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PubMed1984

The beta-globin gene in Sardinian delta beta 0-thalassemia carries a C----T nonsense mutation at codon 39.

Sardinian delta beta 0-thalassemia is an inherited syndrome characterized by the inactivity of the beta-globin gene and the persistent activity of the fetal gamma-globin genes, particularly the A gamma-globin gene. Previous mapping studies with restriction enzymes failed to show any abnormality in the non-alpha globin gene cluster. We have now examined the possibility that this syndrome might result from a single rather than two different defects. Restriction enzyme polymorphisms linked to the delta beta 0-thalassemic non-alpha globin fragments were defined providing the basis for cloning the delta beta 0-thalassemic beta-globin gene from the DNA of a heterozygous patient. This gene appears to carry a C----T single mutation causing the appearance of a stop codon at amino acid position 39 of the beta-globin gene. This mutation was previously reported in beta 0-thalassemic patients, in linkage with different haplotypes. We conclude that Sardinian delta beta 0-thalassemia is the result of two separate mutations, the former one (unknown) responsible for persistent expression of gamma-globin genes, the latter for beta 0-thalassemia.

Base Sequence↗
PubMed2003

Interscanner reproducibility of cardiovascular magnetic resonance T2* measurements of tissue iron in thalassemia.

PURPOSE: To assess interscanner reproducibility of tissue iron measurements in patients with thalassemia using gradient echo T2* measurements on two different MRI scanners. MATERIALS AND METHODS: Twenty-five patients with thalassemia major had liver and myocardial T2* assessment using a Picker Edge 1.5T Scanner and a Siemens Sonata 1.5T scanner, with similar gradient echo sequences. In a subset of 13 patients, two scans on the Siemens scanner were performed to assess interstudy reproducibility. RESULTS: There was a highly significant, linear correlation between T2* values obtained for both the heart (r = 0.95) and the liver (r = 0.99) between scanners. The mean difference, coefficient of variability, and 95% confidence intervals between scanners were 0.8 msec, 9.4% and -5.0 to 6.7 msec for the heart; and 0.9 msec, 7.9% and -2.0 to 3.9 msec for the liver. The interstudy mean difference and coefficient of variability on the Siemens scanner was 0.3 msec and 4.8% (r = 0.99) for the heart, and 0.04 msec and 1.9% (r = 0.99) for the liver. CONCLUSION: The T2* technique for measuring tissue iron is reproducible between the two manufacturers' scanners. This suggests that the widespread implementation of the technique is possible for clinical assessment of myocardial iron loading in thalassemia.

Adult↗
PubMed2006

Peroxidative stress and antioxidant enzymes in children with beta-thalassemia major.

OBJECTIVE: Regular blood transfusions and secondary iron overload make thalassemic erythrocytes prone to peroxidative injury. Although some reports suggest endogenous free radical damage in thalassemia, there remains discrepancy in the status of antioxidant enzymes. The aim of this study was to evaluate the extent of lipid peroxidation and status of antioxidant enzyme in children with beta-thalassemia. METHODS: Fifty transfusion-dependent beta-thalassemics were subjected to analysis of lipoperoxides as malondialdehyde (MDA), nitric oxide (NOx), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) along with serum iron and ferritin, liver functions and uric acid. Plasma MDA was analyzed to indicate the oxidative parameters, whereas the erythrocyte SOD, GPx, and plasma NOx were measured to show the antioxidant status of the children. All these parameters in 30 non-anemic healthy controls attending the child health promotion clinic of hospital were also studied. RESULTS: All the patients were iron overloaded. Markers of free radical injury such as MDA and antioxidant enzyme SOD and NOx levels were significantly elevated in thalassemic children while mean GPx levels were decreased in patients compared to controls (P < 0.001). All these markers significantly correlated with serum ferritin levels. There was no significant difference in levels of GSH measured but it correlated with serum iron levels. CONCLUSION: Our study results suggest that iron overload causes peroxidative damage in beta-thalassemia and antioxidant systems try to compensate for reducing lipid peroxidation to lower tissue damage.

Adolescent↗
PubMed2007

Survival, mortality, and complications in patients with beta-thalassemia major in northern Taiwan.

BACKGROUND: Advances in treatment have improved the prognosis in beta-thalassemia major. We present the survival and complications pattern of those patients in northern Taiwan born after 1970. PROCEDURE: One-hundred and sixty patients with beta-thalassemia major born after 1970 were collected. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Cox regression models were used to examine the associations of bone marrow transplantation (BMT), time of BMT procedure, and time of complications with survival. RESULTS: Better survival was observed for patients born after 1980 (P = 0.0121). Heart disease, BMT-related deaths, and infections were the main causes of death. Among the living patients over age 15, hypogonadotropic hypogonadism, HCV infection, diabetes, heart failure, and arrhythmia were the common complications. No patients under age 15 had complications. CONCLUSIONS: Survival for patients with beta-thalassemia major has improved significantly in Taiwan. More time is required to demonstrate whether these modalities added to the treatment of these patients will impact favorably on their outcome. Our success with BMT is improving and we are now in a position to offer this curative alternative.

Adolescent↗
PubMed2004

Profile of beta-thalassemia in eastern India and its prenatal diagnosis.

OBJECTIVE: To control the birth of thalassemic children in India. METHODS: Mutations present in the population of eastern India and in carrier parents seeking prenatal diagnosis were detected by the PCR-based technique of ARMS (amplification refractory mutation system) or gap-PCR. To screen for maternal tissue contamination in CVS, haplotypes associated with the beta-globin gene clusters were constructed using six polymorphic restriction sites. Prenatal diagnosis was accomplished by checking presence of parental mutation in the DNA from chorionic villus sampling (CVS) collected at 8 to 10 weeks' gestation by appropriate technique. RESULTS: Six hundred and fifty (650) unrelated beta-thalassemia chromosomes were screened for 11 common mutations to characterize the mutation distribution in this population. Starting from early 2000, 63 families from different parts of West Bengal and from surrounding areas have been offered prenatal counseling for beta-thalassemia. CONCLUSION: The population of this region is conscious and willing to accept prenatal diagnosis as a means of control of thalassemia.

Chorionic Villi Sampling↗
PubMed2003

Birth of healthy children after preimplantation diagnosis of beta-thalassemia by whole-genome amplification.

Preimplantation genetic diagnosis (PGD) offers couples at risk for transmitting an inherited disorder the possibility to avoid the need to terminate affected pregnancies. PGD for monogenic diseases is most commonly accomplished by blastomere biopsy from cleavage-stage embryos, followed by PCR-based DNA analysis. However, the molecular heterogeneity of many monogenic diseases requires a diagnostic strategy capable of detecting a range of mutations and compound genotypes. With the above considerations, we developed an accurate and reliable strategy for analysis of beta-globin gene mutations, applicable for PGD for the wide spectrum of beta-thalassemia major mutations in the Chinese population. The strategy involves primer-extension preamplification (PEP), followed by nested PCR and reverse dot blot (RDB) for mutation detection since it facilitates simultaneous analysis of more than one mutation in a single cell. This report describes the application of the strategy in two clinical IVF/PGD cycles at risk for transmitting beta-thalassemia major, which resulted in the first thalassemia-free children born after PGD in China.

Adult↗
PubMed1986

HLA compatibility for patients with thalassemia: implications for bone marrow transplantation.

In order to evaluate the possibility of a patient with thalassemia finding an HLA-identical sibling donor, we performed an analysis of HLA antigens in families of thalassemic patients. The pattern distribution was not significantly different from the expected ratio 25:50:25. When the siblings were subdivided according to the age of the patients (under or over 5 years), the above pattern remained unmodified for both the age groups. The average size of the 129 thalassemic families was 2.4. Thus, taking into account that thalassemic patients have an average of 1.4 siblings and that the HLA genotype distribution is expected as such, HLA-matched siblings are available for 33% of the patients. Because an additional 8.5% of the patients were found HLA-phenotypically identical to one parent, the chance for a patient with thalassemia to find a suitable donor for bone marrow transplantation would be increased to 41.5%. Our preliminary data cannot be extrapolated to the overall Italian thalassemic population; however, it can be inferred that for a patient with thalassemia, the chance of finding a suitable donor for bone marrow transplantation is not reduced.

Bone Marrow Transplantation↗
PubMed1992

Peripheral blood hematopoietic progenitor cells in beta-thalassemia major.

Colony assays in methylcellulose (semisolid medium) of erythroid precursors and granulocyte-macrophage precursors from the peripheral blood of 34 patients with beta-thalassemia major and 31 age-matched normal controls were studied. In patients homozygous for beta-thalassemia, a significant increase of circulating erythroid progenitor cells to 3-5 times of normal controls was observed. Furthermore, the number of circulating colony forming units-granulocyte-macrophage (CFU-GM) and colony forming units-mixed (CFU-Mixed) also increased significantly. In these subjects, there was a linear relationship between the number of burst forming units-erythroid (BFU-E) and CFU-GM. The serum level of erythropoietin (EPO) was also significantly higher than that of normal controls (p < 0.05). The increased hematopoiesis, indicated by an increased number of circulating hematopoietic progenitor cells and an elevated serum level of EPO, suggests that the physiologic regulation of erythropoiesis still operated in patients with beta-thalassemia major.

Adolescent↗
PubMed1993

Detection of beta-thalassemia carrier by direct analysis of beta-globin gene lesions.

DNA was prepared from peripheral blood mononuclear cells of 114 Chinese with low erythrocyte mean corpuscular volume and analyzed by allele-specific DNA amplification for the presence of mutant alleles in the beta-globin gene that account for about 90% of beta-thalassemia in Chinese. A total of 9 mutations of the five most frequent mutant alleles were detected in 8 individuals. All mutant sequences were confirmed later by DNA sequencing. However, no mutation of these mutant alleles was detected in the remaining 106 individuals with low erythrocyte mean corpuscular volume including 22 who also had Hb A2 content of 6.0% or more. Our results seem to suggest that the presence of beta-thalassemia allele does not correlate very well with red blood cell indices and that direct DNA analysis by allele-specific DNA amplification is an accurate method to identify beta-thalassemia heterozygotes.

Alleles↗
PubMed2000

Oral isobutyramide therapy in patients with thalassemia intermedia: results of a phase II open study.

A pilot phase II open study on 12 patients with thalassemia intermedia (7 men, 5 women; age 31 +/- 2.0 years SE) treated with oral isobutyramide, a derivative of butyric acid (150 mg/kg body wt/day), was performed in order to evaluate the effect of this compound in stimulating hemoglobin F (HbF) production. No patient underwent blood transfusion in the 1-year time frame prior to the study. Nine patients were splenectomized. Safety was monitored by clinical and laboratory tests. Efficacy was assessed in terms of the non-alpha/alpha globin chain biosynthetic ratio and the percentage increase of HbF. The study design consisted of a screening phase, a treatment phase of 28 days, and a posttreatment follow-up of 28 days. All patients completed the study. Compliance to treatment was 100%. No drug-related adverse event was recorded. We observed little or no increase in the non-alpha/alpha ratio in the majority of patients. Six patients showed a percentage increase of HbF at the end of treatment and in 5 of those 6 further increases at the end of the follow-up period were observed. The change in percentage of HbF over time was close to significance both in the treatment period (P = 0. 06) and in the follow-up period (P = 0.08). These results indicate that butyrate derivatives can stimulate fetal hemoglobin in patients with intermediate thalassemia. Testing of the effects of different schedules of administration of isobutyramide will be required in order to determine the optimal use of this compound in the treatment of the beta-thalassemia syndromes.

Administration, Oral↗
PubMedDate not supplied

Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial.

Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.

Adolescent↗
PubMed1992

Entrapment of purified alpha-hemoglobin chains in normal erythrocytes as a model for human beta thalassemia.

Entrapment of purified alpha-hemoglobin chains within normal erythrocytes resulted in structural and functional changes very similar to those observed in human beta thalassemic erythrocytes (Table 1). Membrane proteins and reactive thiol groups were decreased in a pattern similar to that observed in vivo in beta thalassemia. In addition, the alpha-chain loaded cells exhibited evidence of enhanced oxidant stress. Functionally, entrapment of alpha-chains resulted in the loss of cellular and membrane deformability, an important pathologic characteristic of the beta thalassemic erythrocytes. These results also demonstrate that the loss of membrane proteins and thiols as well as the functional loss of cellular and membrane deformability characteristic of the beta thalassemic cell occur very rapidly in the presence of soluble alpha-chains. Utilizing this model of the thalassemic erythrocyte, it is now possible to directly investigate the mechanisms underlying the cellular pathophysiology induced by excess alpha-chains. An understanding of these mechanisms may allow for the development of therapeutic interventions that would improve effective erythropoiesis and prolong erythrocyte survival in the peripheral circulation of individuals with beta thalassemia. Successful therapeutic interventions would diminish the frequency and/or necessity of blood transfusions and chelation therapy in beta thalassemia.

Erythrocyte Deformability↗
PubMed1994

A unique origin for Sicilian (delta beta) (0)-thalassemia in 33 unrelated families and its rapid diagnostic characterization by PCR analysis.

Direct sequencing and restriction enzyme digestion of the polymerase chain reaction (PCR) product encompassing the breakpoint were used to characterize the Sicilian (delta beta)(0)-thalassemia deletion in 33 unrelated Italian subjects. All cases showed the same sequencing features at the breakpoint region, suggesting a unique origin for this deletion in Italy. We also describe a one-step PCR assay for the rapid screening of homozygotes and carriers of Sicilian (delta beta) (0)-thalassemia by the simultaneous use of three specific oligonucleotides. This procedure could have an impact on genetic counseling of couples at risk for this type of thalassemia, and with respect to compound heterozygotes bearing a Sicilian chromosome.

Base Sequence↗
PubMed1990

Prenatal diagnosis of alpha-thalassemia by polymerase chain reaction and dual restriction enzyme analysis.

Asian couples at risk for a fetus with homozygous alpha-thalassemia (hydrops fetalis) are often identified by their low erythrocyte mean corpuscular volume (MCV) and normal hemoglobin electrophoresis when little time remains to test their genotypes by restriction enzyme analysis. DNA analysis is performed directly on chorionic villi or amniocytes remaining after an aliquot is used to establish a backup cell culture. The polymerase chain reaction (PCR) protocol quickly determines whether the fetus has hydrops fetalis without waiting for cultured cells to grow. Previously, growing cultured fetal cells to obtain more fetal material to establish unambiguously the fetal genotype with two independent restriction enzyme digests absorbed a significant portion of the time remaining to complete prenatal diagnosis. A dual restriction enzyme digestion protocol was development using a 3' zeta-globin probe to clearly distinguish the most common alpha-thalassemia deletions that represent nearly all the alpha-thalassemia haplotypes in Southeast Asia.

Base Sequence↗
PubMed1990

Detection of beta-thalassemia mutations in the Chinese using amplified DNA from dried blood specimens.

This paper describes DNA polymerase chain reaction (PCR) amplification directly from dried blood specimens for the detection of the beta-thalassemia mutation in China. Target DNA was amplified to span the beta-globin gene regions, which included ten types of mutation sites specific for Chinese beta-thalassemias. Ten kinds of oligonucleotide probes were constructed and used to hybridize with the amplified DNA. A total of 170 beta-thalassemia alleles originating from eastern, southwestern and southern China were analyzed. The results revealed that the distributions of different types of mutations were different in the three regions. The most common types in southern China were a frameshift at codons 41/42 and a C----T substitution at IVS II n.654, the most frequent types in southwestern China were codon 17 and IVS II n.654 mutations, and the predominant mutations in eastern China were frameshifts at codons 41/42 and 71/72.

Base Sequence↗
PubMed1989

The spectrum of beta-thalassemia mutations in northern and northeastern Thailand.

A total of 123 beta-thalassemia genes from northern (n = 113) and northeastern (n = 10) Thailand were examined. Using five oligonucleotide probes, the mutation in 108 genes (88%) was identified: 50 nonsense 17, 49 frameshift 41-42, 4-28(A----G), 2 IV1 nt5(G----C), 2IVS2 nt654, and 1 deletion removing the entire beta-globin gene. The nonsense 17 mutation (n = 39) was linked to a single haplotype, whereas the frameshift 41-42 mutation occurred with several haplotypes. The results of the present study indicate that prenatal diagnosis of clinically important beta-thalassemia syndromes using a limited set of oligonucleotides is feasible in approximately 80% of affected families in northern Thailand and most of the families with beta-thalassemia-Hb E disease in northeastern Thailand.

Base Sequence↗
PubMed1994

Filipino beta-thalassemia due to a large deletion: identification of the deletion endpoints and polymerase chain reaction (PCR)-based diagnosis.

The gene frequency of beta-thalassemia among Filipinos is estimated to be 0.02, although little is known about the mutations involved. Recently, an extensive beta-thalassemia deletion was reported in several unrelated individuals of Filipino descent. The deletion begins approximately 4 kb upstream of the beta-globin gene, and extends 3' beyond the beta-globin gene. In this report, we identify the 5' and 3' deletion endpoints and present a polymerase chain reaction (PCR) strategy for rapid DNA diagnosis of the Filipino beta-thalassemia deletion.

Base Sequence↗
PubMed1992

Molecular screening and fetal diagnosis of beta-thalassemia in the Italian population.

This paper reports our experience of molecular screening and fetal diagnosis of beta-thalassemia in 457 at risk couples of Italian descent. Molecular screening was carried out by dot blot analysis on amplified DNA with oligonucleotide probes complementary to the eight most common mutations in Italians [beta zero 39 (C----T); beta zero 6 (-A); beta+ -87 (C----G); beta+ IVSI nt 110 (G----A); beta zero IVSI nt 1 (G----A); beta+ IVSI nt 6 (T----C); beta zero IVSII nt 1 (G----A); beta+ IVSII nt 745 (C----G)]. By using this approach, we have been able to define the mutation in 92.8% of cases. The rest (all but four) were defined by direct sequencing and this led to the detection of nine rare mutations [beta zero 76 (-C); beta+ IVSI nt 5 (G----A); beta+ IVSI nt 5 (G----C); beta+ IVSI -1 (cod 30) (G----C); beta+ -87 (C----T), beta zero -290 bp del.; beta+ -101 (C----T)], and to the characterization of a novel mutation consisting of the deletion of the G at the invariant AG of the IVSII splice acceptor site of the beta-globin gene (beta IVSII nt 850 -1 bp). In the remaining four cases, the beta-globin gene showed entirely normal sequences and the beta-globin gene cluster was intact, as indicated by Southern blot analysis. Fetal diagnosis was carried out by dot blot analysis with the oligonucleotide probes defined in the parents. The procedure is simple and reliable, and the results can be obtained within 1 week of sampling. No misdiagnosis has so far occurred. The results indicate that fetal diagnosis of beta-thalassemia by DNA analysis may be obtained in practically all cases (even in a population showing marked heterogeneity of beta-thalassemia) by the combination of dot blot analysis for detecting common mutations, and direct sequencing for defining those that are uncommon.

Base Sequence↗