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PubMed1999

Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and deltabeta-thalassemia affects beta- but not gamma-globin gene expression.

The analysis of a number of cases of beta-globin thalassemia and hereditary persistence of fetal hemoglobin (HPFH) due to large deletions in the beta-globin locus has led to the identification of several DNA elements that have been implicated in the switch from human fetal gamma- to adult beta-globin gene expression. We have tested this hypothesis for an element that covers the minimal distance between the thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-thalassemia, located 5' of the delta-globin gene. This element has been deleted from a yeast artificial chromosome (YAC) containing the complete human beta-globin locus. Analysis of this modified YAC in transgenic mice shows that early embryonic expression is unaffected, but in the fetal liver it is subject to position effects. In addition, the efficiency of transcription of the beta-globin gene is decreased, but the developmental silencing of the gamma-globin genes is unaffected by the deletion. These results show that the deleted element is involved in the activation of the beta-globin gene perhaps through the loss of a structural function required for gene activation by long-range interactions.

Animals↗
PubMed2004

Thalassemia in Sri Lanka: a progress report.

The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.

Genetics, Population↗
PubMed1988

A novel beta thalassemia gene with a single base mutation in the conserved polypyrimidine sequence at the 3' end of IVS 2.

An adult Algerian patient with homozygous beta thalassemia was found to have a unique beta thalassemia gene. Cloning and sequencing revealed that the only abnormality present in this beta gene is a transversion in the polypyrimidine stretch at the 3' end of the large intervening sequence (IVS 2) six bases 5' to the consensus AG dinucleotide sequence (CCGCCCACAG instead of CCTCCCACAG). In addition, digestion of the cloned fragment by the enzyme Mnl I demonstrates the disappearance of a restriction site as expected. This is the first example of a defect in the consensus sequence at the 3' end of an IVS leading to a thalassemia phenotype presumably due to decreased splicing.

Adult↗
PubMed1988

Molecular characterization of a novel form of (A gamma delta beta)zero-thalassemia deletion with a 3' breakpoint close to those of HPFH-3 and HPFH-4: insights for a common regulatory mechanism.

We have molecularly characterized a novel (A gamma delta beta)zero-thalassemia associated with increased synthesis of HbF in three members of a German family. The levels of HbF in the peripheral blood red cells of the heterozygotes ranged between 9.9% and 12.5% with a heterocellular distribution in the red cells, as detected by immunofluorescence. The mutation resulted from a deletion starting about 1.5 to 1.9 kb from the 3' end of the G gamma-gene and ending 27 +/- 0.5 kb 3' to the beta-globin gene. Thus, the total deletion is 52 +/- 0.5 kb. Its 5' breakpoint is similar to that of the previously described (A gamma delta beta)zero-thalassemias, while the location of the 3' breakpoint is placed very close to the 3' breakpoints of HPFH-4 and HPFH-3 deletions. The proximity of the 3' breakpoint of the German (A gamma delta beta)zero-thalassemia to those of HPFH-3 and HPFH-4 deletions raises the possibility that a common mechanism, such as the juxtaposition of an enhancer, might underlie the activation of the gamma-globin genes in these three mutants.

Chromosome Deletion↗
PubMed1981

Two cloned beta thalassemia genes are associated with amber mutations at codon 39.

Two beta globin genes from patients with the beta(+) thalassemia phenotype have been cloned and sequenced. A single nucleotide change from CAG to TAG (an amber mutation) at codon 39 is the only difference from normal in both genes analyzed. The results are consistent with the assumption that both patients are doubly heterozygous for beta(+) and beta degrees thalassemia, and that we have isolated and analyzed the beta degrees thalassemia gene.

Base Sequence↗
PubMed2004

Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies.

HbVar (http://globin.cse.psu.edu/globin/hbvar/) is a relational database developed by a multi-center academic effort to provide up-to-date and high quality information on the genomic sequence changes leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Extensive information is recorded for each variant and mutation, including sequence alterations, biochemical and hematological effects, associated pathology, ethnic occurrence and references. In addition to the regular updates to entries, we report two significant advances: (i) The frequencies for a large number of mutations causing beta-thalassemia in at-risk populations have been extracted from the published literature and made available for the user to query upon. (ii) HbVar has been linked with the GALA (Genome Alignment and Annotation database, available at http://globin.cse.psu.edu/gala/) so that users can combine information on hemoglobin variants and thalassemia mutations with a wide spectrum of genomic data. It also expands the capacity to view and analyze the data, using tools within GALA and the University of California at Santa Cruz (UCSC) Genome Browser.

Databases, Genetic↗
PubMed1988

Thalassemia: molecular pathology and management.

Recent advances in molecular biology have allowed us to develop an almost complete picture of the molecular pathology of the thalassemia syndromes. The different classes of mutations that are responsible for the thalassemia syndromes will be discussed along with the special insights they have provided into the controls of eukaryotic gene expression. While management of these disorders has not kept pace with our understanding of their cause, there have been notable advances in treatment. Perhaps even more exciting is what the future holds, as the continued march of molecular biology is melded with novel approaches to the definitive treatment of thalassemias.

Base Sequence↗
PubMed2005

Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia.

Acute splenic sequestration crisis is a potentially fatal condition mostly seen in children with sickle cell anemia (HbSS) up to 6 years of age. Sickle cell-beta thalassemia has been associated with development of splenic sequestration crisis in rare reports. There have also been rare reports of the development of fatal acute splenic sequestration crisis together with severe multiorgan failure in adult patients with sickle cell-beta thalassemia. We describe a case of fatal splenic sequestration crisis together with multiorgan failure in a 34-year-old African-American woman with sickle cell-beta thalassemia syndrome.

Adult↗
PubMed2002

Recurrent thromboembolism in a patient with beta-thalassemia major associated with double heterozygosity for factor V R506Q and prothrombin G20210A mutations.

Double heterozygosity for factor V R506Q and prothrombin G20210A mutations was identified in a 24-year-old man with beta-thalassemia major. The patient experienced a first thrombotic event at the age of 19 years and three recurrent thromboses in a short time interval, the third occurring while the patient was receiving long-term anticoagulant treatment. This case suggests that patients with major thalassemia and congenital thrombophilic mutations need intensive and long-lasting anticoagulant treatment. Thus, even if thrombotic events could be explained by a hypercoagulable state observed in patients with major thalassemia, after a first thrombotic event has occurred these patients should be screened for acquired and congenital thrombophilia.

3' Untranslated Regions↗
PubMed1984

Impaired immune regulation in children and adolescents with hemophilia and thalassemia in Israel.

The immune function was assessed in 22 children, adolescents and young adults with asymptomatic hemophilia, and 15 with thalassemia, in Israel. Five patients with hemophilia and two with thalassemia were found to be severely abnormal, having cutaneous anergy, very low T-helper cells, elevated T-suppressor cells, inverted T-helper/suppressor ratio, reduced response to mitogens and antigens, and nonfunctional NK cells. Four of the five hemophilia patients exhibited profound lymphopenia also. Decreased T-helper and mildly elevated T-suppressor cells with inverted T4/T8 ratio were observed in the hemophiliacs as a group. In the severe group, the reduction in T-helpers and T4/T8 ratio was more pronounced. The thalassemics as a group were found to have increased numbers of T-suppressor cells with decreased T-helper cells in those with intact spleen only. Both groups studied were found to have elevated IgG levels and low natural killer (NK) activity and normal response to mitogens. Cutaneous anergy was found to be a reliable indication for severe T-cell dysfunction and may serve as an early indication of impending AIDS. These results indicate that patients with hemophilia and with heavily hypertransfused thalassemia may be at increased risk of AIDS as they approach adolescence.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Hemoglobin D-beta (0) thalassemia. A case report and family study.

Findings are presented on a Pakistani family in Doha, Qatar with hemoglobin D-Los Angeles (alpha 2 beta 3 121 (glutamine----glycine) and thalassemia trait. The propositus, a child, has hemoglobin D-beta(0) thalassemia, and suffers from moderately severe hemolytic anemia. The father has beta-thalassemia trait, and the mother is heterozygous for hemoglobin D-Los Angeles. This, the eighth confirmed case in the medical literature, is reported to emphasize its clinical manifestations and genetic basis.

Hemoglobins, Abnormal↗
PubMedDate not supplied

Asian immigration and public health in California: thalassemia in newborns in California.

PURPOSE: This study reviews Asian immigration in California and the effect it has had on public health in the state in terms of genetic disease detection. This is documented in terms of the numbers of cases of thalassemia detected, including Hemoglobin (Hb) E/beta-thalassemia, beta-thalassemia major, and Hb H disease. PATIENTS AND METHODS: California has been screening all newborns for hemoglobinopathies since 1990 and tests approximately 530,000 newborns per year. Samples are collected on filter paper during the first I to 2 days of life and sent to one of eight contract laboratories. The screening methodology is cation exchange high-performance liquid chromatography. Confirmatory testing is performed at Children's Hospital Oakland hemoglobin laboratory using a variety of methods. RESULTS: Approximately five to seven cases each of Hb E/beta-thalassemia and beta-thalassemia major are detected annually. Most cases are of Southeast Asian origin. Prevalence rate of Hb E/beta-thalassemia among Southeast Asians is approximately 1 in 2,200 births. A pilot program for Hb H disease screening was successful and this disorder has now been incorporated in newborn screening, detecting approximately 40 cases per year. CONCLUSIONS: Increases in Asian immigration and births in the U.S., particularly California, have been dramatic during the past 10 years and have led to detection of previously rare diseases like Hb E/beta-thalassemia. It has also changed the way other thalassemic disorders are viewed, such as Cooley anemia, which previously affected mainly individuals of Mediterranean origin. Now, most affected patients are of Asian origin.

Asia, Southeastern↗
PubMedDate not supplied

Bone marrow transplantation for beta-thalassemia: the University of California San Francisco experience.

We report the results of allogeneic HLA-matched family donor stem cell transplantation in 17 North American children with beta-thalassemia major or hemoglobin E/beta-thalassemia who received transplants at the University of California San Francisco. Pretransplantation conditioning was with busulfan, cyclophosphamide, and antithymocyte globulin and graft-versus-host prophylaxis used cyclosporine, usually with added methotrexate. Twelve children are alive, well, and free of the clinical manifestations of thalassemia. Four experienced graft rejection and autologous recovery, and one died from complications shortly after transplantation. Overall survival was 94% and event-free survival 71%, results similar to those obtained by other transplantation centers. Improved conditioning regimes and enlargement of the donor pool will be needed to improve the outcome of transplantation and to make this treatment available to more children with thalassemia.

Adolescent↗
PubMed1997

Treatment of beta-thalassemia.

The striking improvement in the life expectancy of patients with homozygous beta-thalassemia observed over the past three decades is mainly due to the institution of adequate transfusion regimens and effective iron chelation therapy with nightly subcutaneous desferrioxamine. The prognosis appears particularly favorable for children with thalassemia born since these methods have become widely available. The first successful "cure" of beta-thalassemia was achieved in 1981 after bone marrow transplantation. Recent advances in transfusion techniques, pharmacology, molecular genetics, transplant immunology, and clinical practice today offer considerable promise in further advancing our knowledge and treatment of this disease.

Blood Transfusion↗
PubMed2006

Recent advances in globin gene transfer for the treatment of beta-thalassemia and sickle cell anemia.

PURPOSE OF REVIEW: The beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic hematopoietic stem cell transplantation. This therapeutic option, however, is not available to most patients due to the lack of an HLA-matched bone marrow donor. The transfer of a regulated globin gene in autologous hematopoietic stem cells is therefore a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid specific, differentiation and stage restricted, elevated, position independent, and sustained over time. RECENT FINDINGS: Using lentiviral vectors, May et al. demonstrated that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated beta-globin expression in vivo, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have extended these findings to various models of beta-thalassemia and sickle cell disease. While the addition of the wild-type beta-globin gene is naturally suited for treating beta-thalassemia, several alternatives have been proposed for the treatment of sickle cell disease, using either gamma or mutant beta-globin gene addition, trans-splicing or RNA interference. SUMMARY: These recent advances bode well for the clinical investigation of stem cell-based gene therapy in the severe hemoglobinopathies.

Anemia, Sickle Cell↗
PubMed2006

Evaluation of bone mineral density of the lumbar spine in patients with beta-thalassemia major with dual-energy x-ray absorptiometry and quantitative computed tomography: a comparison study.

Osteoporosis is a common, multifactorial cause of morbidity in patients with beta-thalassemia. The present study was performed to compare bone mineral density (BMD) results in the lumbar spine of thalassemic patients measured by both dual-energy x-ray absorptiometry (DEXA) and quantitative computed tomography (QCT), and to determine their correlations with the markers of bone turnover. BMD was measured in the lumbar spine of 13 regularly transfused patients with beta-thalassemia major by both DEXA and QCT. Blood and urine samples were obtained for the determination of biochemical and hormonal profiles. Both T-scores and Z-scores were higher when measured by QCT (T-score = -0.41 +/- 1.31, Z-score = -0.56 +/- 1.08, mean +/- SD) compared with the values given by DEXA (T-score = -2.57 +/- 0.88, Z-score = -2.32 +/- 1.11, P = 0.0005). In comparison to DEXA, QCT T-scores were more closely correlated with age (r = -0.19 vs. r = -0.70, P = 0.0068). Strong negative correlation was found between QCT values and age (r = -0.67, P = 0.01). In comparison to DEXA T-scores, QCT T-scores were more closely correlated with osteocalcin, urine N-telopeptide cross-links of type I collagen, and deoxypyridinoline, but without statistical significance. DEXA T-scores were better correlated only with urine C-terminal telopeptides of type I collagen, but again without statistical significance. These results imply that the two methods cannot be used interchangeably in assessing BMD in thalassemic patients. However, which one of these two techniques more precisely determines the overall strength of vertebrae in patients with beta-thalassemia remains to be investigated.

Absorptiometry, Photon↗
PubMed2007

Growth impairment in beta-thalassemia major: the role of trace element deficiency and other potential factors.

A serious problem in thalassemia major is growth impairment for which several possible etiologies have been proposed. Sixty-seven patients with thalassemia were randomly enrolled into the study, divided into 2 groups with and without growth failure and the correlation between growth failure and the following parameters was evaluated: age, sex, serum ferritin level, serum zinc and copper concentrations, serum copper-zinc ratio, regularity of blood transfusion, and the regularity and duration of chelation therapy. Among all studied parameters, only age, duration, and type of chelation therapy and age of beginning chelation therapy were significantly different between the 2 groups. Binomial multivariate logistic regression showed that the only significant independent correlation was between age and growth failure. A 1-year increase in age is associated with a 1.57-fold increase in the risk of growth impairment. The results of this study indicated that a temporally cumulative damage to growth-mediating mechanisms except those considered here is responsible for growth failure in thalassemia major.

Adolescent↗
PubMed2004

Flow cytometric analysis of fetal hemoglobin in erythroid precursors of beta-thalassemia.

Fetal hemoglobin (HbF), the major hemoglobin species in fetal life, drops to <1% in normal adults, where it is restricted to a few 'F-cells', which may increase in various acquired and genetic conditions, including thalassemia. Using flow cytometry, we studied the percentage of HbF-containing cells and their HbF content in RBC, reticulocytes (retics) and normoblasts (NRBC) present in the peripheral blood of patients with beta-thalassemia. Thiazol orange, a nucleic acid-specific dye, and anti-CD45 antibodies identified the various blood cells and antihuman HbF antibodies quantitated HbF. The results indicated that F-RBC were more numerous in beta-thalassemic (both transfused and nontransfused) patients than in normal donors, but, in most cases, their HbF content was comparable, suggesting that increased HbF in thalassemia is mainly due to higher %F-cells rather than an increased HbF per cell. Among the retics, the %F-cells and their HbF content were highest in immature retics and decreased with maturation to levels of RBC. This may reflect preferential maturation of F-retics into RBC in the circulation. The NRBC population contained the lowest %F-cells. This could be due to preferential maturation of F-NRBC, having more normal phenotype than non-F-NRBC, in the bone marrow into F-retics, while non-F-NRBC enter the circulation.

Case-Control Studies↗