Submitted February 11, 2005
Accepted May 6, 2005
A novel molecular basis for 
thalassemia intermedia poses new questions about its pathophysiology
Anuja Premawardhena, Christopher A Fisher, Nancy F Olivieri, Shanthimala de Silva, Jackie Sloane-Stanley, William G Wood, and David J Weatherall*
Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom
Hemoglobinopathy Research, University Health Network, Toronto, Canada
Lady Ridgeway Hospital, Colombo, Sri Lanka
* Corresponding author; email: liz.rose{at}imm.ox.ac.uk.
During a study of the molecular basis for severe forms of 
thalassemia in Sri Lanka two patients were found to be heterozygous for thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated 
globin genes in combination with heterozygous thalassemia. The other is homozygous for a triplicated globin gene arrangement and heterozygous for thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the two propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with thalassemia intermedia associated with extended globin gene arrangements. The hemoglobin F levels in these patients with severe thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended globin gene interactions and in dominant thalassemia, raising the possibility that increased levels of Hb F production in thalassemia may require mutations at both globin gene loci.
