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PubMed1983

A beta-thalassemia lesion abolishes the same Mst II site as the sickle mutation.

Digestion of DNA from a patient with homozygous beta zero thalassemia from Calabria, Italy with the restriction endonuclease Mst II produced a pattern similar to the one obtained with sickle cell trait DNA in that the Mst II site at the beta 6 position on one chromosome was abolished. We cloned the DNA from this beta-thalassemia chromosome and performed sequence analysis. The deletion of a single nucleotide (A) at the GAG codon of the beta 6 position results in a frame shift and early beta-globin chain termination. This mutation occurs on a chromosome with a haplotype similar to two other Mediterranean beta-thalassemia lesions. The Mst II enzyme is useful for prenatal diagnosis of beta thalassemia in this population.

Base Sequence↗
PubMed1985

A Chinese G gamma + (A gamma delta beta)zero thalassemia deletion: comparison to other deletions in the human beta-globin gene cluster and sequence analysis of the breakpoints.

A clone was isolated that contains the deletion junction region from an individual with a deletion associated with Chinese G gamma + (A gamma delta beta)zero thalassemia. A clone containing the normal DNA corresponding to the 3' breakpoint of this deletion was also isolated. Portions of these two clones were sequenced and compared to the region in the A gamma-globin gene where the 5' breakpoint occurs. This comparison reveals that the breakage and reunion event was nonhomologous and that it probably involved the insertion of 36-41 bases of DNA belonging to the L1 (KpnI) family of repetitive DNA. Genomic mapping revealed that the DNA on the 3' side of this deletion is closely linked in normal DNA to the 3' breakpoints of two different large deletions that are associated with hereditary persistence of fetal hemoglobin (HPFH). We cloned and mapped 35 kbp of normal DNA from this region (greater than 45 kbp downstream of the human beta-globin gene) that contains the 3' breakpoints of the Chinese thalassemia and the two HPFH deletions. An endogenous retrovirus-like element and several other repetitive sequences are located within this region. We show that the Chinese thalassemia deletion is greater than 80 kbp in length and differs in size from the two HPFH deletions by less than 6%. We also show that the Chinese thalassemia deletion is at least 40 kbp larger than several other deletions associated with a very similar phenotype.

Base Sequence↗
PubMed1996

Recombinant human erythropoietin trial in thalassemia intermedia.

It has been shown that high doses of human recombinant erythropoietin (r epo) increase haemoglobin levels by augmentation of F-cells, and Hb-F production in animal models and in human trials. In this study, r epo was used in patients with beta thalassemia intermedia. Our purpose was to improve haemoglobin levels by at least 2 g and maintain an average level between 10 and 12 g/dl. Ten patients aged 6-29 years (mean 14 +/- 7.6 years) with thalassemia intermedia were treated with r epo. It was given subcutaneously in rising doses from 500 to 1000 U/kg three times weekly for 3 months. During r epo therapy eight cases (80 per cent) showed an increase in haemoglobin, haematocrit, and reticulocyte levels, and an increase of at least 2 g of haemoglobin was obtained. Blood transfusion was not needed during the study except in one case. Five cases (50 per cent) improved life quality with therapy. Hb levels of all patients returned to baseline values over 1 or 2 months after r epo was discontinued. There was no significant change in absolute Hb-F, F-cells, and ferritin levels during treatment. Generally, the drug was well tolerated. No patient had hypertension. Recombinant erythropoietin seems to be an effective treatment for anaemia of beta-thalassemia intermedia, but longer term randomized trials are needed especially in patients with beta thalassemia major.

Adolescent↗
PubMed1992

Beta-thalassemia intermedia with exceptionally high hemoglobin A2: relationship to mutations in the beta-gene promoter.

Small deletions of the 5' portion of the beta-globin gene that remove the promoters but stop 3' to the delta-globin gene are recognized as the sole cause of beta-thalassemia with exceptionally high hemoglobin A2 (HbA2) levels. Two patients with beta-thalassemia intermedia and exceptionally high levels of HbA2 (10.4 and 12.0%) were examined. One patient was a combined heterozygote for the -88 C----T and a novel -87 C----A mutation, while the other was homozygous for the -29 A----G beta(+)-thalassemia mutation. The remainder of the beta genes were normal. There was no evidence for deletions involving the 5' portion of the beta gene or the region between the beta and delta genes. Gene mapping studies excluded the possibility of a beta delta-anti-Lepore hemoglobin gene with beta promoters and delta coding sequences. There were no mutations in the promoters of the G gamma or A gamma-globin genes that have been associated with the hereditary persistence of HbF phenotype. The delta-globin gene promoters were normal from codon 17 to position -145 relative to the mRNA capping site. There appears to be considerable heterogeneity of HbA2 and HbF levels in patients who are homozygous or mixed heterozygotes for mutations in the TATA box and other promoter elements of the beta-globin gene. The capacity for proteolysis within the erythrocyte may vary among individuals. The authors hypothesize that in the exceptionally high HbA2 beta-thalassemia intermedia phenotype, proteolysis of superfluous alpha-globin chains is less efficient than in patients with customary levels of HbA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Beta-thalassemia syndromes and pregnancy.

The literature relating to homozygous beta-thalassemia and the problems these patients have during their pregnancy is reviewed and another case report of a twin pregnancy in a homozygous beta-thalassemia individual is included. The majority of cases described refer to the intermedia clinical form of the hematological problem because patients with thalassemia major generally have poor sexual development. Although the reported cases had a greater frequency of delayed development, only one woman suffered from infertility and required ovulation induction agents. The thalassemia pregnant mother faces deleterious consequences resulting from chronic anemia and in nonsplenectomized patients there remains the risk of the onset of a hypersplenic crisis. The problems of splenectomized patients during pregnancy is also discussed. The chronic anemia of thalassemic patients predisposes to a poor fetal outcome with greater fetal loss, preterm labor, and intrauterine growth retardation.

Adult↗
PubMed1996

Co-inheritance of Hb D-Punjab (codon 121; GAA-->CAA) and beta (0) -thalassemia (IVS-II-1;G-->A).

PURPOSE: Homozygosity for Hb D-Punjab (or Hb D-Los Angeles; codon 121; GAA-->CAA) is rare among Arabs. The co-inheritance of Hb D with beta(0)-thalassemia trait is even rarer, with only 10 previous cases reported worldwide. PATIENTS AND METHODS: We present clinical and hematological data for two Hb D homozygotes and three compound heterozygotes for Hb D-Punjab and beta(0)-thalassemia (IVS-II-1; G-->A). All the individuals belong to a consanguineous Kuwaiti Arab family. The hemoglobin variant and the beta-thalassemia allele were characterized by sequencing, allele-specific amplification, and oligonucleotide hybridization. RESULTS: The hematology was unremarkable except for a moderate elevation of Hb F (3-4%) and significant hypochromia and microcytosis in the subject with Hb D/beta(0)-thalassemia. CONCLUSION: This report confirms the benign nature of homozygosity for Hb D.

Adult↗
PubMedDate not supplied

Sibling HLA-matched cord blood transplant for beta-thalassemia: report of two cases, expression of fetal hemoglobin, and review of the literature.

PURPOSE: A program of cord blood stem cell (CBSC) transplants for patients with beta-thalassemia major was initiated in conjunction with the prenatal diagnostic service in 1994. Two patients who received HLA-matched related CBSC transplants with posttransplant fetal hemoglobin (HbF) expression are described and the literature is reviewed. PATIENTS AND METHODS: After screening 12 pregnancies, matched sibling CBSC transplants were performed for 2 girls with beta-thalassemia major when they were 3.8 and 2.2 years old, respectively. Their HbF was assayed serially. RESULTS: The nucleated cell counts/kg were 11.4 x 10(7) and 6.2 x 10(7), which engrafted on days 19 and 24, respectively. The children are now transfusion-independent at 3 years and 1.2 years posttransplant. Their HbF levels showed a rapid rise posttransplant and reached peak levels of 37.2% and 42.2% on day 83 and day 88, respectively. The HbF levels declined to 1.0% and 3.8% on day 581 and day 305, respectively. Nine other sibling CBSC transplants for thalassemias have been reported with an engraftment rate of approximately 50%. Graft rejection was related to insufficient CBSC number in one. CONCLUSIONS: HbF levels in patients with beta-thalassemia major after CBSC transplants could be influenced by many factors, including reactivation of HbF synthesis, intrinsic rate of Hb switching of CBSC, and mixed chimerism.

Female↗
PubMedDate not supplied

Clinical manifestation of beta-thalassemia/hemoglobin E disease.

PURPOSE: To review the clinical manifestation and changes in hematologic parameters of patients with beta-thalassemia/hemoglobin (Hb) E. MATERIALS AND METHODS: Retrospective analysis of the clinical manifestation of 378 patients with beta-thalassemia/Hb E attending the hematology clinic at Siriraj Hospital between 1957 and 1982. RESULTS: A wide spectrum of clinical phenotypes has been observed. Most patients show clinical symptoms by 10 years of age. The majority of patients survive with or without occasional transfusion. Splenectomy was performed in 26.5% of patients. Patients come to the hospital because of anemia, fever, abdominal mass, and jaundice. Gastrointestinal tract disturbances are the most common presenting symptoms (34.6%), especially abdominal pain (10%) and cholecystitis (5.1%). Respiratory tract infections were found in 21.8% of patients and cardiovascular complications, including congestive heart failure, occurred in 11.9%. Other less common symptoms and complications included bone pain, chronic leg ulcers, paraplegia and hypertension-associated convulsions, and cerebral hemorrhage after multiple blood transfusion. Patients usually die between 20 to 40 years of age (67%), mainly from congestive heart failure and septicemia. Septicemia was often caused by Gram-negative bacteria. CONCLUSION: These clinical features observed in patients with beta-thalassemia/Hb E are probably the results of chronic anemia and iron overload. The study of the life history and clinical courses of patients with beta-thalassemia/Hb E should provide important information for the better management of these patients.

Adult↗
PubMedDate not supplied

Collection of sibling donor cord blood for children with thalassemia.

Bone marrow transplantation has curative potential for patients with thalassemia major who have a matched sibling marrow donor, but usefulness of alternative stem cell sources is undergoing investigation. Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source. Whereas many families caring for a child with thalassemia major (or other transplant-treatable condition) experience an additional pregnancy, most give birth at hospitals without the infrastructure needed to collect and process the new infant's CB. To address this, and with funding from the National Institutes of Health, we have developed the first noncommercial CB program, operating across the United States, designed specifically to facilitate medically indicated CB collections from sibling donors. Using a case-management model, we have collected CB for 25 thalassemia families in eight states. Three of these CB units have now been used for transplantation; two others are human leukocyte antigen-identical and contain adequate nucleated cell dose to perform transplantation in their intended recipient. We conclude that a CB bank focused on sibling donations may be a useful stem cell resource and that families with specific medical need, such as a child with thalassemia, should consider preserving CB from siblings.

Blood Specimen Collection↗
PubMed2002

Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia.

PURPOSE: To determine the prevalence of hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. PATIENTS AND METHODS: A total of 28 transfusion-dependent patients with beta-thalassemia were interviewed, and their serum calcium, phosphate, magnesium, and intact parathyroid hormone levels were checked. Serum ferritin levels were measured to monitor the effect of chelation therapy. Blood urea nitrogen, creatinine, total protein, and albumin were measured in patients with undetectable or low intact parathyroid hormone levels. RESULTS: The prevalence of hypoparathyroidism was 10.7% (3/28). Mean age at diagnosis was 18 years. The serum ferritin levels of patients with hypoparathyroidism were 1,032, 2,102, and 7,680 microg/L. Only one patient had clinical symptoms of hypocalcemia. All three of the patients with hypoparathyroidism had hypogonadism, and 66.7% (2/3) of the patients had insulin-dependent diabetes mellitus. CONCLUSIONS: Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia seems to be accompanied by other endocrinopathies. Serum ferritin may not have been a reliable indicator of iron overload in the three patients with hypoparathyroidism. Severe iron overload would easily explain these multiple endocrinopathies. This pattern is commonly seen in iron-overloaded patients with thalassemia elsewhere.

Adolescent↗
PubMed2004

Unrelated umbilical cord blood transplantation for an infant with beta-thalassemia major.

BACKGROUND: beta-thalassemia major, one of the most prevalent hemoglobinopathies throughout the world, can be cured by allogeneic stem cell transplantation therapy. Many patients, however, lack a suitably matched related donor. Unrelated umbilical cord blood can be used as an alternative stem cell source for some of these patients. This report describes the successful transplantation of a 2-month-old infant with beta-thalassemia major using partially HLA-matched unrelated umbilical cord blood. METHODS: After cytoreduction with busulfan, cyclophosphamide, and antithymocyte globulin (ATG), the patient underwent transplantation at the age of 2 months with a 4/6 HLA matching umbilical cord blood unit from an unrelated donor. RESULTS: The patient engrafted promptly with 100% donor chimerism. His only major complication was an autoimmune hemolytic anemia that resolved 2 years after transplantation. He is currently surviving, event-free, 5 years after transplantation with normal growth and cognitive development and full donor chimerism without evidence of beta-thalassemia. CONCLUSIONS: Umbilical cord blood transplantation from related and unrelated donors should be considered for patients with beta-thalassemia major who lack traditional bone marrow donors. As most newborns undergo screening for hemoglobinopathies, those with disease could be transplanted early in life before experiencing the morbidity and mortality caused by transfusion therapy, alloimmunization, and iron overload, increasing the likelihood of successful transplantation therapy.

Fetal Blood↗
PubMed1997

Transgenic and gene knock-out mouse models of sickle cell anemia and the thalassemias.

Sickle cell anemia and the thalassemias are globally the most common class of inherited disorders. Current treatment options are limited (transfusion, iron chelation) and are not suited to large-scale use in developing countries where the population of affected individuals is expected to undergo a tremendous increase in the near future. As such, the development of more practical and more permanent therapies is urgently needed. Recently, transgenic and gene knock-out technologies have been used to create mouse models for sickle cell anemia and all of the clinically relevant thalassemias (hemoglobin Bart's hydrops fetalis, hemoglobin H disease, beta-thalassemia intermedia, beta-thalassemia major/Cooley's anemia). These newly developed murine models should play an important role in the development of improved approaches for treating these commonly occurring genetic diseases.

Anemia, Sickle Cell↗
PubMed2002

Pathophysiology of thalassemia.

Despite discoveries concerning the molecular abnormalities that led to the thalassemic syndromes, it still is not known how accumulation of excess unmatched alpha-globin in beta thalassemia and beta-globin in alpha thalassemia leads to red blood cell hemolysis in the peripheral blood, and in the beta thalassemias particularly, premature destruction of erythroid precursors in marrow (ineffective erythropoiesis). Oxidant injury may cause hemolysis, but there is no evidence that it causes ineffective erythropoiesis. Hemoglobin E/beta thalassemia is now a worldwide clinical problem. The reasons underlying the heterogeneity and occasional severity of the syndrome remain obscure. Ineffective erythropoiesis now appears to be caused by accelerated apoptosis, in turn caused primarily by deposition of alpha-globin chains in erythroid precursors. However, it is not clear how alpha-globin deposition causes apoptosis. The author uses new observations on the control of erythropoiesis to provide a framework for studying the enhanced thalassemic erythroid apoptosis.

Apoptosis↗
PubMed2003

Unique features of laparoscopic cholecystectomy in Beta thalassemia patients.

Beta Thalassemia patients suffer from a high incidence of gallstones as well as systemic complications of iron overload. We performed laparoscopic cholecystectomy in 8 beta thalassemia patients and describe their specific features. Diagnosis was based on patients' clinical presentation and sonography. Trocars were readjusted due to the hepatomegaly. No intraoperative cholangiograms were performed. Follow-up included clinical assessment and abdominal sonography. All procedures were completed laparoscopically. Pigment cirrhosis and fibrosis around the cystic duct were noted in all patients. No biliary injury occurred. Post operatively, 4 patients suffered fluid leakage through the trocar site, treated conservatively. No major cardiopulmonary complications occurred. During a mean follow-up time of 65 months, all patients are symptom free and without evidence of biliary lithiasis. Thalassemia patients are difficult and often high-risk patients. Improvement in anesthesia and monitoring enables better management of these patients. Laparoscopic cholecystectomy should be advised in carefully selected thalassemia patients.

Adult↗
PubMed2006

Infusion of autologous retrodifferentiated stem cells into patients with beta-thalassemia.

Beta-thalassemia is a genetic, red blood cell disorder affecting the beta-globin chain of the adult hemoglobin gene. This results in excess accumulation of unpaired alpha-chain gene products leading to reduced red blood cell life span and the development of severe anemia. Current treatment of this disease involves regular blood transfusion and adjunct chelation therapy to lower blood transfusion-induced iron overload. Fetal hemoglobin switching agents have been proposed to treat genetic blood disorders, such as sickle cell anemia and beta-thalassemia, in an effort to compensate for the dysfunctional form of the beta-globin chain in adult hemoglobin. The rationale behind this approach is to pair the excess normal alpha-globin chain with the alternative fetal gamma-chain to promote red blood cell survival and ameliorate the anemia. Reprogramming of differentiation in intact, mature, adult white blood cells in response to inclusion of monoclonal antibody CR3/43 has been described. This form of retrograde development has been termed "retrodifferentiation", with the ability to re-express a variety of stem cell markers in a heterogeneous population of white blood cells. This form of reprogramming, or reontogeny, to a more pluripotent stem cell state ought to recapitulate early hematopoiesis and facilitate expression of a fetal and/or adult program of hemoglobin synthesis or regeneration on infusion and subsequent redifferentiation. Herein, the outcome of infusion of autologous retrodifferentiated stem cells (RSC) into 21 patients with beta-thalassemia is described. Over 6 months, Infusion of 3-h autologous RSC subjected to hematopoietic-conducive conditions into patients with beta-thalassemia reduced mean blood transfusion requirement, increased mean fetal hemoglobin synthesis, and significantly lowered mean serum ferritin. This was always accompanied by an increase in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in such patients. No adverse side effects in response to the infusion of autologous RSC were noted. This novel clinical procedure may profoundly modify the devastating course of many genetic disorders in an autologous setting, thus paving the way to harnessing pluripotency from differentiated cells to regenerate transiently an otherwise genetically degenerate tissue such as thalassemic blood.

Adolescent↗
PubMed2005

Lack of prognostic value of normalized integrated backscatter analysis of myocardium in patients with thalassemia major: a long-term follow-up study.

BACKGROUND: Patients with beta-thalassemia major often present with severe anemia and must undergo continuous transfusion therapy, consequently developing iron overload leading to hemochromatosis. Because of these the iron deposits and/or secondary structural changes, patients develop an increase in myocardial integrated backscatter (IB). AIM: To investigate the prognostic value of analyzing acoustic quantitative properties of the myocardium in patients with beta-thalassemia major. PATIENTS AND METHODS: Between 1989 and 1990, 38 patients (mean age: 18 years, range: 7-26, 21 males) with beta-thalassemia major and without clinical signs of cardiac failure were enrolled prospectively. All patients were on chelation therapy (desferroxiamine). To obtain quantitative operator-independent measurement of the IB signal of the left ventricular septum and posterior wall, the ultrasonic radiofrequency signal integrated values were normalized to the pericardial interface and expressed in percentage (IB%). RESULTS: Follow-up was 122 +/- 36 months, during which 15 events (7 cardiac deaths and 8 heart failures) occurred. The event-free survival was comparable in patients with normal and abnormal IB%. Septal IB% was 33 +/- 14 in the 15 patients with events, and 33 +/- 12 in the 25 patients without events (P = ns). The %IB had no prognostic value in this population. A prognostic value was found in multivariate analysis for patient refusal/noncompliance of chelation therapy (P = 0.02, OR: 4.37, 95% CI: 1.72-16.9) and also body mass index (P = 0.04, OR: 1.2, 95% CI: 1.0-1.4). CONCLUSION: Analysis of end-diastolic IB% of myocardium in patients with beta-thalassemia and iron overload was not predictive of adverse cardiac events during long-term follow-up in this study.

Acoustics↗
PubMed1980

Clinical, hematological and genetic features of sickle-cell anemia and sickle cell-beta thalassemia in a Brazilian population.

Clinical, hematological and genetic studies were carried out on 40 patients with symptomatic sickle-cell disease, selected on the basis of a predominant HbS fraction and absence of other abnormal hemoglobin variants. Family studies showed they included 26 homozygotes for the sickle-cell gene (SS) and 14 double heterozygotes for both the sickle-cell and the (0)beta-thalassemia genes ((S)(0)beta-thalassemia). Comparison of the two groups revealed the more common occurrence of splenomegaly, lower MCV and mCH, and higher HbA2 in (S)(0)beta-thalassemia. Total hemoglobin was slightly lower in SS disease but the difference was not significant. Fetal hemoglobin (HbF) was moderately elevated to similar levels in both groups. These results suggest a high incidence of S beta (0)-thalassemia in certain Brazilian mixed populations and confirm the severity of the double heterozygous state. The distinction between the two disorders is often difficult, but can be made on the basis of the hematological data taken together with family studies.

Adolescent↗
PubMed1996

Prevalence of hemoglobin S and beta-thalassemia in northern Jordan.

OBJECTIVE: The aim of this study was to determine the incidence of HbS and beta-thalassemia in the Northern Jordan. STUDY DESIGN: The investigation targeted 3 areas of Northern Jordan. Blood samples from 2,290 volunteers were evaluated to determine the prevalence of HbS and beta-thalassemia by preparing a hemolysate for cellulose acetate electrophoresis. An additional 568 newborn samples were collected from the umbilical and analyzed for the presence of HbS using electrophoresis. RESULTS: The overall prevalence of HbS and beta-thalassemia was 4.45% and 5.93%, respectively. The incidence of sickle cell trait in the newborn sample was 3.17%. The prevalence of both HbS and beta-thalassemia was higher in the Al-Gor area in comparison to Ajloun and Irbid. CONCLUSION: A better understanding of the demographics of these diseases has the potential to aid in the more efficient utilization of health care resources and improved planning and provision of health care services.

Adult↗