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PubMed2002

A simplified screening for alpha-thalassemia 1 (SEA type) using a combination of a modified osmotic fragility test and a direct PCR on whole blood cell lysates.

In order to provide a rapid method for identifying alpha-thalassemia 1 in a region with massive population and limited resources, we have tested a rapid screening strategy. Preliminary screening was done using a modified one tube osmotic fragility test (OF test) followed by RBC indices; Hb analysis and detection of alpha-thalassemia 1 with the Southeast Asian deletion (SEA type) were performed by PCR. One hundred and seventy-five adult Thai subjects were studied. Fifty-one of the 175 subjects (29.1%) were positive for a modified OF test. They all had significantly lower MCV and MCH but higher RDW-CV values as compared to the OF negative group. A successful identification of alpha-thalassemia 1 deletion using a direct PCR on cell lysates was demonstrated. Among the 51 OF-test-positive subjects, 7 were found to be alpha-thalassemia 1 carriers, 3 of whom were also carriers of Hb E. No alpha-thalassemia 1 was detected in the OF-test-negative group. A combination of a modified OF test and a direct PCR analysis on whole blood cell lysates would therefore provide an effective screening for alpha-thalassemia 1 in the regions where a program of prevention and control of the disease remains underserved.

Adult↗
PubMedDate not supplied

Prenatal diagnosis in beta-thalassemia: an Indian experience.

OBJECTIVES: Thalassemia is the most common single gene disorder and is widely distributed in Asian Indians with an average prevalence rate of 4%, with a high prevalence among Sindhis, Punjabis, Gujratis and Bengalis. Prevention and control of beta-thalassemia disease require the accurate diagnosis of carriers and proper genetic counseling. METHOD: Prenatal diagnosis can be performed in the first or second trimester of pregnancy by DNA analysis using polymerase chain reaction. Since there are 17 mutations as well as rare ones causing beta-thalassemia in Asian Indians, the point mutation detection by reverse dot blot (RDB) allele-specific oligonucleotide hybridization for common mutations along with the amplification refractory mutation system (ARMS) technique was developed for prenatal diagnosis. Maternal contamination of fetal DNA was ruled out by the variable number of tandem repeat analysis using apolipoprotein B site. RESULTS: Using both techniques (RDB and ARMS) we were able to offer complete diagnosis in 53 pregnancies. On molecular analysis 23% were found to be normal, 48.0% were carriers, and 29.0% were affected with beta-thalassemia. Parents were counseled to continue the pregnancy when the fetuses were either normal or had traits whereas in the case of an affected fetus, the parents opted for termination of the pregnancy. CONCLUSION: Prenatal diagnosis of beta-thalassemia by the RDB or ARMS technique can prevent the birth of an affected child in developing countries in which beta-thalassemia is quite prevalent.

DNA Mutational Analysis↗
PubMed2004

Molecular analysis of beta-thalassemia and sickle cell anemia in Antalya.

We have studied 918 chromosomes for mutations leading to beta-thalassemia and sickle cell anemia, which are the two most frequently found monogenic disorders in Antalya, Turkey. Three hundred and seventy-seven postnatal and 82 prenatal cases were studied between 2000 and May 2003 in our center using reverse dot blot hybridization (RDBH) with 22 probes specific for Mediterranean populations. In this study, IVSI-110 (G-->A) appeared to be the most common mutation with an occurrence rate of 44.4% among the 16 different mutations found to be associated with beta-thalassemia. Heterozygosity for IVSI-110 was the most prevalent combination, whereas 34 of our 377 postnatal cases showed homozygosity for this mutation, a genotype leading to beta-thalassemia major. The total percentage of postnatal patients clinically diagnosed as beta-thalassemia major was 18.6%, whereas 5% of the cases were diagnosed clinically as beta-thalassemia intermedia. One new Hb variant, Hb Antalya, and one new mutation, Cod 3 (+T) were found. HbS accounted for 10.3% of all mutations; homozygosity was found in 1.9% of all cases. Of the 82 cases analysed prenatally for beta-globin gene mutations and by cytogenetic techniques for possible chromosomal abnormalities, 21 fetuses were found to be affected with beta-globin gene mutations. One of these fetuses was also found to have a 45,X karyotype, and 1 had a 46,XY/47,XY,+22 karyotype. Quite a high rate of consanguineous marriages in Antalya (35.17%) renders mutation screening, genetic counseling, and educational programs held by our Thalassemia Unit essential. This study was the first to be performed specifically in our region where hemoglobinopathies are most frequent as a consequence of migrations of racially and culturally distinct groups to the area in the distant past.

Adolescent↗
PubMedDate not supplied

Genotype-phenotype analysis in HbS-beta-thalassemia.

Genotypes and phenotypes were studied in 31 Turkish HbS-beta-thalassemia patients. In 19 patients the beta-thalassemia mutations were beta+ and in 12 the beta 0 phenotype. The IVSI-110 mutation was found in 45% of the patients. IVSI-1, beta 39, IVSII-1 and FSC8 are the genotypes associated with beta 0-thalassemia. Hematological data were evaluated at the time of diagnosis and 4 years after diagnosis. The mean HbF value was 13 +/- 7.8% at diagnosis and 9.7 +/- 7.8% 4 years later. A significant negative correlation was observed between the age of the patients and the HbF value (p < 0.05). No statistically significant differences were observed between the mean of hematological parameters in beta(+)- and beta 0-thalassemia patients except for the mean HbF value which were 10.7 +/- 6.9 and 15.9 +/- 7.7% in beta(+)- and beta 0-thalassemia, respectively (p < 0.05). The study indicated that beta-thalassemia mutations in trans to the HbS mutation do not exert any beneficial effect on the manifestation of the disease.

Adolescent↗
PubMed1994

Molecular basis of beta-thalassemia in Japan: heterogeneity and origins of mutations.

Characterization of beta-thalassemia mutations was attempted for 13 unrelated Japanese patients heterozygous for beta-thalassemia. We have systematically analyzed beta-thalassemia genes using polymerase-chain-reaction-related techniques; dot blot hybridization with oligonucleotide probes complementary to known mutations, restriction endonuclease assay and direct sequencing of amplified genomic DNA. Seven different mutations were detected. Six of them are an amber mutation in codon 90 (GAG to TAG), a four-base-pair deletion in codons 41 and 42 causing premature termination due to frameshift, a C-T substitution at position 654 of IVS-2, a G-A substitution at position 1 of IVS-2 and a C-G substitution at position 848 of IVS-2, leading to splicing defects, and an ocher mutation (GAA-TAA) in codon 121 causing a thalassemia intermedia phenotype with inclusion body formation in erythrocytes. A silent mutation (CTG-TTG) was also detected in codon 91 of the allele with the IVS-2 position 1 mutation. These mutations have been reported previously in the Japanese population. The other mutation is a novel one in the Japanese, an amber mutation (TGG-TAG) in codon 15, causing a beta zero-thalassemia phenotype by premature termination of the beta-globin chain synthesis. We analyzed haplotypes of chromosomes bearing each beta-thalassemia mutation. Origins and a spectrum of mutations in comparison with those detected in malaria-endemic regions are discussed.

Adolescent↗
PubMed1987

A paucity of thalassemia trait in Italian men with myocardial infarction.

We studied the prevalence of thalassemia trait in a group of Italian male myocardial infarction (MI) patients and an ethnically similar group of men admitted for other conditions. Italian men constituted approximately 13% of each group. Of 359 Italian men with a MI, only 2 had thalassemia trait. In contrast, of 330 adult Italian males in the non-MI group (mean age 59.6 years), 11 had thalassemia trait. Because the frequency of thalassemia trait was significantly (p less than 0.01) lower in the myocardial infarct group, we conclude that thalassemia trait may be a protective attribute as regards MI. A prospective study of individuals with thalassemia minor is indicated to elucidate the mechanism for the observed protective effect and to determine what risk factors may offset the protective effect in those that do experience MI.

Heterozygote↗
PubMed1999

Association of heart failure in homozygous beta-thalassemia with the major histocompatibility complex.

BACKGROUND: In beta-thalassemia major, heart failure primarily affecting left ventricular systolic function is the most common complication and cause of death. Apart from iron deposition, it has been recently reported that myocarditis might be another contributing factor in the pathogenesis of acute or chronic heart failure, acting possibly through an autoimmune mechanism. In an attempt to assess the role of immunogenetic factors in the development of heart failure associated with beta-thalassemia major, we studied the frequency of major histocompatibility antigens/alleles A, B, DR, and DQ in homozygous beta-thalassemic patients with and without heart failure primarily affecting the left ventricle. METHODS AND RESULTS: Forty-five consecutive unrelated Greek patients with homozygous beta-thalassemia and left-sided chronic heart failure were studied. Fifty-eight unrelated Greek patients with homozygous beta-thalassemia without heart failure and 130 unrelated Greek healthy controls were also studied. In all subjects, class I HLA-A and -B typing was performed by the complement-mediated lymphocytotoxicity assay, whereas class II HLA-DR and -DQ typing was performed by polymerase chain reaction. HLA-DRB1*1401 allele frequency was significantly increased in patients with beta-thalassemia major without left-sided heart failure compared with those with heart failure (corrected P [P(c)]=0. 02, odds ratio 0.1) and healthy controls (P(c)=0.001). HLA-DQA1*0501 allele frequency was increased in patients with heart failure compared with patients without heart failure (P(c)=0.04, odds ratio 14) and healthy controls (P(c)=0.004). CONCLUSIONS: Differences exist in the immunogenetic profile between homozygous beta-thalassemic patients with and without left-sided heart failure, raising the possibility that genetically defined immune mechanisms may play an important role in the pathogenesis of heart failure in beta-thalassemia.

Adolescent↗
PubMed2002

Efficiency of premarital screening of beta-thalassemia trait using MCH rather than MCV in the population of Fars Province, Iran.

Iran is a country with high prevalence of about 5-10% of beta-thalassemia trait. The prevalence of Cooly's anemia has declined from 11.6 in 10000 population to 7.2 in 10000 in a five-year period due to screening program of beta-thalassemia trait before marriage. This study was conducted to compare the sensitivity of mean corpuscular hemoglobin (MCH) < 27 pg and mean corpuscular volume (MCV) < 80 fl as a screening test in first step of screening of beta-thalassemia trait. From 2449 couples (4898 cases) participating in the premarital screening to our clinic, 902 cases with either MCH < 27 pg, MCV < 80 fl, anemia, pallor or family history of beta-thalassemia were enrolled in the study. MCV, MCH as well as Hb A2 were measured in all cases. MCH and MCV had sensitivities of 98.5% and 97.6% for the diagnosis of beta-thalassemia trait, respectively. A false negative value of MCH is about 1% lower than that of MCV. MCH is a more sensitive screening test for detecting beta-thalassemia minor before marriage.

Erythrocyte Indices↗
PubMed1972

Translation of -globin m-RNA in -thalassemia and the S and C hemoglobinopathies.

Genetic and biochemical evidence indicates that in beta-thalassemia there is impaired synthesis of the beta-globin chains of hemoglobin A. In patients heterozygous for the hemoglobinopathies, hemoglobin S and hemoglobin C, the mutant beta-chain is produced in smaller amounts than normal beta(A). Defective m-RNA translation has been suggested as a possible cause of decreased beta-globin polypeptide synthesis in thalassemia and the hemoglobinopathies. In the present study, the ribosomal assembly of beta-globin chains was examined in the peripheral, nucleated red blood cells and reticulocytes of patients with Cooley's anemia, thalassemia intermedia, sickle thalassemia, sickle cell anemia, hemoglobin C disease, and in hemolytic anemias not associated with a hemoglobinopathy. The translation times of beta(A), beta(S), and beta(C) did not differ significantly (average times; beta(A) = 75 sec, range 43-114, beta(S) = 69 sec, beta(C) = 92 sec). In thalassemia, no evidence was found for a delay in translation as the cause of the marked impairment of beta-globin synthesis. In several specimens of peripheral blood from thalassemic patients, the translation time of the beta-chain was even shorter than in nonthalassemic specimens (average time = 45 sec, range 35-59). The results suggest that the defect in beta-globin synthesis in beta-thalassemia is due to impaired initiation of beta-globin chain assembly or a quantitative deficiency in m-RNA.

Adolescent↗
PubMed1985

Alpha thalassemia changes erythrocyte heterogeneity in sickle cell disease.

Homozygous alpha-thalassemia has the beneficial effect in sickle cell anemia of reducing the hemolytic severity while changing several other hematological parameters. We examined in detail the cellular basis of some of these hematologic alterations. We find that the broad distribution in erythrocyte density and the large proportion of dense cells associated with sickle cell anemia are both reduced with coexisting alpha-thalassemia. Measurements of glycosylated hemoglobin levels as a function of cell density indicate that the accelerated increase in cell density, beyond normal cell aging, in sickle cell anemia is also reduced with alpha-thalassemia. The patients with homozygous alpha-thalassemia and sickle cell disease have slightly lower levels of hemoglobin F than the nonthalassemic sickle cell patients. Examination of hemoglobin F production revealed that the proportion of hemoglobin F containing reticulocytes remained unchanged, as did the proportion of hemoglobin F in cells containing hemoglobin F (F cells). Preferential survival of F cells occurs in sickle cell anemia, with or without alpha-thalassemia, and the slight difference in hemoglobin F levels appear to reflect differences in numbers of circulating F cells. Thus, in sickle cell disease with coexisting alpha-thalassemia, the change in the erythrocyte density profile, possibly due to inhibition of polymerization-related increases in cell density, explains the hematological improvement.

Anemia, Sickle Cell↗
PubMed1987

Hemoglobin Mississippi (beta 44ser----cys). Studies of the thalassemic phenotype in a mixed heterozygote with beta +-thalassemia.

Hemoglobin Mississippi (HbMS: beta 44ser----cys) has anomalous properties that include disulfide linkages with normal beta-, delta-, gamma-, and alpha-chains, and the formation of high molecular weight multimers. While heterozygotes for HbMS are clinically and hematologically normal and carriers of the beta +-thalassemia gene in our family had mild microcytic anemia, the proband with HbMS-beta +-thalassemia had a hemoglobin level of 7 g/dl, mean corpuscular volume (MCV) of 68 fl, reticulocytes of 2-6%, HbF of 18%, marked anisocytosis and poikilocytosis, and splenomegaly, all features of thalassemia intermedia. With oxidant stress, her erythrocytes developed multiple dispersed Heinz bodies, but HbMS was only mildly unstable. HbMS was susceptible to proteolytic degradation in the presence of ATP. The unexpectedly severe clinical findings in HbMS-beta +-thalassemia may result from the proteolytic digestion of HbMS, as well as the excessive alpha-chains characteristic of beta +-thalassemia, which combined provide the increment of cellular damage that results in the phenotype of thalassemia intermedia.

Child↗
PubMed2005

Gene Therapy for beta-thalassemia.

Gene transfer for beta-thalassemia requires gene transfer into hematopoietic stem cells using integrating vectors that direct regulated expression of beta globin at therapeutic levels. Among integrating vectors, oncoretroviral vectors carrying the human beta-globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression. In recent studies, human immunodeficiency virus-based lentiviral (LV) vectors were shown to stably transmit the human beta-globin gene and a large LCR element, resulting in correction of beta-thalassemia intermedia in mice. Several groups have since demonstrated correction of the mouse thalassemia intermedia phenotype, with variable levels of beta-globin expression. These levels of expression were insufficient to fully correct the anemia in thalassemia major mouse model. Insertion of a chicken hypersensitive site-4 chicken insulator element (cHS4) in self-inactivating (SIN) LV vectors resulted in higher and less variable expression of human beta-globin, similar to the observations with cHS4-containing retroviral vectors carrying the human gamma-globin gene. The levels of beta-globin expression achieved from insulated SIN-LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with human thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo. In summary, LV vectors have paved the way for clinical gene therapy trials for Cooley's anemia and other beta-globin disorders. SIN-LV vectors address several safety concerns of randomly integrating viral vectors by removing viral transcriptional elements and providing lineage-restricted expression. Flanking the proviral cassette with chromatin insulator elements, which additionally have enhancer-blocking properties, may further improve SIN-LV vector safety.

Animals↗
PubMed2005

Induction of fetal globin in beta-thalassemia: Cellular obstacles and molecular progress.

Accelerated apoptosis of erythroid progenitors in beta-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with beta+-thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one beta 0-globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.

Animals↗
PubMed1976

Sickle cell syndromes. I. Hemoglobin SC-alpha-thalassemia.

Hematologic and globin synthesis studies were performed in a black American family in which the genes for alpha-thalassemia and hemoglobins (Hb) S and C were segregating. The following distribution of these abnormalities was found: father, sickle cell trait + alpha-thalassemia; mother, HbC trait + alpha-thalassemia, propositus, HbSC + alpha-thalassemia; older sibling, alpha-thalassemia trait; and younger sibling, hemoglobin H disease. The child with HbSC-alpha-thalassemia demonstrated more severe anemia and a more hemolytic picture than is typical of HbSC disease. Her erythrocytes exhibited decreased osmotic fragility in comparison with HbSC erythrocytes, but had an indistinguishable oxygen equilibrium curve and 2, 3-diphosphoglycerate (2, 3-DPG) level. Erythrocyte sickling in the patient, however, was significantly reduced, with less than 35% sickle forms observed at nearly complete oxygen desaturation. The sibling with hemoglobin H disease exhibited 26% Bart's (gamma4) hemoglobin at birth, a level comparable with that seen in infants with HbH disease in Far Eastern populations. At age 5 months typical findings of mild hemoglobin H disease appeared, with HbH making up 6.5% of the total hemoglobin.

Anemia, Sickle Cell↗
PubMed2005

A reliable screening protocol for thalassemia and hemoglobinopathies in pregnancy: an alternative approach to electronic blood cell counting.

Primary screening for thalassemia and hemoglobinopathies usually involves an accurate blood count using an expensive electronic blood cell counter A cheaper alternative method was tested by using a modified osmotic fragility (OF) test and a modified dichlorophenolindophenol (DCIP) test. Altogether 423 pregnant Thai women participated in this project. Hemoglobin patterns and globin genotypes were determined using an automated high-performance liquid chromatography analyzer and polymerase chain reaction analysis of alpha- and beta-globin genes. Among the 423 subjects, 264 (62.4%) carried thalassemia genes. The combined OF and DCIP tests detected all pregnant carriers of the 3 clinically important thalassemias, ie, alpha0-thalassemia, beta-thalassemia, and hemoglobin E with a sensitivity of 100.0%, specificity of 87.1%, positive predictive value of 84.5%, and negative predictive value of 100.0%, which show more effectiveness than these values for the standard method based on RBC counts. A combination of modified OF and DCIP tests should prove useful and applicable to prenatal screening programs for thalassemia and hemoglobinopathies in communities with limited facilities and economic resources.

Adult↗
PubMed2003

Multiplex minisequencing screen for common Southeast Asian and Indian beta-thalassemia mutations.

BACKGROUND: Beta-thalassemia is endemic to many regions in Southeast Asia and India, and <20 beta-globin gene mutations account for > or =90% of beta-thalassemia alleles in these places. We describe a multiplex minisequencing assay to detect these common mutations. METHODS: Gap-PCR was used to simultaneously amplify the beta-globin gene from genomic DNA and to detect the Delta619bp deletion mutation. Multiplex minisequencing was then performed on the amplified beta-globin fragment to detect an additional 15 common Southeast Asian and Indian beta-thalassemia mutations. Site-specific primers of different lengths were subjected to multiple rounds of annealing and single-nucleotide extension in the presence of thermostable DNA polymerase and the four dideoxynucleotides, each labeled with a different fluorophore. Minisequencing products were separated and detected by capillary electrophoresis, followed by automated genotyping. The optimized assay was subjected to a double-blind validation analysis of 89 beta-thalassemia and wild-type DNA samples of known genotype. RESULTS: Homozygous wild-type or mutant DNA samples produced electropherograms containing only a single colored peak for each mutation site, whereas samples heterozygous for a specific mutation displayed two different-colored peaks for that mutation site. Samples were automatically genotyped based on color and position of primer peaks in the electropherogram. In the double-blind validation analysis, all 89 DNA samples were genotyped correctly (100% assay specificity). CONCLUSIONS: The described semiautomated multiplex minisequencing assay can detect the most common Southeast Asian and Indian beta-thalassemia mutations, is amenable to high-throughput scale up, and may bring population-based screening of beta-thalassemia in endemic regions a step closer to implementation.

Asia, Southeastern↗
PubMedDate not supplied

Bone mineral density in children and young adults with beta-thalassemia trait.

BACKGROUND: Homozygous beta-thalassemia is a hereditary hematological disease due to defective beta-globin synthesis. Consequently, there is ineffective erythropoiesis and increased peripheral hemolysis. Increased erythropoiesis in bone marrow results in expansion of marrow cavity and reduced bone mass. Patients with heterozygous beta-thalassemia or beta-thalassemia trait may have mild anemia, and consequently mildly increased erythropoiesis. Whether modestly increased erythropoiesis might decrease bone mass is not well established. OBJECTIVE: To evaluate bone mineral density (BMD) in children and young adults with beta-thalassemia trait. METHODS: Thirty-one healthy young adults aged 20-45 yr and 26 healthy children aged 8-15 yr with beta-thalassemia trait were enrolled in the study. BMD was determined by dual X-ray absorptiometry (DEXA). Determinations of intact parathormone (PTH), 25-hydroxyvitamin D (25-OHD), and bone markers were performed. RESULTS: In adults, all had z-scores of BMD more than -2 above the mean. The mean z-scores of BMD of lumbar spine, radius and femoral neck were 0.11, -0.10 and 0.41, respectively. In children, only two of 26 had z-scores of lumbar spine BMD more than -2 below the mean. The mean z-scores of BMD of total body, lumbar spine, radius and femoral neck were 0.12, -0.28, 0.30 and -0.14, respectively. All subjects had normal PTH, 25-OHD and bone markers levels. CONCLUSION: beta-Thalassemia trait is not a contributing factor for osteopenia/osteoporosis in children and young adults.

Adolescent↗
PubMed1986

Alpha thalassemia British type (alpha alpha/--Brit) in an Australian family.

Alpha thalassemia is rarely diagnosed in Australian families of British or Northern European ancestry. In 1972, a third generation Australian was shown to have alpha thalassemia. In the absence of known Mediterranean or South East Asian ancestry it was reported as being the first example of alpha thalassemia in an Australian family. Further study of the proposita in 1985 using DNA mapping of the alpha globin gene complex, shows a distinctive molecular defect identical to the British type of alpha thalassemia. The latter is clearly different from the commonly encountered Mediterranean and South East Asian alpha zero haplotypes. Recognition that alpha zero thalassemia occurs in Australians is important since it may produce a microcytic hypochromic anemia. Its inheritance together with other forms of alpha thalassemia may lead to severe Hb H disease or Hb Bart's hydrops fetalis.

Adult↗