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PubMed2006

Human chorionic gonadotropin and plasma protein-A in alpha0-thalassemia pregnancies.

OBJECTIVE: Maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) have been used effectively in the screening of Down syndrome in the first trimester. In this study, we aim to measure the value of first-trimester maternal serum free beta-hCG and PAPP-A as predictors of homozygous alpha0-thalassemia-affected pregnancies. METHODS: Free beta-hCG and PAPP-A concentrations were measured in stored maternal serum samples obtained at 12 weeks of gestation from 22 women with fetuses affected by homozygous alpha0-thalassemia and from 436 controls matched for maternal age, ethnicity, and weight, as well as gestation at blood sampling. RESULTS: Maternal serum concentration of free beta-hCG was significantly increased in women with pregnancies affected by homozygous alpha0-thalassemia than in controls (P = .001). Concentrations of PAPP-A did not differ between the cases affected by homozygous alpha0-thalassemia and the controls (P = .652). CONCLUSION: Pregnancies affected by homozygous alpha0-thalassemia are associated with increased maternal serum free beta-hCG at 11-14 weeks of gestation. This serum analyte alone may not be clinically useful as a predictor of pregnancies affected by homozygous alpha0-thalassemia. However, the absence of ultrasound features of fetal anemia and hydropic changes, together with normal maternal serum free beta-hCG and PAPP-A in the first trimester, will be reassuring signs of normality for fetuses at risk of homozygous alpha0-thalassemia and, hence, enable women to avoid invasive tests in unaffected pregnancies.

Adult↗
PubMed2006

Stiffness of the abdominal aorta in beta-thalassemia major patients related with body iron load.

OBJECTIVES: Increased iron stores have been implicated in the association with increased risk of cardiovascular events. We evaluated whether the abdominal aortic stiffness was altered in the patients with beta-thalassemia major in relation with body iron load. METHODS: Sixty-two (32 males and 30 females) beta-thalassemia major patients aged 16.47 +/- 4.8 years were enrolled into the study. Healthy 52 subjects matched for age and sex were recruited as controls. In all subjects, hemoglobin, fasting glucose, cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol levels were measured. The average serum ferritin level and liver iron concentration (LIC) were assessed in thalassemia patients. Left ventricular function and mass were evaluated echocardiographically and aortic strain (S), pressure strain elastic modulus (Ep), and normalized Ep (Ep*), aortic distensibility (DIS), and beta stiffness index (beta index) were calculated in all subjects. RESULTS: There was no statistically significant difference between the study and control groups in sex, mean age, body mass index, heart rate, and systolic blood pressure (P > 0.05). However, pulse pressure and left ventricular mass index (LVMI) were found higher in thalassemia major patients compared with the control group. In beta-thalassemia major patients S (0.21 +/- 0.027 vs. 0.26 +/- 0.017, P < 0.0001) and DIS (1.07 +/- 0.25 vs. 1.56 +/- 0.37, P < 0.0001) were significantly lower compared with the control group. However, Ep (196.9 +/- 44.86 vs. 134.20 +/- 29.10, P < 0.0001), Ep* (3.26 +/- 0.98 vs. 2.04 +/- 0.60, P < 0.0001), and beta index (2.44 +/- 0.58 vs. 1.61 +/- 0.37, P < 0.0001) were significantly higher in beta-thalassemia patients than controls. There was a statistically significant negative correlation between LIC and S, DIS. There was also negative correlation between LVMI and S. However, there was a statistically significant positive correlation between LIC and Ep, Ep*. CONCLUSIONS: Increased abdominal aortic stiffness was detected in beta-thalassemia major patients and this increase in arterial stiffness correlated with LIC and LVMI.

Adolescent↗
PubMed1985

Molecular pathology of alpha-thalassemia.

The different classes of mutations found in the alpha- and beta-thalassemia syndromes are summarized in FIGURE 5. Mutations affecting almost every stage of globin gene expression have been described. The only lesion not yet characterized is one affecting enhancing sequences, although such sequences have not yet been identified in the globin gene system. The clinically important alpha-thalassemias are the deletion types, which occur with much higher frequency than the nondeletion lesions. In contrast, apart from one deletion beta-thalassemia lesion found in Pakistan, all the clinically significant beta-thalassemia lesions are not caused by gene deletion. The common beta-thalassemia lesions in the Mediterranean region and Asia are caused by defective mRNA synthesis, processing, or translation. Why deletion lesions predominate in the alpha-thalassemias and nondeletion ones in the beta-thalassemias remains an enigma.

Amino Acid Sequence↗
PubMedDate not supplied

alpha-thalassemia in Bantu population from Congo-Brazzaville: its interaction with sickle cell anemia.

Deletional alpha(+)-thalassemia (-alpha(3.7)) was investigated in four groups of unrelated individuals from the Bantu population (newborns, normal adults, sickle cells trait carriers, sickle cell anemia patients) of Brazzaville, Congo. The frequency of the (-alpha(3.7)) chromosome was similar between newborns (f = 0.40) and adult subjects (f = 0.36), and between sicklers and nonsickler subjects. The frequency of the (-alpha(3.7)) chromosome in sickle cell anemia patients (SS patients) did not change when age was stratified. The hematological characteristics of SS patients with (-alpha/alphaalpha, -alpha/-alpha) and without (alphaalpha/alphaalpha) alpha(+)-thalassemia were similar to those reported in Jamaican and US sickle cell anemia patients. alpha(+)-Thalassemia had an effect on the percentage of hemoglobin S in sickle cell trait carriers. Thus, the high frequency of alpha(+)-thalassemia in the Congolese population presumably results from this disorder having a selective advantage favoring survival. However, the frequency of alpha(+)-thalassemia was not affected by age. Although in this selective tropical environment, alpha(+)-thalassemia as elsewhere markedly affects the hematological characteristics of sickle cell anemia patients, however our data provide no evidence that alpha(+)-thalassemia increases survival of SS patients.

Adolescent↗
PubMed1999

The delta-globin RNA transcript level in beta-thalassemia carriers.

Increased levels of hemoglobin A(2) (HbA(2)) are present in most beta-thalassemia carriers. The mechanism of this effect is not understood, although the increase may result from transcriptional and posttranscriptional changes. In the present study, we quantitate delta-globin mRNA levels in peripheral-blood-enriched reticulocytes and characterize the variation of delta-mRNA levels in 30 beta-thalassemia heterozygotes who individually carry one of the four common Chinese beta-thalassemia alleles [codons 41/42 (-TTCT); codon 17 (A-->T); IVS-II-654 (C-->T); -28 (A-->G)]. A sensitive and quantitative competitive reverse-transcriptase polymerase chain reaction method was developed and used to assess the absolute amounts of delta-mRNA transcripts in these peripheral erythroid cells. The results showed a large increase in delta-mRNA amounts in all the carriers examined (72.3 +/- 9.0 amol/microg RNA) as compared with those in 12 controls (1.2 +/- 0.2 amol/ microg RNA). There was a direct correlation between the delta-mRNA levels and types of beta-thalassemia alleles; generally, the delta-mRNA levels are higher in heterozygotes for beta(0)-thalassemia mutations than beta(+)-thalassemia mutations. The delta-mRNA levels correlated inversely with hemoglobin and red cell indices but directly with HbA(2) levels in heterozygotes of each of the group of beta-thalassemia mutations. These results suggest that a greater impairment in beta-globin gene expression results in increased transcription of delta-globin gene and in a higher level of HbA(2).

Asian People↗
PubMed2006

Lung function in beta-thalassemia patients: a longitudinal study.

Patients with beta-thalassemia often present with a restrictive pattern at pulmonary function tests (PFTs) due to several pathogenetic factors. However, the long-term evolution is unknown. We performed a longitudinal study of pulmonary function in asymptomatic, non-smoking patients with beta-thalassemia major and intermedia. We looked for temporal changes in lung function and characteristics that would predict the development of PFT abnormalities. In 1996, 18 patients with major beta-thalassemia (9 males and 9 females; age range: 18-35 years) and 11 patients with intermediate beta-thalassemia (5 males and 6 females; age range: 25-51 years) underwent clinical assessment and PFT, including body plethysmography and gas transfer study (carbon monoxide diffusion capacity, DL(CO)). Patients were reassessed in 2003. An echocardiographic evaluation was also obtained to exclude pulmonary hypertension. In 55.5% of major and 45.4% of intermediate beta-thalassemia patients, a restrictive pattern was found in 1996; in 2003 only 38.8 and 27.2% of patients, respectively, exhibited total lung capacities below the predicted values. DL(CO) was unchanged in both groups of patients, being reduced in 5 thalassemia major patients and within the normal range in intermediate patients. We conclude that asymptomatic patients with beta-thalassemia have a high prevalence of PFT abnormalities, but without significant increases over time. An improvement may be observed when good control of the iron balance is reached with optimal chelation therapy.

Adolescent↗
PubMed2006

Alpha(0)-thalassemia and related disorders in northeast Thailand: a molecular and hematological characterization.

Alpha(0)-thalassemia is the most severe form of alpha-thalassemia commonly encountered in Asians. To provide relevant information for effective prevention and control of this disorder, we have examined the molecular basis and hematological features of alpha(0)-thalassemia-related disorders in northeast Thailand. A multiplex polymerase chain reaction for simultaneous detection of the southeast Asian (SEA) and the THAI alpha(0)-thalassemia determinants was developed and used for screening of 1,541 Thai individuals who were positive at the preliminary screening in an ongoing thalassemia control program. Alpha(0)-thalassemia deletions were detected in 397 (25.8%) cases, 396 with the SEA deletion and 1 with the THAI deletion. While the latter was found in association with the Hb Constant Spring in a patient with severe Hb H disease, the former was encountered in as many as 12 thalassemia genotypes whose hematological features were comparatively presented. The results obtained should prove useful in carrier screening and prenatal diagnosis programs of this common genetic disorder in the region.

Erythrocyte Indices↗
PubMed1988

Alpha-thalassemia in northern Thailand. Frequency of deletional types characterized at the DNA level.

The frequency of alpha-thalassemias in northern Thailand was estimated using DNA techniques. Among 106 healthy adult Thais from the Chiangmai area, 28 were shown to carry alpha-globin gene anomalies. There were 19 heterozygotes and 1 homozygote for alpha-thalassemia-2. One of the alpha-thalassemia-2 deletions was of the -alpha 4.2 type and the remaining 20 of the -alpha 3.7 type (subtype I). Deletions of both alpha-globin genes on one chromosome (alpha-thalassemia-1) of the Southeast Asian type were observed in 5 cases, and 3 alpha-globin gene triplications were identified. Compared with a previous report on alpha-thalassemia in northern Thailand which was based on the determination of hemoglobin Bart's in cord blood, the present DNA study reveals a similar frequency of alpha-thalassemia-2 but a considerably lower frequency of alpha-thalassemia-1.

Chromosome Deletion↗
PubMed1973

Hemoglobin messenger RNA from human bone marrow. Isolation and translation in homozygous and heterozygous beta-thalassemia.

A method for isolating human hemoglobin messenger RNA (mRNA) from bone marrow cells was developed to investigate the molecular basis for the defect in globin synthesis in beta thalassemia. Active mRNA was isolated from the bone marrow cells and peripheral reticulocytes of patients with homozygous beta thalassemia, heterozygous beta thalassemia, sickle cell trait, double heterozygosity for beta thalassemia and sickle cell trait, as well as from a patient with normal hemoglobin synthesis but with an elevated reticulocyte count secondary to hereditary spherocytosis. The mRNA was prepared for assay in an mRNA-dependent rabbit reticulocyte cell-free system and the amount of alpha and beta globin chains synthesized was determined by carboxymethylcellulose column chromatography. The relative synthesis of alpha to beta chains in response to normal hemoglobin mRNA was found to be a function of the amount of mRNA added to the assay system: increasing the amount of mRNA led to a decrease in the alpha-to-beta-chain synthetic ratio. Therefore, assays were carried out at limiting concentrations of mRNA. The molecular defect in homozygous beta thalassemia was shown to be carried in the mRNA of bone marrow cells as well as in the mRNA from peripheral reticulocytes, because much less beta than alpha globin was produced in the cell-free system in response to mRNA from either type of cell. In patients doubly heterozygous for beta thalassemia and sickle cell trait, little or no synthesis of beta(A) globin occurred in the bone marrow cells or the peripheral reticulocytes. The alpha to beta(S) synthetic ratio of the intact bone marrow cells was approximately 1, while the same ratio in the peripheral reticulocytes was between 1.5 and 2. The virtual absence of translatable beta globin mRNA in the mRNA prepared from the cells of these doubly heterozygous patients further demonstrates that the molecular defect produced by the beta thalassemia gene is in the beta globin mRNA.

Adolescent↗
PubMed1981

beta zero thalassemia in Sardinia is caused by a nonsense mutation.

We report the characterization of a molecular lesion of beta thalassemia in Sardinia. Beta thalassemia in this area is predominantly the beta zero type with low levels of beta-globin mRNA. Translation assay of this messenger RNA in a cell-free system showed beta-globin chain synthesis only with the addition of an amber (UAG) suppressor transfer RNA. Double-stranded complementary DNA prepared from reticulocyte mRNA from a Sardinian patient was cloned in a bacterial plasmid and a beta-globin complementary DNA containing clone was isolated and sequenced. At the position corresponding to amino acid number 39, a single nucleotide mutation converted a glutamine codon (CAG) to an amber termination codon (UAG). We previously reported an amber nonsense mutation at amino acid 17 as a cause of Chinese beta zero thalassemia. Thus, beta zero thalassemia in Sardinia represents the second example of a nonsense mutation, and we predict that other beta zero thalassemias with mutations at various points along the beta-globin chain will be found to form a discrete subgroup of beta zero thalassemia. These experiments further illustrate the heterogeneity of lesions that lead to defective globin chain synthesis in beta thalassemia.

Bacteriophage lambda↗
PubMed1998

Arterial calcifications in beta-thalassemia.

The purpose of this study was to define the incidence of arterial calcifications in patients with beta-thalassemia. Beta-thalassemia patients have been shown to present a high prevalence of angioid streaks and skin lesions characteristic of pseudoxanthoma elasticum (PXE). Given the fact that vascular involvement in the form of arterial calcifications is also a common manifestation of PXE, the authors investigated radiographically the presence of arterial calcifications in beta-thalassemia patients. They studied 40 patients with beta-thalassemia over 30 years of age. Forty healthy, age- and sex-matched subjects were chosen as a control group. Radiographs of the tibias were performed in order to disclose arterial calcifications. The occurrence of PXE skin lesions and of angioid streaks (AS) was also investigated. Arterial calcifications were detected in the posterior tibial artery in 22 (55%) beta-thalassemia patients and in six (15%) controls (P < 0.01 for the comparison). PXE skin lesions and AS were found in eight (20%) and 21 (52%) patients respectively. A total of 34 patients (85%) had at least one of the three lesions, namely, arterial calcifications, angioid streaks, and/or PXE-like skin lesions. Stepwise logistic regression analysis did not reveal prognostic value in independent variables such as transfusions, chelation therapy, pseudoxanthoma elasticum skin lesions and/or angioid streaks, diabetes, hemoglobin, serum ferritin, and uric acid. It was concluded that arterial calcifications are common in older beta-thalassemia patients. This finding could be a manifestation of an acquired PXE syndrome associated with beta-thalassemia, and consequently, vascular events complicating PXE should be expected in these patients.

Adult↗
PubMed2004

Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector.

beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human beta-globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the beta-globin expression cassette. Thus far, mouse studies have shown correction of the beta-thalassemia intermedia phenotype and a partial, variable correction of beta-thalassemia major phenotype. We tested a lentiviral vector carrying the human beta-globin expression cassette flanked by a chromatin insulator in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human beta-globin in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3 to 4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human thalassemia major phenotype.

Animals↗
PubMed2002

The hypercoagulable state in thalassemia.

Thalassemia is a congenital hemolytic disorder caused by a partial or complete deficiency of alpha- or beta-globin chain synthesis. Homozygous carriers of beta-globin gene defects suffer from severe anemia and other serious complications from early childhood. The disease is treated by chronic blood transfusion. However, this can cause severe iron overload resulting in progressive organ failure. Some forms of alpha thalassemia are also associated with a similar clinical picture. Despite the difficulties associated with treatment, standards of care for thalassemic patients have improved in recent years, resulting in almost doubling of the average life expectancy. As a consequence, additional previously undescribed, complications are now being recognized. In particular, profound hemostatic changes have been observed in patients with beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI) and also in patients with alpha thalassemia (hemoglobin H disease). The presence of a higher than normal incidence of thromboembolic events, mainly in beta-TI, and the existence of prothrombotic hemostatic anomalies in the majority of the patients, even from a very young age, have led to the recognition of the existence of a chronic hypercoagulable state in thalassemic patients. Despite the appearance of numerous publications on the frequent occurrence of thromboembolic complications in thalassemia, this complication has not been emphasized or comprehensively reviewed. This review summarizes the current literature and discusses possible mechanisms of the lifelong hypercoagulable state that exists in thalassemia.

Anemia, Sickle Cell↗
PubMed2005

Stem cell transplantation with S-59 photochemically treated T-cell add-backs to establish allochimerism in murine thalassemia.

Hematopoietic cell transplantation (HCT) from HLA-identical sibling donors has curative potential for beta-thalassemia. The probability of surviving free of thalassemia under these conditions is approximately 85%. The application of this therapy is limited because many patients lack an HLA-identical sibling donor. HLA-mismatched stem cell transplantation for thalassemia is severely restricted by graft rejection and the risks for graft-versus-host disease (GVHD). Thus, the development of a novel method that facilitates immunological tolerance and improves the safety of HLA-mismatched HCT would greatly expand the opportunity of HCT for thalassemia patients. We hypothesized that removal of T cells from the donor hematopoietic stem cell preparation and subsequent add-back after photochemical treatment with S-59, a psoralen, would promote and stabilize the engraftment and significantly reduce the risk of GVHD. This was tested in a MHC-mismatched HCT model of murine thalassemia. S-59-treated T cells were infused simultaneously with bone marrow-derived stem cells into mice with a heterozygous deletion of one beta-globin alleles that had been conditioned with a sublethal dose of total body irradiation. Mice that received treated T cells showed increased engraftment compared to those that did not receive T cells. T-cell treatment improved survival without GVHD compared to recipients that received untreated T cells. We conclude that photochemical treatment of T cells facilitates engraftment and minimizes GVHD in allo-HCT for murine thalassemia, and sets the stage for further development of such protocols for the treatment of patients with thalassemia.

Animals↗
PubMed2005

Successful correction of the human Cooley's anemia beta-thalassemia major phenotype using a lentiviral vector flanked by the chicken hypersensitive site 4 chromatin insulator.

beta-Thalassemias are the most common single-gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human beta-globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the beta-globin expression cassette. Mouse studies using LVs have shown correction of the beta-thalassemia-intermedia phenotype and a partial, variable correction of the mouse beta-thalassemia major phenotype, despite the use of beta-globin-hypersensitive sites that are known to result in position-independent effects. Our group used the alpha-globin-hypersensitive site in self-inactivating (SIN) LVs with long-term expression in secondary mice that resisted methylation-associated proviral silencing. However, these vectors also suffered from chromatin position effects. We therefore flanked a SIN-lentiviral vector carrying the human beta-globin expression cassette with a chromatin insulator and studied expression in bone marrow from four patients with transfusion-dependent human thalassemia major. We demonstrated normal levels of human beta-globin expression in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.

Animals↗
PubMed2005

Outcomes of preimplantation genetic diagnosis therapy in treatment of beta-thalassemia: A retrospective analysis.

Thalassemia is one of the most common single-gene disorders that can be cured by hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling donor. In families that have an affected child, preimplantation genetic diagnosis (PGD) can be used to select an unaffected, HLA-identical embryo. In brief, this procedure requires in vitro fertilization, oocyte retrieval, fertilization, and blastomere biopsy for identification of unaffected HLA-identical embryos. After delivery, umbilical cord blood from the sibling donor is collected for HCT. The objective of this study was to determine the outcomes of families using PGD therapy for cure of beta-thalassemia and to review the limitations of PGD therapy. Families affected with beta-thalassemia who attempted PGD therapy were retrospectively identified and reviewed for indication, attempted cycles, successful pregnancy, and transplantation outcomes. Eight identified families affected by thalassemia underwent PGD. The diagnosis of their affected children included six cases of beta-thalassemia major and two cases of transfusion-dependent hemoglobin E-beta-thalassemia patients. A total of 14 cycles of PGD were attempted, ranging from one to four attempts per family. Following successful identification of HLA-identical cells, two pregnancies occurred, of which one resulted in engraftment of a beta-thalassemia child. PGD therapy offers the possibility of recruiting a suitable donor for HCT, yet is limited by financial cost due to labor-intensive techniques, low probability of obtaining an HLA-matched unaffected embryo, variable implantation capacity, and significant emotional impact. Improvements in PGD therapy's efficacy and cost will make this a more viable option for affected families.

Blastomeres↗
PubMed2003

Infrared spectroscopic identification of beta-thalassemia.

BACKGROUND: The aim of this study was to investigate the potential of infrared (IR) spectroscopy as a fast and reagent-free adjunct tool in the diagnosis and screening of beta-thalassemia. METHODS: Blood was obtained from 56 patients with beta-thalassemia major, 1 patient with hemoglobin H disease, and 35 age-matched controls. Hemolysates of blood samples were centrifuged to remove stroma. IR absorption spectra were recorded for duplicate films dried from 5 microL of hemolysate. Differentiation between the two groups of hemoglobin spectra was by two statistical methods: an unsupervised cluster analysis and a supervised linear discriminant analysis (LDA). RESULTS: The IR spectra revealed changes in the secondary structure of hemoglobin from beta-thalassemia patients compared with that from controls, in particular, a decreased alpha-helix content, an increased content of parallel and antiparallel beta-sheets, and changes in the tyrosine ring absorption band. The hemoglobin from beta-thalassemia patients also showed an increase in the intensity of the IR bands from the cysteine -SH groups. The unsupervised cluster analysis, statistically separating spectra into different groups according to subtle IR spectral differences, allowed separation of control hemoglobin from beta-thalassemia hemoglobin spectra, based mainly on differences in protein secondary structure. The supervised LDA method provided 100% classification accuracy for the training set and 98% accuracy for the validation set in partitioning control and beta-thalassemia samples. CONCLUSION: IR spectroscopy holds promise in the clinical diagnosis and screening of beta-thalassemia.

Adult↗
PubMed2000

Molecular characterization of beta-thalassemia in Syria.

This study concerns the determination of beta-thalassemia alleles and other hemoglobin variants in 82 patients from Syria. We have characterized 146 chromosomes and found 17 different beta-thalassemia mutations, and one beta-globin chain variant that gives rise to the abnormal Hb S. The eight most common beta-thalassemia mutations were the IVS-I-110 (G-->A), IVS-I-1 (G-->A), codon 5 (-CT), -30 (T-->A), codon 39 (C-->T), IVS-I-6 (T-->C), IVS-II-1 (G-->A), and codon 15 (TGG-->TAG). These mutations accounted for almost 75% of the total beta-thalassemia chromosomes. We identified 34 different genotypes with a high level of homozygosity. The various beta-thalassemia mutations were characterized using gene amplification with specific oligonucleotide primers, restriction enzyme analysis, denaturing gradient gel electrophoresis and direct sequencing. By combining these three approaches we were able to detect mutations in almost 90% of the chromosomes studied. Our findings provide a sound foundation on which to base a preventive program for thalassemia and we believe that the data that we present will facilitate the improvement of medical services such as carrier screening, genetic counseling, and prenatal diagnosis. Furthermore a detailed knowledge of the molecular pathology of beta-thalassemia will strongly improve the prenatal diagnosis services in Syria.

Adolescent↗