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PubMed2004

Umbilical cord blood transplantation in children with beta-thalassemia diseases.

To evaluate factors affecting the outcome of sibling and unrelated donor umbilical cord blood transplantation (CBT) in Thai children with beta-thalassemia diseases. The case-series study of all children undergoing such transplants in our institute was conducted Six children with thalassemia major were diagnosed at a median age of 1.5 years and CBT was performed at a median age of 5.5 years (range 2-15). Six donors consisted of three HLA-identical siblings, one two-allele, one three-antigen mismatched sibling, and one one-allele mismatched unrelated cord blood. The median number of nucleated cells infused was 2.83 x 10(7)/kg (range 1.49-5.3); the median number of CD34+ cells infused was 1.94 x 10(5)/kg (range 0.2-5.3). In all, two patients had complete donor engraftment; three had mixed chimerism (MC); one patient died of cerebral thrombosis and neutropenic septicemia. Of the two complete donor-engrafted patients, two developed grade 2 acute graft-versus-host disease (GVHD) which responded well to immunosuppressive therapy. Of the three mixed-chimeric patients, two were clinically cured. With a median follow-up of 7 months (range 2-30), five children survived and have done well with transfusion-independent. Umbilical cord blood provides a reasonable option for hematopoietic stem cell source to transplant for beta-thalassemia diseases and the outcome in the present study was good.

Adolescent↗
PubMed1992

Diagnostic strategy for thalassemias and other hemoglobinopathies: a program applied to the Hellenic Army recruits.

A program for the detection of thalassemias and other hemoglobinopathies in high-risk populations is described. This program, based on two screening tests, was applied to the Hellenic Army recruits and was found to work well. Red cell one-point osmotic fragility was used for the detection of thalassemic samples and hemoglobin electrophoresis for screening of other hemoglobinopathies. Samples with decreased red cell osmotic fragility and/or abnormal electrophoretic pattern were submitted for further detailed investigation. Following this program, 64,814 recruits, representing 0.651% of the total Greek population and 9.917% of the 20-year-old Greek male population, were tested. beta-Thalassemia was found with an average incidence of 5.476% and alpha-Thalassemia with an incidence of 0.201%. Hemoglobinopathy Lepore was detected in 51 samples (0.079%) and hemoglobinopathy-S in 352 samples (0.543%).

Adult↗
PubMed2005

From splenic anemia in infancy to microcythemia. The Italian contribution to the description of the genetic bases of Thalassemia.

This article traces out part of the history of studies of the genetic bases of thalassemia carried out in Italy. In particular it illustrates the research and discussions that between the late 1920s and the second half of the 1940s led to the description of the genetic basis of beta-thalassemia. The article encountered by Italian research, explaining why, despite the large number of thalassemia cases and data collected for this disease, Italian researchers succeeded in demonstrating its Mendelian transmission only at the same time as the US researchers.

Biomedical Research↗
PubMed1992

A new codon 31 (-C) mutant resulting in beta zero-thalassemia.

A new beta zero-thalassemia mutation, a frameshift mutation with deletion of a single cytosine nucleotide in codon 31, is described. The propositus, which is compound heterozygous for this mutation and the 17 beta A-T beta zero-thalassemia mutation, has the phenotype of severe beta-thalassemia major.

Base Sequence↗
PubMed2006

Hematologic and molecular characterization of a Sicilian cohort of alpha thalassemia carriers.

Detailed hematologic and molecular analyses were carried out on a cohort of Sicilian individuals with suspected or asymptomatic beta-thalassemia. Iron deficiency, mild beta-thalassemia alleles and most common Mediterranean alpha-globin deletional mutations were excluded. All negative individuals were then tested for alpha-thalassemia point mutations by a denaturing high-performance liquid chromatography (DHPLC)-based assay. Four rare alpha-globin variants (Hb Interlaken, Hb Chesapeake, Hb Lombard, Hb Sun Prairie) and one point mutation (polyA: AATAAA-G in alpha2) were identified in 15 out of 80 carriers. Direct sequence analysis carried out in the remaining 65 negative individuals revealed no further sequence variants.

Cohort Studies↗
PubMed1991

[A novel Chinese beta-thalassemia mutation--4bp deletion (AAAC) downstream from the cap site].

During the molecular study of the Chinese beta thalassemia, we encountered a mutation that could not be detected by any of the oligonucleotide probes specific for the known Chinese beta thalassemia mutations. Molecular cloning and DNA sequencing analysis by both DNA chain termination and PCR direct sequencing methods revealed a previously undescribed mutation--deletion of 4bp (-AAAC) at the positions of nucleotide 40 to 43 from the cap site of the beta globin gene. With this new mutation, an additional Dde I recognition site is created and it could be directly detected by analysis of the abnormal restriction fragment. Unlike the other beta thalassemia mutations, this newly described mutant is the first mutation within the 5' untranslated region of beta globin gene as well as any other genes. This unique example will elicit valuable insight in the relationship between the structure and function of the 5' untranslated sequences.

Base Sequence↗
PubMed2006

Frequencies of peripheral blood myeloid cells in healthy Kenyan children with alpha+ thalassemia and the sickle cell trait.

The high frequencies of both alpha+ thalassemia and the sickle cell trait (hemoglobin AS [HbAS]) found in many tropical populations are thought to reflect selection pressure from Plasmodium falciparum malaria. For HbAS, but not for alpha+ thalassemia, protection appears to be mediated by the enhanced phagocytic clearance of ring-infected erythrocytes. We have investigated the genotype-specific distributions of peripheral blood leukocyte populations in two groups of children living on the coast of Kenya: a group of healthy P. falciparum parasite-negative children sampled at cross-sectional survey during a period of low malaria transmission, and a group of children attending the hospital with acute malaria. We report distinctive distributions of peripheral blood myeloid dendritic cells and monocytes in children with alpha+ thalassemia and HbAS during healthy periods and disease, and suggest ways in which these might relate to the mechanisms of protection afforded by these conditions.

Child↗
PubMed2005

Validation of osmotic fragility test and dichlorophenol indophenol precipitation test for screening of thalassemia and Hb E.

The strategy for screening of thalassemia and Hb E by a combination of osmotic fragility (OF) test and dichlorophenol indophenol precipitation (DCIP) test was validated with 436 unrelated Thai subjects. Hemoglobin (Hb) typing, Hb A2 quantitation, PCR and DNA sequence analysis were used as confirmatory methods for diagnosis of thalassemia and hemoglobinopathy. The sensitivity and specificity of this strategy was 100% and 79.7%, respectively. The results assessed by two medical scientists were exactly the same with 93.3% accuracy in comparison with the confirmatory methods. A combination of OF and DCIP has been shown to be a reliable, rapid, simple and sensitive strategy for screening thalassemia and Hb E in the Thai population.

2,6-Dichloroindophenol↗
PubMed2006

Exchange blood transfusions for the treatment of leg ulcerations in thalassemia intermedia.

Thalassemia intermedia is a heterogeneous, transfusion-independent form of b-thalassemia, with a clinical course dominated by multi-organ effects of chronic tissue hypoxia, in which hemoglobin F percentage seems to play an important role. We describe the case of a transfusion-independent thalassemia intermedia patient (total hemoglobin 10.7 g/dl) with high hemoglobin F percentage (70%), who presented with persistent leg ulcerations. The patient was successfully treated with one-year exchange blood transfusions, which reduced hemoglobin F percentage to 35%.

Adult↗
PubMed2006

Insulin resistance and beta cell function in chronically transfused patients of thalassemia major.

OBJECTIVE: To assess the glycometabolic function in chronically transfused patients of beta- thalassemia major in terms of glucose tolerance, insulin secretion, insulin resistance index, and beta cell function index and to determine their relationship with clinical and biochemical profile. METHODS: 30 homozygous thalassemia major children (aged 8-15 years) receiving regular blood transfusion and 10 age and sex matched normal children attending a tertiary level hospital were subjected to glucose tolerance test, estimation of fasting plasma insulin level, insulin resistance index and beta cell function index. Liver enzymes, liver size and indicators of iron overload (serum ferritin, total units of blood transfused, splenic size) were recorded. RESULTS: There was no diabetes mellitus or impaired glucose tolerance test in either the cases or the controls. Fasting plasma insulin levels were significantly higher in cases than controls (P = 0.004), and correlated well with indicators of iron overload like total units of blood transfused (r = 0.41, P = 0.03), serum ferritin (r = 0.38, P = 0.038) and splenic size (r = 0.43, P = 0.03). Insulin resistance was higher in cases compared to controls (P = 0.01). It correlated well with age (r = 0.56, P = 0.006), fasting blood glucose (r = 0.8, P = 0.003), fasting plasma insulin (r = 0.95, P = 0.00001), total units of blood transfused (r = 0.52, P = 0.005), serum ferritin (r = 0.4, P = 0.02) and splenomegaly (r = 0.51, P = 0.004). Insulin resistance was higher in patients not on chelation therapy compared with those on chelation therapy (P = 0.003). The beta cell function index was higher in cases compared to the controls, but not of statistic significance (P = 0.077). It did not correlate well with total amount of blood transfused (r = -0.32, P = 0.08), serum ferritin (r = -0.138, P = 0.46), spleen size (r = 0.16, P = 0.36), or chelation therapy (P = 0.98). CONCLUSION: Diabetes mellitus or impaired glucose was not seen in chronically transfused patients of thalassemia major (between 8 and 15 years of age), in our study. Insulin resistance, compensated by hyperinsulinemia, sets in early even before the onset of frank diabetes mellitus and correlated well with age, chelation therapy and indicators of iron overload like total units of blood transfused, splenomegaly and serum ferritin.

Adolescent↗
PubMed2005

Dengue hemorrhagic fever in patients with thalassemia.

Dengue hemorrhagic fever (DHF) causing by dengue viral infection is endemic in Thailand and Southeast Asian countries where thalassemias are prevalent. Thalassemic patients are also at risk to acquire dengue viral infections and to develop DHF. However, they can have different clinical manifestations and complications as well as more severity than general population requiring special awareness for proper diagnosis and management. We reported 20 thalassemic patients (10 boys and 10 girls) with DHF admitted to Department of Pediatrics, Siriraj Hospital during 1977 to 2001. Their ages ranged from 2-16 years (average 9.5 years). These cases included 5 cases of Hb H disease, 5 cases of Hb H with Hb Constant Spring (CS), 9 cases of beta-thalassemia/Hb E disease and 1 case of beta-thalassemia major. Two cases were in Grade I, 10 cases in grade II, 7 cases in Grade III and one case in grade IV severity of DHF. Though there were evidences of plasma leakage, instead of hemoconcentration, eighteen patients (90 percent) had hematocrit dropped at the range of 11-66% of the initial level. Fifteen patients (75 percent) required at least one packed red cell transfusion. Nine patients (45 percent) had mild bleeding symptoms, one of them had upper gastrointestinal hemorrhage requiring platelet concentrate transfusion. Two patients (10 percent) had serious complications including one with infection-associated hemophagocytic syndrome (IAHS) requiring intravenous immunoglobulin (IVIG) and packed red cell transfusion and the other had generalized seizure due to hyponatremia and hypotension. No mortality was observed among this group of patients. Early recognition of the DHF in thalassemic patients and appropriate packed red cell transfusion in patients with anemic symptoms is warranted to reduce morbidity and mortality in these patients.

Adolescent↗
PubMed2006

A successful strategy for Preimplantation Genetic Diagnosis of beta-thalassemia and simultaneous detection of Down's syndrome using multiplex fluorescent PCR.

OBJECTIVES: Preimplantation Genetic Diagnosis (PGD) is an alternative to prenatal diagnosis providing couples the chance to start a pregnancy with an unaffected fetus. The objective of the present study was to develop and apply quick, sensitive and accurate single cell PCR protocols for PGD of beta-thalassemia and Down's syndrome detection. MATERIAL AND METHOD: Two couples carrying beta-thalassemia codon41-42 mutation underwent routine IVF procedures. Embryo biopsy was performed on Day-3 post-fertilisation and single cell multiplex fluorescent PCR was employed for mutation analysis, contamination detection and diagnosis of trisomy 21 cases. RESULTS: Seventeen embryos were tested in two clinical PGD cycles. This resulted in the first birth following PGD for a single gene disorder in Thailand and South East Asia, confirmed by prenatal testing. Two embryos were shown to be affected by Down's syndrome. CONCLUSION: Successful strategy for PGD of beta-thalassemia and Down's syndrome detection using multiplex fluorescent PCR was introduced.

Adult↗
PubMed2006

Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the effect of zoledronic acid (ZA) on thalassemia-induced osteoporosis. DESIGN AND METHODS: We studied 66 thalassemia patients with osteoporosis, who were randomized to receive 4 mg ZA iv, every 6 months (23 patients; group A) or every 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for a period of 1 year. Bone mineral density (BMD) of the lumbar spine, femoral neck and wrist was determined before and 12 months after treatment. Pain scores and markers of bone resorption [C-telopeptide of collagen type-I (CTX), 5b-isoform of TRAP], bone formation [bone-alkaline phosphatase (bALP), osteocalcin (OC), C-telopeptide of procollagen type-I (CICP)], and osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin] were also measured at baseline and before each treatment administration. RESULTS: The values of CTX, bALP, CICP, sRANKL, and OPG were higher in the all patients than in the controls. Patients in group A showed no differences in BMD of all sites at 12 months, while they had reductions in bone pain, bALP, OC and OPG. Conversely patients in group B had a significant increase in their lumbar spine BMD, which was accompanied by dramatic reductions in bone pain, CTX, bALP, CICP, and OC. Patients in group C showed no alteration in BMD of any studied site or in bone pain, while they had an aggravation in bone resorption. INTERPRETATION AND CONCLUSIONS: ZA, at a dose of 4 mg, iv, every 3 months is an effective treatment for increasing BMD and reducing bone resorption in thalassemia-induced osteoporosis.

Bone Density↗
PubMed1990

Observations on the levels of Hb A2 in patients with different beta-thalassemia mutations and a delta chain variant.

Hb A2 and its variant B2 (alpha 2 delta 2(16)(A13)Gly----Arg) were quantitated in the blood of subjects with three different types of beta-thalassemia and with the delta-B2 anomaly in cis or in trans to the beta-thalassemia determinant. In one family, the delta-B2 mutation was in cis to a newly discovered codon 47 (+A) frameshift. The levels of Hbs A2 and B2 were nearly the same and approximately 70% higher than those in simple Hb B2 heterozygotes. In two additional families, the delta-B2 variant was in trans to either a deletional beta-thalassemia (1,393 bp) involving part of the beta-globin gene and part of the beta-globin gene promoter, or to the -88 C----T promoter mutation. In both instances, the Hb B2 level was increased by approximately 80%, but the Hb A2 level was increased by approximately 270% and 200%, respectively. These data indicate two mechanisms that will cause an increase in delta chain production. One is consistent with a general mechanism concerning the relative excess of alpha chains in beta chain deficiencies which will combine with delta chains to form variable levels of Hb A2 dependent on the severity of the beta chain deficiency. The second concerns the loss of beta-globin gene promoter activity, perhaps by an absence of (or decreased) binding of specific protein(s) to this segment of DNA and a concomitant increase in delta-globin gene promoter activity in cis.

Adolescent↗
PubMed2006

Liver expression of hepcidin and other iron genes in two mouse models of beta-thalassemia.

BACKGROUND AND OBJECTIVES: Homozygous beta-thalassemia patients may develop iron overload even if untransfused, due to inappropriately high intestinal iron absorption. Reduction of hepcidin synthesis has been reported both in patients and in animal models. We have measured liver hepcidin and other iron gene transcripts in two different mouse models of beta-thalassemia at different ages. DESIGN AND METHODS: Mice Hbb(th/th), characterized by spontaneous homozygous deletion of the major b1 globin gene were studied at 2 and 8 months. Mice Hbb(th/3+), characterized by the heterozygous deletion of b1 and b2 globin genes were studied at 4 and 10 months. Hematologic data were obtained and iron overload estimated by Perls' staining of the liver. Expression of liver hepcidin, Tfr2, Hjv, Fpn and Hfe RNA was assessed by real-time polymerase chain reaction. Levels of serum cytokines (interleukin-6, IL-1beta, IL-10, granulocyte-macrophage colony-stimulating factor) levels were assayed by enzyme-linked immunosorbent assay. RESULTS: Hemoglobin, hematocrit and mean corpuscular volume were significantly reduced in both beta-thalassemia models, more significantly in Hbb(th/3+), which have the greater, age-dependent, iron overload. Hepcidin RNA was not increased despite iron overload in both strains. Fpn RNA was increased and Tfr2 was decreased in older animals. Inflammatory cytokine levels were striking variable and unrelated to hepcidin levels. INTERPRETATION AND CONCLUSIONS: Although anemia is reported to inhibit hepcidin expression, normal hepcidin synthesis was maintained in both thalassemic models studied. However, hepcidin levels were inappropriate for the body iron, especially in Hbb(th/3+) 10-month-old animals. As we previously reported in wild type mice after parenteral iron overload, Tfr2 is reduced and Fpn RNA increased in thalassemic mice. Inflammatory cytokines did not play a major role in increasing hepcidin levels or in modifying iron homeostasis in this study.

Animals↗
PubMed2006

Beta thalassemia IVS-I-5(G-->C) heterozygosity masked by the presence of HbJ-Meerut in a Dutch-Indian patient.

We describe the genotype/phenotype correlation in a 35 year old anemic female referred to our laboratory because a fast eluting minor fraction on HPLC, mild hemolysis and hematological parameters suggesting a Thalassemia trait, eventually in combination with iron depletion. Direct sequencing of the alpha globin genes revealed heterozygosity for HbJ-Meerut, a Glu-->Ala substitution at residue 120 not justifying the hematological parameters. No other point mutations were found on the alpha genes and Gap-PCR excluded the 6 common deletion defects. Direct sequencing of the beta-globin genes revealed the IVS-I-5 (G-->C) transversion in absence of the elevated HbA2 levels usually measured in carriers of this beta-Thalassemia mutation. The HbA2 tetramer in the presence of HbJ-Meerut divides in two parts. One alphaN2/delta2 migrating on the right spot on HPLC. The other alphaJ2/delta2 migrating under the HbA fraction. Classic alkaline electrophoresis and the modern capillary electrophoresis CE showed these two tetramers and the reduction of the elevated HbA2 level of the beta-Thalassemia trait by at least 20% due to HbA2 Meerut.

Adult↗
PubMed1991

[Thalassemia minor with iron overload: genetic and clinical study of a family].

A patient with thalassemia minor (TM) is reported who ingested 80 g of alcohol/day and presented an important overload of iron with deposits and a hepatic iron ratio compatible with primary hemochromatosis. The results obtained from the study of histocompatibility antigens, clinical manifestations and family analysis discarded the possibility of two genetic diseases, beta-thalassemia and primary hemochromatosis, being concomitantly present in the same progeny. Thalassemia minor and alcoholic hepatopathy are considered as having acted together and being responsible for the iron overload. The relation between alcohol ingested, TM and iron deposits is discussed.

Adult↗
PubMed1991

Beta-thalassemia intermedia and IVS-1 NT6 homozygosis in Brazil.

1. The molecular abnormality of a patient with thalassemia intermedia was identified by DNA amplification (PCR) combined with the use of synthetic oligonucleotide probes. 2. The patient is a homozygote for the T----C substitution at position 6 of the first intervening sequence (IVS1-6) of the beta globin gene. 3. On the basis of this finding, the family, which had been previously reported by us to be a carrier of an unusually mild beta-thalassemia gene, was actually the first example reported of the clinical and biochemical features of beta-thalassemia-Portuguese type.

Adult↗