Unusual types of α Thalassemia

© Cambridge University Press 2009. Introduction: In this chapter we describe three relatively rare, clinically complex syndromes in which the occurrence of α thalassemia provided the clue to understanding the molecular basis of each condition. These conditions exemplify the important interplay between clinical observation and human molecular genetics. Two of these syndromes (ATR-16 [OMIM: 141750] and ATR-X [OMIM: 301040]) in which α thalassemia is associated with multiple developmental abnormalities (including mental retardation, MR) are inherited. The third condition (ATMDS [OMIM: 300448]) is an acquired disorder in which α thalassemia appears for the first time in the context of myelodysplasia. Α Thalassemia Associated with Mental Retardation and Developmental Abnormalities: The rare association of α thalassemia and mental retardation (MR) was recognized more than 25 years ago by Weatherall and colleagues. It was known that α thalassemia arises when there is a defect in the synthesis of the α-globin chains of adult hemoglobin (HbA, α2β2). When these authors encountered three mentally retarded children with α thalassemia and a variety of developmental abnormalities, their interest was stimulated by the unusual nature of the α thalassemia. The children were of northern European origin, where α thalassemia is uncommon, and although one would have expected to find clear signs of this inherited anemia in their parents, it appeared to have arisen de novo in the affected offspring. It was thought that the combination of α thalassemia with MR (ATR), and the associated developmental abnormalities represented a new syndrome and that a common genetic defect might be responsible for the diverse clinical manifestations.