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PubMedDate not supplied

Left ventricular diastolic abnormalities in children with beta-thalassemia major: a Doppler echocardiographic study.

Left ventricular filling patterns were assessed by Doppler echocardiography in 63 beta-thalassemia major patients, aged for to 21 years, with no clinical evidence of congestive heart failure and 63 age- and sex-matched normal controls. The patients with beta-thalassemia major were divided into three age groups, namely four to nine years (6.8 +/- 1.5 years), 10-15 years (12.1 +/- 1.6 years) and older than 15 years (17.3 +/- 1.7 years). They were compared with age- and sex-matched normal controls in respects of Doppler diastolic indices. The ratio between the early and late (atrial) peaks of flow velocity was higher and peak flow velocity in late diastole was significantly lower in patients with beta-thalassemia major as compared to controls in all three age groups (p < .001). As compared with the controls, peak early diastolic flow velocity was also significantly higher in the thalassemics aged 10 to 15 years (92 +/- 16 vs 80 +/- 12 cm/s, P < .01) and in those older than 15 years (95 +/- 16 vs 79 +/- 13 cm/s, p < .001). Restrictive left ventricular diastolic abnormalities were detected in a total of 34 (54%) patients with beta-thalassemia major, whereas left ventricular systolic abnormalities were identified only eight (13%) of them. None of the patients without left ventricular diastolic abnormalities showed left ventricular systolic abnormalities. There was not any significant correlation between the hematologic parameters, such as mean serum ferritin, maximum serum ferritin and the number of blood units transfused, and left ventricular Doppler diastolic indices (p > .05). From the data presented here, we therefore conclude that left ventricular diastolic abnormalities develop in patients with beta-thalassemia major in the early phase of the disease and before the appearance of systolic abnormalities, when clinical symptoms of congestive heart failure are absent.

Adolescent↗

PubMed2005

New strategies in the treatment of the thalassemias.

In addition to the severe beta thalassemias, hematologists have begun to recognize the more severe forms of alpha thalassemia, namely hemoglobin (Hb) H disease and Hb H/Hb Constant Spring, as well as the beta compound heterozygote, beta thalassemia/HbE. Clinically, variably severe anemia becomes apparent in the first year accompanied by occasionally massive expansion of erythropoiesis. The most anemic patients require regular red blood cell transfusions to avoid death from cardiac failure. However, the inevitable iron accumulation leads to dysfunction, primarily involving the heart, liver, and endocrine system; thus, regularly transfused patients require iron chelation. A major discovery was that allogeneic bone marrow (stem cell) transplantation in severely affected subjects with both alpha and beta thalassemia could result in cure. Current work deals with specific complications, such as iron overload and endocrine, cardiopulmonary, thrombophilic, and osteopenic problems. The thalassemias are likely to benefit in the future from specific gene therapy. There are also important advances in genetic counseling based on results of early fetal diagnosis.

Anemia, Hemolytic, Congenital↗

PubMed1996

[Congenital hemolytic anemia--hemoglobin abnormality--thalassemia].

Thalassemias are a group of genetic disorders caused by unbalanced synthesis of alpha- and non-alpha chains of globins due to impaired globin genes. Clinical characteristics of the thalassemias are ineffective erythropoiesis and hemolytic anemia with microcytic-hypochromic erythrocytes. Surplus polypeptide chain synthesized by normal globin gene causes harmful effects to skeleton proteins of erythrocyte membrane, such as spectrin, ankirin and 4.1 protein, via a few different ways and normal integrity of membrane is disturbed. Basic mechanism of pathophysiology of thalassemias have been made clear but many problems remain to be overcame in clinical practice. Several methodological improvements in diagnosis have been coming out using DNA amplification technique and applied to prenatal diagnosis and mass-screening of thalassemias. In therapeutic methods, little improvement has been observed for last decade since introduction of bone marrow transplantation.

Humans↗

PubMed2004

Fast and sensitive diagnosis of thalassemia by capillary electrophoresis.

This paper demonstrates the diagnosis of beta-thalassemia by capillary electrophoresis in conjunction with laser-induced fluorescence using poly(ethylene oxide) (PEO) solutions in the presence of electroosmotic flow (EOF). During the electrophoretic separation, PEO solution entered a capillary from the anodic vial by EOF. The separation of a mixture of the polymerase chain reaction (PCR) products (330 and 334 base pairs) from a healthy person and a beta-thalassemia patient was accomplished within 15 min at 15 kV using 1.5% PEO containing 2 M urea at 30 degrees C. The electropherogram patterns instead of migration times were used to diagnose beta-thalassemia, with an accuracy of 100% for the analyses of 11 blood samples from suspected patients. After injecting a large volume of the mixture to the capillary filled with 800 mM Tris-borate buffer (pH 10.0), the DNA fragments stacked due to increases in viscosity and sieving when migrating into 1.5% PEO solution. As a result of improved sensitivity, only 15 PCR cycles were required when using 500 ng of DNA templates. The results shown in this study indicate the potential of this simple, rapid, and cost-effective method for the diagnosis of beta-thalassemia.

Buffers↗

PubMedDate not supplied

Partial embolization of the spleen in patients with thalassemia.

PURPOSE: The role of partial splenic embolization in alleviating hyperslenism was evaluated in children with thalassemia. PATIENTS AND METHODS: Five children with thalassemia (three with alpha-thalassemia, two with beta-thalassemia) underwent embolization with polyvinyl alcohol particles. In two patients, a second splenic embolization was required. RESULTS: Of the four patients who were transfusion dependent before embolization, two no longer needed transfusion after embolization and two had decreased requirements. In fifth patient who was not transfusion dependent, the hemoglobin level increased from 7.5 g/dL to 8.2 g/dL (75 to 82 g/L) after embolization. The mean platelet count also increased after embolization in all five patients from 266 x 10(9)/L to 480 x 10(9)/L, and the mean leukocyte count increased in four of the five patients from 7.29 x 10(9)/L to 10.1 x 10(9)/L. In the fifth patient, it was unchanged. In all five patients, there was a decrease in spleen size. All patients experienced abdominal pain, but no other severe complications were noted. CONCLUSION: In these five patients, partial splenic embolization was a safe procedure that may be an acceptable alternative to partial or total surgical splenectomy. Transfusion requirements and the spleen size were reduced and the leukocyte and platelet counts increased.

Abdominal Pain↗

PubMed1998

The role of partial splenectomy in children with thalassemia.

Partial splenectomy was performed on 12 patients with thalassemia (9 beta-thalassemia major and 3 Hb H disease) to reduce blood transfusion requirements. The indication for partial splenectomy was the presence of splenomegaly and increased blood transfusion requirements (i.e. Hb drop > 0.5 g per week). Their ages ranged from 3 to 10 years (mean 6.9 years). On follow-up, ranging from 1.1-5.5 years (mean 2.6 years), two of the three patients with Hb H disease required no more blood transfusions while the third continued to receive blood transfusions, but at a lower frequency. For those with beta-thalassemia major, the transfusion requirements and Hb drop per week decreased in the majority of patients. This is specially so during the first 1-2 years following partial splenectomy. In all, about 1/3 of the size of the normal spleen was preserved (either upper or lower pole) which was judged functional as there has been no significant infection in any of the patients, no change in IgM level, no Howell-Jolly bodies and visualization on scintigraphy. Partial splenectomy is recommended to start with for those with Hb H disease. For patients with beta-thalassemia major, partial splenectomy is beneficial as a temporary measure and in those children who are less than 5 years of age, as they are at greater risk of post splenectomy sepsis.

Blood Transfusion↗

PubMed2006

Genotypic heterogeneity and correlation to intergenic haplotype within high HbF beta-thalassemia intermedia.

OBJECTIVES: A molecular study was carried out of beta-thalassemia intermedia patients, compound heterozygotes for mutations usually found in beta-thalassemia major, with high levels of HbF in the absence of hereditary persistence of fetal hemoglobin (HPFH) syndrome. Our objective was to locate cis-DNA structures, DNA haplotypes, motifs, or polymorphisms that may correlate with the presence of high HbF. METHODS: Allele-specific oligonucleotide (ASO) hybridization was used for the detection of mutations and restriction fragment length polymorphism (RFLP) analysis and automated sequencing for motifs, haplotypes, and polymorphisms. Southern blot was used for investigating alpha-thalassemia and/or alpha- or gamma-globin genes triplications. RNA extracted from burst forming unit-erythroid (BFU-e) colonies of peripheral blood mononuclear cell cultures was used in reverse transcriptase-polymerase chain reaction (RT-PCR) to investigate intergenic transcription. RESULTS: We established that (i) the combination: T haplotype of the Agamma-delta-globin intergenic region, the motif (TA)9N10(TA)10 in the HS2 site of locus control region (LCR), and TAG pre-Ggamma haplotype is sufficient but not necessary for high HbF, (ii) the genetic determinant(s) for high HbF involves an element associated with this combination and must be present in the specific R haplotype occurring in beta-thalassemia intermedia and (iii) the genetic determinant(s) for high HbF does not involve the abolition of intergenic transcription in the Agamma-delta-globin intergenic region. CONCLUSIONS: The genetic determinant(s) of high HbF in the absence of HPFH is linked to intergenic haplotype T and does not disrupt intergenic transcription.

Adult↗

PubMed2002

Molecular characterization of thalassemia intermedia associated with HPFH-6/beta-thalassemia and HPFH-6/Hb E in Thai patients.

We report the molecular and hematological characterizations of thalassemia caused by interactions of the hereditary persistence of fetal hemoglobin (HPFH)-6 with beta-thalassemia in 2 Thai patients and the HPFH-6 with Hb E in another Thai patient. Marked hypochromic microcytosis, characteristics of thalassemia intermedia, were obvious in the former 2 cases but the latter had much milder clinical phenotype with normal Hb and a slightly reduced mean corpuscular volume (MCV) value. Hb analysis revealed no Hb A but Hb A(2)F patterns in the compound HPFH-6/beta-thalassemia patients and the EF pattern in the HPFH-6/Hb E patient. The (G)gamma-globin chain predominated in all cases. Globin gene analyses demonstrated that all patients carried the 101-kb HPFH-6 deletion in trans to the beta-thalassemia genes with the IVS1#5 G-C mutation and the G insertion between codons 8/9 and the beta(E)-gene, respectively. Hematologic data of the patients were compared to those of the HPFH-6 heterozygotes found in their family members and different genotype-phenotype interactions of this HPFH determinant in these Thai patients are illustrated.

Aged↗

PubMed2003

Mild beta-thalassemia intermedia caused by compound heterozygosity for (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia and molecular characterization of the defect in four Chinese families.

Molecular characterization of the compound heterozygous condition - (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia - in four families showing mild beta-thalassemia intermedia was carried out using DNA amplification techniques. Using the Amplification Refractory Mutation System (ARMS) to confirm the beta-mutations and DNA amplification to detect the 100-kb Chinese-specific (G)gamma((A)gammadeltabeta)(o)-deletion, ()two families were confirmed to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia with the IVSII No. 654 beta(+)-allele. In the third family, the (G)gamma((A)gammadeltabeta)(o)-deletion was confirmed in the father and the mother was a beta-thalassemia carrier with the cd 41-42 beta(o)-allele. Their affected child with (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia was found to be transfusion dependent. The same (G)gamma((A)gammadeltabeta)(o)-deletion and beta-thalassemia (cd 41-42) was also confirmed in a fourth family. In addition, the mother was also diagnosed with Hb H disease (genotype -alpha(3.7)/-(SEA)). Both the children were found to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia but they were not transfusion dependent and this could be due to co-inheritance of alpha-thalassemia-2 (genotype-alpha(3.7)/alphaalpha) in the children together with their compound heterozygous condition.

Adult↗

PubMed2026

Nanoplate Digital PCR for Identification of α0-Thalassemia (SEA Deletion): Carrier Screening and Possible Application to Prenatal Diagnosis.

The Southeast Asian deletion (--SEA), the most prevalent α0-thalassemia mutation in Southeast Asia, is a major target of regional thalassemia prevention programs. Coinheritance of α0-thalassemia with other hemoglobinopathies, particularly hemoglobin E (Hb E), complicates routine hematological screening and requires reliable molecular confirmation. This study developed and validated a duplex nanoplate digital polymerase chain reaction (dPCR) assay for simultaneous identification of the wild-type α-globin and --SEA deletion alleles in a single reaction. The assay was established on the QIAcuity nanoplate platform and evaluated using 171 blinded leftover DNA specimens from individuals with Hb E. Diagnostic performance was compared with conventional gap-PCR. Distinct fluorescence amplitude patterns enabled discrimination among normal, heterozygous, and homozygous --SEA genotypes in a single closed tube. Among the 171 specimens, 70 were identified as --SEA carriers and 101 as non-carriers, showing 100% concordance with gap-PCR. All subjects with Hb E + A2 levels ≥ 25% were negative for the --SEA deletion, whereas 56.0% of those with levels < 25% carried the deletion. In the representative prenatal case, duplex dPCR accurately identified parental carrier status and a homozygous --SEA fetus. This assay provides an accurate and practical molecular confirmatory assay for thalassemia screening and prenatal diagnosis in Southeast Asia.

Humans↗

PubMed1992

Size distribution curves of blood cells in thalassemias and hemoglobin H diseases.

Thalassemias and hemoglobinopathies in Thailand have been examined with a blood cell counter based on electroimpedance principle and obtained size distribution curves of red cells and platelets. Among various disorders, beta-thalassemia/hemoglobin E and homozygous hemoglobin Constant Spring showed severe anemia. Their red cell size distribution curve shifted to the left and overlapped with the platelet size distribution curve. Red cell distribution width expressed by coefficient of variation and the degree of the overlapping were stronger in beta-thalassemia/HbE than HbH. Heterozygous beta-thalassemia showed a narrow red cell distribution curve width with small standard deviation and low England's value. Although the overlapping of size distribution curves cause inaccurate red cell count and platelet count, careful observation of the size distribution curves was proved to have high diagnostic value.

Blood Platelets↗

PubMedDate not supplied

Serum interleukin-8 levels in thalassemia intermedia.

In this study we determined serum IL-8 levels in 18 untransfused patients with beta-thalassemia intermedia and in 14 subjects affected by HbH disease. As reported in polytransfused homozygous beta-thalassemia, untransfused beta-thalassemia and HbH disease show significantly (p < 0.005) higher serum IL-8 levels than normal controls. Our data suggests that there could be an intrinsic cause for the IL-8 increase in thalassemia intermedia. We think than the hyperactivity of thalassemic macrophages related to chronic hemolysis is the main cause for the increment in cytokines, such as IL-8, found in thalassemic syndromes.

Adolescent↗

PubMed1990

Lead poisoning and thalassemia trait or iron deficiency. The value of the red blood cell distribution width.

The cause of microcytosis and anemia in lead poisoning was investigated using red blood cell distribution width as a screening parameter in 21 consecutive patients with lead poisoning and seven nonrandomly selected patients with iron deficiency and lead poisoning. Of the 21 consecutive patients, 11 had microcytosis as defined by a mean corpuscular volume of less than 72 fL, nine had thalassemia trait (alpha or beta), one had both alpha thalassemia trait and iron deficiency, and one had iron deficiency. The red blood cell distribution width was less than 17.0 in those with thalassemia trait and greater than 17.0 in the iron-deficient subjects. Results of our study suggest that microcytosis in children with lead poisoning is due to coexistent iron deficiency or thalassemia trait. The red blood cell distribution width may be of value in the rapid assessment of the cause of microcytosis in children with lead poisoning.

Anemia, Hypochromic↗

PubMed1999

Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia.

Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.

Adult↗

PubMed2000

Molecular characterization and PCR detection of a deletional HPFH: application to rapid prenatal diagnosis for compound heterozygotes of this defect with beta-thalassemia in a Chinese family.

Hereditary persistence of fetal hemoglobin (HPFH) is one of the hemoglobinopathies in which the fetal gamma-globin genes remain active in adult life. Most HPFHs are caused by a large deletion involving a variable extent of DNA segment on the beta-globin gene cluster. We report the molecular defects associated with a deletional HPFH, which has previously been described in Cambodians and Vietnamese, in two unrelated Chinese individuals. To define the sequence around the breakpoints of the deletion, both the deletion junction fragment and the normal DNA across the breakpoints were cloned by PCR and sequenced. We found that the 5' breakpoint is located between nucleotides 986 and 987 upstream from the startpoint of the beta-globin gene, which further confirmed the Southeast Asian (SEA) HPFH deletion previously determined, whereas the 3' breakpoint, which is clarified for the first time by us, lies approximately 2.3 kb downstream from the 3' HS1 site of the beta-globin gene. It is suggested that deletions were the result of a non-homologous recombination event. Based on our novel sequence data, we designed a PCR amplification method with three primers bridging the 3' breakpoint. With this method and reverse dot blot (RDB) for detecting beta-thalassemia mutations, a Chinese family that had a 6-year-old propositus with severe thalassemia intermediate and that had requested prenatal diagnosis for the second pregnancy was found to be compound heterozygotes of HPFH defects with beta-thalassemia. The fetal genomic DNA diagnosis showed the same results as those in propositus, i.e., both of them inherited the deletion from their mother and inherited a codons 14-15 (+G) frameshift mutation causing beta-thalassemia from their father.

Adult↗

PubMed2000

Rare beta-thalassemia mutations in Asian Indians.

Among 365 carriers of beta-thalassemia, 13 subjects remained uncharacterized after ARMS analysis. Among these 13 individuals, 8 mutations were identified by direct sequencing of the PCR-amplified product, which have not been described in Asian Indians earlier. These included (1) T-C substitution at IVS II position 591, a new beta-thalassemia mutation which probably creates an alternative donor splice site in antisense strand; (2) the mutations CoD4 (T-A), CoD5 (C-T), CoD6 (G-T) at cis location; (3) CoD13 (C-T), CoD26 (G-A), CoD 27/28(-C) at cis location; (4) CoD 8 (A-G); (5) CoD30 (G-C); (6) CoD5 (-CT); (7) IVSI-1 (G-A); and (8) FS47/48 (+ATCT). The latter four have been described in other populations but are identified in Asian Indians for the first time. This completes the characterization of beta-thalassemia mutations in 365 carriers of Asian Indian origin, enabling us to provide a comprehensive prenatal diagnosis of beta-thalassemia in our population.

Asia↗

PubMed2003

First observation of homozygous hemoglobin hamadan (B 56 (D7) GLY-ARG) and beta thalassemia (-29 G>A)- hemoglobin Hamadan combination in a Turkish family.

During screening surveys for beta thalassemia and abnormal hemoglobins in Mugla, a city located in the Aegean Region of Turkey, a hemoglobin variant was detected in two large families residing in two neigboring cities (i.e., Muğla and Aydin) without any clinical signs. Further analysis of the variant revealed it as Hb Hamadan (B 56 (D7) GLY-ARG). Family screening revealed the father of the propositus as homozygote Hb Hamadan. The grandfather of the index case was detected as combination of Hb Hamadan with beta thalassemia. The beta thalassemia carrier had a promotor mutation at -29 G>A, which is also a novel mutation. Furthermore, we described a simple and rapid restriction enzyme digestion protocol (Hha I) for the verification of Hb Hamadan. The clinical and hematologic data of the index case and his father showed that neither homozygous Hb Hamadan nor combination with beta thalassemia has clinical importance. This is also important especially from the prenatal diagnosis point of view.

DNA Mutational Analysis↗

PubMed2004

Accurate and rapid prenatal diagnosis of the most frequent East Mediterranean beta-thalassemia mutations.

Beta-thalassemia is the most common genetic disorder in the Lebanese population. Of the 200 different mutations in the beta-globin gene that leads to thalassemia, the IVSI-110 (29.87%), IVSI-6 (20.74%), IVSI-1 (14.07%), IVSII-1 (9.13%), Cd29 (9.13%), and Cd30 (3.95%) mutations are the most frequent among Lebanese thalassemic patients. These mutations are also present at high frequencies in the East Mediterranean region. Due to this high prevalence of certain beta-thalassemia mutations, a rapid technique for the prenatal diagnosis of these mutations was implemented. The technique used is based on Real-Time PCR quantification and melting curve analysis of the amplified fragment using the LightCycler. The DNA samples used for amplification were obtained from CVS or amniotic fluid. Six mutations were easily and efficiently detected using only 3 sets of probes. With this method, mutant genotypes can be easily distinguished from normal alleles. In prenatal diagnosis, the accuracy and the speed of testing are paramount. The method of prenatal beta-thalassemia mutations detection described here is efficient and fast, with the entire procedure including DNA preparation taking less than half a workday. It is safe, does not involve radioactivity, and is accurate showing 100% concordance with conventional DNA sequencing methods.

Base Sequence↗