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The beta-thalassaemias are a heterogeneous group of inherited disorders caused by mutations in and around the structural gene of the beta-chain of the adult haemoglobin (HbA). Studies at the gene level have identified a large number of beta-thalassaemia gene variations in different populations. These findings have implications for the use of molecular diagnosis for genetic counselling and prenatal detection of the beta-thalassaemias. In our unit, we initiated studies to investigate the molecular defects in beta-thalassaemias in Saudi Arabia using amplification-refractory mutation systems, dot blot analysis and restriction endonuclease analysis, and identified mutations producing beta(+)- and beta zero-thalassaemias. Twenty of the mutations encountered in the Asian, Mediterranean, Chinese and other Arab populations were investigated. The most commonly encountered mutations in Saudi beta-thalassaemia patients were IVS-I-110, IVS-II-1, CD 39, IVS-I-5 and IVS-I 3' end (-25), while frameshifts at CD 8/9, Cap+1 (A--C) and CD 6 mutations were identified at a low frequency. These mutations account for 84.94% of the total beta-thalassaemia mutations. The remaining 15% remain unknown. This is the first report on the type and nature of mutations in Saudi beta-thalassaemia patients. It presents frequencies of twenty mutations and emphasises the need for further detailed investigations to clarify the whole spectrum of beta-thalassaemia mutations in the Saudi population.

This paper reports the case of a 17-year-old male student from the Jaizan area in south-western Saudi Arabia who had sickle cell anaemia and possessed three alpha-genes on one chromosome (alpha alpha alpha anti3.7) and two on the other. The clinical manifestations were severe, with frequent blood transfusion requirements and frequent episodes of painful crises, severe anaemia and tissue involvement. In comparison with age and sex-matched sickle cell anaemia patients with one alpha-gene deletion (-alpha/alpha alpha), or a normal alpha-gene arrangement (alpha alpha/alpha alpha), a more severe disease presentation was obvious in the propositus. It is suggested that with the surplus alpha-globin chains, more severe haematological and clinical abnormalities occur, these influence the phenotypic expression of sickle cell anaemia. However, more patients with this type of gene arrangement must be studied before a definite conclusion can be reached regarding the influence of excess alpha-globin chains on the presentation of sickle cell anaemia.

The beta S-globin gene haplotypes were investigated using restriction endonucleases Hinc II and Hind III in 22 sickle cell anaemia patients from the eastern province, 67 sickle cell anaemia patients from the south-western province and 4 sickle cell anaemia patients from north-western province. The beta S was found to be mainly linked to the haplotype + + - + + in the eastern province (50% homozygous and 45.45% heterozygous), and - - - - + haplotypes in the south-western (44.77% homozygous and 43.28% heterozygous) and north-western (100% homozygous) provinces. A comparison of the haematological values and clinical manifestations in patients with the two major haplotypes revealed significant differences, with the disease presenting more severely in the south-western compared to the eastern population. The level of Hb F was not significantly different in the two groups and no association could be demonstrated between the beta-globin gene haplotype and Hb F level. These results have led us to suggest that the haplotype + + - + + is in some way linked to a benign sickle cell anemia, though the exact mechanism leading to a benign disease is not clear.

This paper reports the case of a 17-year-old male student from the Jaizan area in south-western Saudi Arabia who had sickle cell anaemia and possessed three alpha-genes on one chromosome (alpha alpha alpha anti3.7) and two on the other. The clinical manifestations were severe, with frequent blood transfusion requirements and frequent episodes of painful crises, severe anaemia and tissue involvement. In comparison with age and sex-matched sickle cell anaemia patients with one alpha-gene deletion (-alpha/alpha alpha), or a normal alpha-gene arrangement (alpha alpha/alpha alpha), a more severe disease presentation was obvious in the propositus. It is suggested that with the surplus alpha-globin chains, more severe haematological and clinical abnormalities occur, these influence the phenotypic expression of sickle cell anaemia. However, more patients with this type of gene arrangement must be studied before a definite conclusion can be reached regarding the influence of excess alpha-globin chains on the presentation of sickle cell anaemia.

This study was conducted on 429 blood samples collected from Saudi males and females from Al-Ula in the north-western province of Saudi Arabia in order to determine the frequency of the sickle cell gene, glucose-6-phosphate dehydrogenase (G6PD) deficiency gene, and alpha- and beta-thalassaemia genes, and to investigate the pattern of their interactions. The frequency of the sickle cell gene was 0.0785, while that of the beta-thalassaemia gene was 0.1195. Heterozygous alpha-thalassaemia 2 (- alpha/alpha alpha) was encountered at a frequency of 0.121, while homozygous alpha-thalassaemia 2 (- alpha/- alpha) occurred at a frequency of 0.0046. HbH disease and hydrops fetalis were not encountered. One case with triple alpha-gene arrangement, alpha alpha alpha anti-3.7, was identified. The G6PD deficiency gene frequency was 0.08 and 0.032 in males and females, respectively. Several cases with 2 abnormal genes were encountered. The haematological and biochemical data from the patients with sickle cell disease suggest that the disease in this population is more severe in comparison with cases reported from the eastern population.

The gamma-globin chains of haemoglobin F are encoded by two non-allelic genes which synthesise two different gamma-chains referred to as G gamma and A gamma. Xmn I restricts on both sides of the genes and normally produces an 8.1-kilobase (kb) fragment containing both gamma-genes. A polymorphic site on the 5' end of the G gamma genes has been reported in some populations and it results in the production of a 7.0-kb fragment containing both gamma-genes. We investigated the Xmn I polymorphic site in normal individuals, haemoglobin S heterozygotes and sickle cell disease patients from three different regions of Saudi Arabia. In the eastern province, 10% of gamma-genes in normal individuals were linked to the 7.0-kb fragment while in the sickle cell disease patients and haemoglobin S heterozygotes the frequency of the polymorphic site was 0.932 and 0.625, respectively. In the south-western province, the frequency of the polymorphic site in normal individuals was 0.096 (similar to that in the eastern province) but in the sickle cell disease patients and sickle cell heterozygotes the frequency was 0.033 and 0.095, respectively. Finally, only 6 sickle cell disease patients from the north-western province were investigated and all had the gamma-globin gene linked to the 8.1-kb fragment. The results of this study in different regions of Saudi Arabia are presented and the possible significance of Xmn I polymorphism is suggested.

To investigate beta-globin gene polymorphism in the Saudi population, samples from 436 individuals from the eastern and north-western provinces of Saudi Arabia were studied using restriction endonucleases Mst II and Hpa I. Three individuals with haemoglobin genotypes AA, AS and SS were identified to each have a 5.6-kilobase (kb) Hpa I fragment in addition to a 13.0-kb fragment. This paper reports for the first time in Saudis a linkage of both the beta A and beta B genes to a 5.6-kb Hpa I fragment.

Using restriction endonucleases Bam HI, Bg1 II, Hpa I, Hind III and Xba I, the alpha alpha alpha anti 3.7/ haplotype was studied in the Saudi population. This paper presents the frequency of the alpha gene haplotype alpha alpha alpha anti 3.7/ in different regions of Saudi Arabia, where thalassaemia occurs at a high frequency.

During an extensive investigation to determine the frequency of sickle cell and thalassaemia genes in the Saudi population, 22 cases with S/ β °-thalassaemia were identified and the h

This paper reports the frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the male and female population of Al-Ula in the northwestern province of Saudi Arabia. The frequency of G6PD

Restriction endonucleases have been used for the investigation of deletion type alpha-thalassaemias in the Saudi population. Using Bgl II digestion, we diagnosed 2 cases with 15.8- and 7.0-kb alpha-globin gene fragments. The 15.8-kb Bgl II fragment is obtained in cases with rightward deletion, while the 7.0-kb fragment occurs in cases with leftward deletion. The 2 cases reported in this paper are heterozygous leftward/rightward deletion cases. The Bam HI digestion results and haematological parameter values are reported. This is the first report of heterozygous leftward/rightward deletion in the Saudi population.

Using restriction endonucleases Bam HI, Bg1 II, Hpa I, Hind III and Xba I, the alpha alpha alpha anti 3.7/ haplotype was studied in the Saudi population. This paper presents the frequency of the alpha gene haplotype alpha alpha alpha anti 3.7/ in different regions of Saudi Arabia, where thalassaemia occurs at a high frequency.

Glucose-6-phosphate dehydrogenase (G-6-PD) exhibits extensive heterogeneity in the Saudi population. The polymorphism of G-6-PD was investigated in different regions of Saudi Arabia, and G-6-PD variants were separated and identified on the basis of their electrophoretic mobility and activity towards glucose-6-phosphate. G-6-PD-B+ was found to be the most common phenotype, G-6-PD-A+ was found in each region but at a variable frequency ranging between 0.007 and 0.046. A second variant with normal activity but lower mobility than G-6-PD-B+ was identified among the Saudis at a frequency ranging from 0.000 to 0.028 in the different regions. In addition, a high frequency of variants with reduced activity was encountered in all regions. In males, a frequency of G-6-PD Mediterranean ranging from 0.046 to 0.261 was obtained, while G-6-PD-A- existed at a frequency ranging from 0.011 to 0.028. Furthermore, other variants with reduced activity but the same electrophoretic mobility as G-6-PD-B+ were detected at a high frequency among the Saudis.

This investigation was conducted on 847 males and females in Al-Baha, the mountainous western province of Saudi Arabia, to determine the prevalence of glucose-6-phosphate dehydrogenase (G6PD) phenotypes and G6PD deficiency. Among the G6PD phenotypes, G6PD B+, G6PD A+, G6PD A-, G6PD Mediterranean and G6PD Mediterranean-like were identified with a gene frequency in the male population of 0.7769, 0.0119, 0.0020, 0.1255 and 0.0817, respectively, and in the females with a frequency of 0.722, 0.003, 0.003, 0.1128 and 0.1311, respectively. Heterozygous females with the phenotypes of G6PD B+/A+ and B+/A- were identified with a frequency of 0.0183 and 0.0090, respectively. The frequency of severe G6PD deficiency in this population was 0.1275 and 0.1158 in males and females, respectively.

Glutathione reductase (GR) deficiency is reported to occur with a variable frequency in some populations of the world. In this study, the populations of two regions of Saudi Arabia which have a high frequency of sickle cell, thalassaemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, were screened for GR deficiency. Studies were also carried out to investigate the frequency of GR deficiency with other genetic blood disorders. The frequencies of complete GR deficiency were 0.0065 and 0.006, while those of partial deficiency were 0.146 and 0.074 in Al-Hafouf and Khaiber, respectively. GR deficiency was encountered in combination with the sickle gene, the G-6-PD deficiency gene and the thalassaemia gene in both regions. Individuals with GR deficiency showed slightly reduced haematological parameters. In thalassaemic/GR-deficient subjects, mean cell volume and mean cell haemoglobin were low, while in sickle cell anaemia patients with GR deficiency the haematological parameters were higher than in sickle cell anaemia patients without GR deficiency.

The frequencies of glucose-6-phosphate dehydrogenase (G-6-PD), pyruvate kinase (PK) and hexokinase (HK) deficiency were determined in different regions of Saudi Arabia. G-6-PD deficiency was found to range from 0.045 to 0.220 for the male and 0.020 to 0.125 for the female population. The highest frequencies were found to exist in the regions which are endemic to malarial parasite and have high frequencies of sickle cell and thalassaemia genes. Partial deficiencies of PK and HK were encountered in each region, however, no case of complete deficiency of these enzymes was identified. Further investigations are in progress to determine the clinical manifestations of enzyme deficiencies in the Saudi population.

During an extensive investigation to determine the frequency of sickle cell and thalassaemia genes in the Saudi population, 22 cases with S/beta 0-thalassaemia were identified and the haematological, biochemical and clinical findings were compared with those in patients with sickle cell anaemia. The values of mean cell volume, mean cell haemoglobin and packed cell volume were found to be lower while all other haematological parameters including Hb A2 were higher in the S/beta 0-thalassaemia group. No statistically significant difference in the Hb F level was found between the two groups. Biochemical parameters were grouped according to organ function tests. Only slight differences were seen in the values of some parameters. The clinical data showed that, in general, patients with sickle cell anaemia had a more severe condition than the S/beta 0-thalassaemia.