heterozygotes for /I thalassaemia, including Po thalassaemia. are clinically asymptomatic with only minor haematological abnormalities, whereas homoaygotes or compound heteroxygotes for /I thalassaemia have thalassaeinia major and are dependent on regulsr blood transfusion for survival (Weatherall & Clegg. 198 1). Therefore, the /j thalassaemias are considered to be autosomal recessive disorders since the inheritance of two abnormal /I globin genes is required to produce a clinically detectable phenotype. Kecently. however, dominant forms of /I thalassaemias have been identified which result in a thalassaemia intermedia phenotype in individuals who have inherited only a single copy of the abnormal p gene. This unusual form of /I’ thalassaemia was probably first identified in an Irish family in 1973: anaemia, enlargement of the spleen, and gross abnormalities of the erythrocytes and their precursors were observed in three generations of the family and were transmitted as a single gene disorder in an autosomal dominant fashion (Weatherall et a!. 1973). The clinical features of severe heterozygous p thalassaemia with a dominant dyserythropoietic anaemia associated with inclusion bodies in bone marrow normoblasts and peripheral red cells after splenectomy were also observed in a Swiss-French family (Stamatoyannopoulos c t a], 1974) and the term ‘inclusion body thalassaemia’ was proposed for this subgroup of 13 thalassaemia. Subsequently, several similarly affected kindreds, from a wide geographical distribution, have been reported. A spectrum of different mutations. underlying these dominantly inherited forms of 8 thalassaemia, have been identified, and it has now become clear that the phenotype of these disorders overlaps both the 8 thalassaemia and the unstable haemoglobin variants.