To evaluate the incidence of hemoglobinopathies in Omani subjects and to forecast its future burden on health resources, we initiated a prospective neonatal screening program in two major cities of the Sultanate of Oman. Consecutive cord blood samples from a total of 7,837 neonates were analyzed for complete blood counts and for hemoglobin (Hb) profile by high performance liquid chromatography (HPLC). No case with Hb H (beta4) was detected. We observed that the overall incidence of alpha-thalassemia (alpha-thal) was 48.5% [based on the presence of Hb Bart's (gamma4)] and the beta-globin-related abnormalities accounted for 9.5% of the samples (4.8% sickle cell trait, 2.6% beta-thal trait, 0.9% Hb E trait, 0.8% Hb D trait, 0.08% Hb C trait, 0.3% sickle cell disease and 0.08% homozygous beta-thal). This is also the first large study to establish reference ranges of cord red blood cell (RBC) indices for Omani neonates.

The paucity of clinical reports in the world literature suggests that, as a disease entity, haemoglobin SE compound heterozygosity is of negligible importance. In view of the significant community prevalence of this haemoglobinopathy in the Sultanate of Oman where it is the second most prevalent sickling disorder, a hospital study of 12 SE compound heterozygotes from six unrelated Arab families was undertaken to determine their clinico-haematological features. Our findings were compared with those reviewed in the literature. Clinical and haematological evaluation was carried out by conventional methods including chromatographic haemoglobin analysis. At least 50% of those studied were asymptomatic throughout the study period but sickling-related complications occurred in the rest and included the acute chest syndrome (1/12), severe vaso-occlusive skeletal pain (2/12), frontal bossing (1/12) possibly indicative of significant chronic haemolysis and recurrent infections of the urinary tract (1/12). Steady-state haemoglobin levels fell within the reference range while MCV and MCH values were, as expected, reduced in most cases; nevertheless, concomitant inheritance of alpha-thalassaemia trait was also likely. Red cell morphology was striking by the absence or rarity of pseudo-sickled cells in the blood films of many patients during the steady state and in crises. Bearing in mind the prevalence of 0.05% of SE compound heterozygosity in Oman, the findings in this single study of the largest number of SE patients and their relatives confirm the predominantly asymptomatic nature of this sickling disorder in individuals in the community at large. HbF levels do not appear to explain the heterogeneous nature of this haemoglobinopathy. Correlation of the variable clinical and haematological features of SE cases with their alpha-globin gene status and beta-cluster haplotypes (linked to the beta(s)- and beta(e)-genes) merits a separate investigation, which is being currently organized.

On the basis of a sample of 117 chromosomes, we have demonstrated the multicentric origin of the sickle mutation in Northern Oman. Three major haplotypes coexist: 52.1% Benin (typical and atypicals), 26.7% Arab-India, and 21.4% Bantu. These haplotypes are not autochthonous to Oman but originated elsewhere and arrived in Oman by gene flow. The distribution of haplotypes is in excellent agreement with the historical record, which establishes clear ancient contacts between Oman and sub-Sahara west Africa and explains the presence of the Benin haplotype; contacts with Iraq, Iran, present-day Pakistan, and India explain the presence of the Arab-India haplotype. More recent contacts with East Africa (Zanzibar/Mombasa) explain the presence of the Bantu haplotype. The pattern of the Arab-India haplotype in the populations of the Arabian peninsula reinforces the hypothesis that this particular mutation originated in the Harappa culture or in a nearby population and in addition reveals that the Sassanian Empire might have been the vehicle by which this Indo-European sickle mutation migrated (gene flow) to the present-day Arabian peninsula, including Oman.

Hemoglobin (Hb) S-Oman has two mutations in the β-chains. In addition to the classic βS mutation (β6 Glu → Val), it contains a second mutation in the same chain (β121 Glu → Lys) identical to that of HbOARAB. We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant −/ thalassemia and those with about 14% of HbS-Oman and concomitant −/− thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a “yarn and knitting needle” shape, in addition to folded and target cells. The CSAT of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates CSAT’s, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the Km for Ca2+ needed to activate the Gardos’ channel (making this transporter more sensitive to Ca2+), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide–stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the β6 Val mutation which are enhanced by the second mutation at β121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at β121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.