Existence of HbF Enhancer Haplotypes at HBS1L-MYB Intergenic Region in Transfusion-Dependent Saudi ß-Thalassemia Patients.

Background and Objectives. ß-Thalassemia and sickle cell disease are genetic disorders characterized by reduced and abnormal ß-globin chain production, respectively. The elevation of fetal hemoglobin (HbF) can ameliorate the severity of these disorders. In sickle cell disease patients, the HbF level elevation is associated with three quantitative trait loci (QTLs), BCL11A, HBG2 promoter, and HBS1L-MYB intergenic region. This study elucidates the existence of the variants in these three QTLs to determine their association with HbF levels of transfusion-dependent Saudi ß-thalassemia patients. Materials and Methods. A total of 174 transfusion-dependent ß-thalassemia patients and 164 healthy controls from Eastern Province of Saudi Arabia were genotyped for fourteen single nucleotide polymorphisms (SNPs) from the three QTL regions using TaqMan assay on real-time PCR. Results. Genotype analysis revealed that six alleles of HBS1L-MYB QTL (rs9376090C p = 0.0009, rs9399137C p = 0.008, rs4895441G p = 0.004, rs9389269C p = 0.008, rs9402686A p = 0.008, and rs9494142C p = 0.002) were predominantly associated with ß-thalassemia. In addition, haplotype analysis revealed that haplotypes of HBS1L-MYB (GCCGCAC p = 0.022) and HBG2 (GTT p = 0.009) were also predominantly associated with ß-thalassemia. Furthermore, the HBS1L-MYB region also exhibited association with the high HbF cohort. Conclusion. The stimulation of HbF gene expression may provide alternative therapies for the amelioration of the disease severity of ß-thalassemia.

Demands and challenges for patients with sickle-cell disease requiring hematopoietic stem cell transplantation in Saudi Arabia.

Allogeneic HSCT is the only curative treatment for SCD. In this study, we estimated the number of Saudi patients with SCD who are candidates for HSCT. We used the presence of overt stroke, recurrent ACS, and frequent severe pain crisis as indications for HSCT. We calculated the frequencies of these complications among a Saudi SCD cohort of 376 patients with SCD, 250 from SW and 126 from Eastern (E) provinces. We found that 59 (23.6%) of SW patients were transplant candidates compared to 22 (17.4%) from E province. It is estimated that about 61 000 patients with SCD live in Saudi Arabia. Thus, the projected number of Saudi patients with SCD who are candidates for HSCT is 10 536 patients. Of those, 2148 are children. The burden of SCD on HSCT centers in Saudi Arabia is substantial and is difficult currently to meet the demand. We recommend recruiting/training more transplant physicians and nurses, expand current capacity of centers if feasible, and open new transplant centers to make HSCT a practical therapeutic option for patients with severe SCD in Saudi Arabia.

Spectrum of α-thalassemia mutations in transfusion-dependent ß-thalassemia patients from the Eastern Province of Saudi Arabia.

Both α- and ß-thalassemia (α- and ß-thal) are highly prevalent in the population of the Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia. This study provides a more precise picture of the α-thal mutations prevalent in 104 transfusion-dependent ß-thal patients in the Eastern Province. Detection of α-thal mutations was carried out using the α-globin StripAssay kit. A total of 12 α-thal mutations (21 genotypes) were identified in 33.7% of the chromosomes (46 patients). The heterozygous and homozygous -α(3.7) (α(+)) deletion mutations were the most prevalent in the ß-thal patients (21.7%). We identified three α(0) deletions [- -(MED), - -(FIL) and -(α)20.5] that have not been previously reported for the population of Saudi Arabia. The seven point mutations identified in the ß-thal patients were: codon 14 [TGG>TAG (α1)], codon 59 [GGC>GAC (α1)] (Hb Adana), polyadenylation signal site (polyA1) [AATAAA>AATAAG (α2)], codon 142 [TAA>TCA (α2)] (Hb Koya Dora), codon 59 [GGC>GAC (α2)] (Hb Adana), initiation codon [ATG>ACG (α2)] and the ααα(anti 3.7) gene triplication. The Hb Koya Dora mutation occurred at the highest frequency (15.38%). Comparison of the clinical phenotype of ß-thal patients, with and without an α-thal mutation, showed that patients with ß-thal alone had a significantly elevated level of alanine transaminase (ALT) (mean 72.5 IU/L) and aspartate transaminase (AST) (mean 71.8 IU/L) (p <0.005). In addition, the ß-thal patients without an α-thal mutation had a higher percentage of osteoporosis (16.6%), fractures (12.5%), and splenectomies (58.3%). This confirms previous data that the co-inheritance of α-thal in ß-thal patients results in the amelioration of the clinical phenotype of ß-thal patients. Moreover, the high frequency of α- and ß-thal in the Eastern Province of Saudi Arabia and their coinheritance, necessitates the inclusion of α-thal testing in the current pre marital testing program to highlight the risk to the offspring of affected individuals.

Regional experience with newborn screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency.

BACKGROUND: Newborn screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency is one of the most important means of decreasing mortality and morbidity in high prevalence areas. Nine years experience in newborn screening in Qatif Central Hospital are summarized. PATIENTS AND METHODS: All newborns in Qatif Central Hospital had cord blood screening for sickle cell disease, other hemoglobinopathies and G6PD deficiency using alkaline and electrophoresis, agar gel electrophoresis for sickle cell disease and fluorescent screening technique for G6PD deficiency. Families of infants with minor hemoglobinopathies and G6PD deficiency were informed about the results in the well baby clinic. RESULTS: From December 1992 to December 2001, 24 012 newborn were screened. 21 858 (91.03%) were Saudi and 2154 (8.97%) were non-Saudi. In the Saudi hemoglobin electrophoresis patterns, AF (normal) was found in 49.52%, hemoglobin FS (sickle cell disease) + FS Bart s (sickle cell disease with alpha thalassemia) in 2.57%, hemoglobin AFS (sickle cell trait) + AFS Bart s (sickle cell trait with alpha thalassemia) in 21.14%, and alpha thalassemia (based on elevated Bart s hemoglobin > or = 2%) in 35.68%. G6PD deficiency was found in 37.02% and 21.27% in males and females, respectively. Of 563 Saudi newborn with a presumptive diagnosis of sickle cell disease, 48 (8.5%) did not come to the hematology clinic or were not contactable. The diagnosis of sickle cell anemia or sickle thalassemia was confirmed in 513 patients, and 2 cases were found to have sickle cell trait on repeat testing. Many parents found it hard to accept the initial diagnosis and the resulting impact on their relationship with one another. CONCLUSION: Prevention and early identification of sickle cell disease, other major hemoglobinopathies and G6PD deficiency remains the cornerstone of management of these diseases. The main barriers to successful neonatal screening for hemoglobinopathies are the level of the education and deficiency in manpower. We recommend including newborn screening for hemoglobinopathies and G6PD deficiency in the national hypothyroidism screening program in the eastern province and the establishment of a special center for hemoglobinopathies with a high standard of medical care in Qatif.