Erol Baysal

α-Thalassemia in the United Arab Emirates

A neonatal screening survey of α-thalassemia (α-thal) among the United Arab Emirates (UAE) nationals was conducted on 418 consecutive cord blood samples. Our findings demonstrate that 49% of the cases studied were found with an α-globin gene defect. The gene frequency of the –α3.7 was 0.2847 and that of the –α4.2 was 0.0072. Four nondeletional α-thal mutations were found; αPA-1, αPA-2, Hb CS and α-5nt del with gene frequencies of 0.0036, 0.0012, 0.0024, and 0.0072, respectively. We also report here the genotype-phenotype correlation in 22 patients with Hb H disease or Hb H-like syndrome. Of these, 6 were homozygous for the αPA-1 mutation, 2 were homozygous for Hb CS, and 14 were compound heterozygous for either αPA-1, Hb CS, α-5nt del or ––MED-I, with the –α3.7. The data reported here demonstrate that a considerable heterogeneity of α-thal mutations occurs in the UAE and that the incidence of α-thal in the indigenous population is one of the highest in the world. Our clinical data suggest that Hb H disease in the UAE has, in general, a mild to moderate phenotypic presentation.

Genotype-Phenotype Correlation of Sickle Cell Disease in the United Arab Emirates

We have identified the beta s-globin gene haplotypes of 85 patients with sickle cell disease attending the Dubai Thalassemia Center and assessed the influence of haplotype, alpha-thalassemia, and fetal hemoglobin on the clinical presentation. Identification of the beta s haplotypes was based on mutation analyses in the promoter sequences of the G gamma- and A gamma-globin genes. The Arabian-Indian haplotype was found in 52% of the beta s chromosomes, whereas the remaining were the Bantu and Benin haplotypes. Those with the Arabian-Indian haplotype in this group had a significantly higher fetal hemoglobin (Hb F) level (mean 27%) and a milder clinical course. In contrast, those with the African haplotypes, Bantu and Benin, expressed relatively lower Hb F levels (mean 11.3%), with a severe clinical presentation. Coinheritance of alpha-thalassemia trait in the African haplotypes had an ameliorating effect on hemolytic episodes, but vaso-occlusive crises were more frequent.

Role of Membrane-Bound Haemoglobin Products in Oxidative Damage in Sickle Cell Membranes

Even though the development of the membrane abnormalities in sickle cell erythrocytes is due to the presence of a mutant gene product, sickle cell anaemia is in a sense a membrane disease. In particular, the presence of iron-containing breakdown products of haemoglobin in the sickle cell membranes provides a source of continued oxidative damage. An understanding of the primary causes of these membrane abnormalities may be useful in the development of effective therapies.

Oxidative Effects of Iron on Erythrocytes

In this work we have investigated the effects of iron-induced free radical formation in normal human erythrocytes in vitro, as a model system for studying iron damage, and in erythrocytes from patients with beta-thalassaemia major. The resulting oxidative effects were measured in terms of methaemoglobin formation and reduced glutathione loss. The effects of desferrioxamine, an iron-chelating agent, were also investigated. The results show that the increased methaemoglobin formation after iron-induced oxidative stress is consistent with a decline in the intracellular glutathione levels and that this process is inhibited by desferrioxamine. Similar treatment of red cell haemolysates produces less methaemoglobin. This suggests that, on exposure of intact erythrocytes to iron-induced free radical effects, the red cell membrane exacerbates the breakdown of the antioxidant defences of the cell and the oxidation of haemoglobin.

Modulation of Iron-Mediated Oxidant Damage in Erythrocytes by Cellular Energy Levels

In this work we have investigated the effects of iron-induced oxidative stress on erythrocytes and their membranes, the importance of haemoglobin oxidation and of the maintenance of the metabolic properties of the cells. The results show that by maintaining the energy requirements of the erythrocyte, methaemoglobin production is minimised under conditions of iron-stress. However, in this situation, the membranes of the erythrocytes become more susceptible to the oxidative damage and increased lipid peroxidation ensues.