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PubMed1996

Influence of alpha-thalassemia trait on spleen function in sickle cell anemia patients with high HbF.

Spleen function was studied in a group of 20 Kuwaiti SS patients (aged 2-12 years), using 99mTc-labeled tin colloid scintigraphy. They were screened for the alpha-thalassemia determinants which are prevalent in the Arabian Peninsula [-alpha (3.7 kb) deletion, alpha2-globin gene polyadenylation signal (AATAAA => AATAAG) mutation, and 5' IVS-I splice junction pentanucleotide (GAGGTGAGG => GAGG) deletion] with a combination of polymerase chain reaction and allele-specific oligonucleotide (ASO) hybridization techniques. The patients were divided into three groups depending on the result of their colloid uptake. Group I consisted of 7 patients (35.0%) with normally visualized spleens, Group II consisted of 5 (25.0%) with partial visualization, and in Group III there were 8 (40.0%) in whom the spleen was not visualized at all. The significant distinguishing features among those in Groups I and III were mean corpuscular volumes (MCVs) of 74.1 +/- 5.1 and 90.1 +/- 6.6 fl (P<0.0001) and mean corpuscular hemoglobins (MCHs) of 22.4 +/- 2.7 and 27.5 +/- 4.0 pg (P<0.05), respectively. The overall frequency of alpha-thalassemia determinants in the study was 35.0%; however, the frequencies in Groups I, II, and III were 57.1, 30.0, and 18.8%, respectively. alpha-Thalassemia trait, therefore, appears to be associated with normal splenic function in these patients.

Age Factors↗
PubMed1996

Effect of alpha-thalassemia and beta-globin gene cluster haplotypes on the hematological and clinical features of sickle-cell anemia in Brazil.

To compare the features of sickle-cell anemia in Brazil with those in other locales, we studied the effects of the beta-globin-like gene cluster haplotype and alpha-thalassemia upon the clinical and hematological features in 85 patients. The distribution of haplotypes differed from that in the United States and Jamaica. The Central African Republic (CAR) haplotype predominated; 34% of patients were CAR haplotype homozygotes, 45% CAR/Benin homozygotes, and 11% Benin homozygotes. No Senegal haplotype chromosomes were observed. Alpha-thalassemia was present in 17.5% of patients. HbF levels were higher in Benin homozygotes, compared with the other two groups (P < 0.05). Nearly half the patients with a CAR haplotype had leg ulcers, compared to 12.5% of the Benin homozygote group; stroke did not occur in alpha-thalassemia carriers, but neither result was statistically significant. As in other studies, our results indicate that the CAR haplotype may be associated with more severe disease.

Adolescent↗
PubMed1997

beta-Thalassemia and hemoglobin types in Argentina: determination of most frequent mutations.

In order to know the spectrum of beta-thalassemia alleles and other mutations affecting the beta-globin gene, we analyzed the hemoglobin abnormalities in 24 patients from the Province of Cordoba in Argentina. Molecular screening of samples was performed by the polymerase chain reaction (PCR), using six sets of oligonucleotides to amplify fragments encompassing the whole beta-globin coding region and splice junctions, as well as the promoter and 3' untranslated regions. The altered fragments were determined by denaturing gradient gel electrophoresis (DGGE), and the corresponding mutations were identified by restriction enzyme analysis or by direct sequencing of PCR products. Using this approach, three different beta-thalassemia mutations were detected, codon 39 (C-->T), IVS-1-110 (G-->A), and IVS-1-1 (G-->A), and also the hemoglobin S trait. This is the first report of beta-thalassemia mutations described in Argentina. Our results show that these mutations are similar to those found in Spain and Italy, possibly due to the important Mediterranean migratory stream received in our country, and could be important for prenatal diagnosis of these diseases in Cordoba, Argentina.

Alleles↗
PubMed1997

Different hematological phenotypes caused by the interaction of triplicated alpha-globin genes and heterozygous beta-thalassemia.

The pathophysiology and clinical severity of beta-thalassemia are related to the degree of alpha/non-alpha-chain imbalance. A triplicated alpha-globin gene locus can exacerbate effects of excess alpha-chains caused by a defective beta-globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the alpha alpha alpha(anti-3.7) allele and a mutation in the beta-globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same beta-thalassemia mutation: in one family, two individuals had the same alpha- and beta-globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated alpha-globin gene, beta39- and delta+27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical alpha- and beta-globin genotypes. Interaction with a triplicated alpha-gene can play a role in the clinical presentation of patients with defective beta-globin gene expression and should be considered in the diagnosis of atypical cases.

Adult↗
PubMed1998

Evaluation of the BeTha gene 1 kit for the qualitative detection of the eight most common Mediterranean beta-thalassemia mutations.

We describe the evaluation of the Bio-Rad BeTha Gene 1 kit (Bio-Rad Laboratories, Hercules, CA), a DNA-probe assay designed for the qualitative determination of the eight most common Mediterranean beta-thalassemia mutations. The kit utilizes the principle of allele-specific oligonucleotide (ASO) hybridization. Following sample preparation and in vitro DNA amplification by the polymerase chain reaction (PCR), an allele-specific detection of the amplified products by a nonradioactive enzymatic assay is performed. Genomic DNA is prepared from an individual's whole blood with a DNA purification matrix. In a second step, the beta-globin gene is amplified in a multiplex PCR reaction containing four 5' biotinylated oligonucleotide primers. In a final step, an aliquot of the PCR reaction is first chemically denatured and then captured in two eight-well strips of a 96-well enzyme-linked immunosorbent assay (ELISA) plate by hybridization to an immobilized ASO probe. Each DNA sequence at each of the eight mutation sites is represented by one normal and one mutant ASO. During this capture/hybridization step, which is performed at 37 degrees C, only perfectly matched PCR products will be captured by an ASO. Subsequently, the allele-specific captured biotin-labeled PCR products are detected by a colorimetric enzymatic reaction. The system permits the detection of 16 beta-thalassemia alleles using a high-throughput format that can be automated easily. A clinical feasibility study was performed to evaluate the functionality (method comparison study, assay validity using samples previously collected and stored at various temperatures for different periods of time, interference on kit performance, and assay validity for prenatal diagnosis) and the usability (ease of use, sample throughput) of the kit. The analysis of 110 samples previously studied with reference methods showed 100% clinical sensitivity and specificity. We demonstrate here that the procedure not only increases the throughput of beta-thalassemia allele genotyping but also provides an accurate, rapid, reliable, and nonisotopic diagnostic tool.

Alleles↗
PubMed1999

A novel 105 basepair deletion causing beta(0)-thalassemia in members of a Thai family.

We identified and characterized a novel beta(0)-thalassemia mutation due to partial deletion of the 5' end beta-globin gene including the mRNA cap site and a part of exon 1. The deletion was precisely 105 basepair (bp) in length extending from position -24 or -25 to +80 or +81 relative to the beta-globin gene mRNA cap site. This mutation was detected in three individuals from a family originating in the area of southern Thailand. The propositus was a 39-year-old female and noted to be heterozygous for beta-thalassemia with hemoglobin (Hb) level of 10.1 g/dl, MCV 70 fl, MCH 23.1 pg, HbA2 6.3%, and HbF 2.4%. Her son was 9 years of age and was also heterozygous for the mutation, having Hb level of 10.8 g/dl, MCV 58 fl, MCH 19.0 pg, HbA2 5.6%, and HbF 4.3%. Her 6-year-old daughter was affected, having a genotype of this mutation and a G-C transition at IVS 1 nt 5. Although the deletion does not include the beta-globin gene promoter sequences, the individuals heterozygous for this mutation have an elevated HbA2 level slightly higher than observed in most carriers of beta-thalassemia caused by point mutations.

Adult↗
PubMed2000

Spectrum of beta thalassemia mutations and their linkage to beta-globin gene haplotypes in the Indo-Mauritians.

The beta thalassemia alleles in 53 thalassemic Indo-Mauritian patients and their families consisting of 23 homozygous beta-thalassemia, 9 HbE/beta-thalassemia, 18 HbS/beta-thalassemia, 1 HbD/beta-thalassemia, 1 deltabeta/beta-thalassemia and 1 HbH/beta-thalassemia from the island of Mauritius were studied. Characterization by polymerase chain reaction-based reverse dot blot hybridization technique revealed that the IVS1-5 (G-->C) mutation accounted for 74% of the beta thalassemic alleles, while six other mutations occurred at much lower frequencies: HbE codon 26 (G-->A); 10.4%, codon 8/9 (+G); 3.5%, codon 30 (AGG-->ACG) also called IVSI (-1).G-->C; 3.5%, codon 15 (G-->A); 3.5%, codon 41/42 (-CTTT); 2.4% and -28 (A-->G); 2.4%. Association of these mutations to specific beta globin gene sequence framework and haplotype allowed to trace their ancestral link. These data are useful in future molecular screening of the population in view of implementing a thalassemia prevention and control program in Mauritius.

Alleles↗
PubMed1996

Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses.

OBJECTIVE: To characterize the sonographic findings of alpha-thalassemia hydrops fetalis. METHODS: Descriptive study of the ultrasound findings in 100 women with antenatal diagnosis of hydrops fetalis due to alpha-thalassemia. RESULTS: Mean (+/- SD) maternal age was 27.5 + 5.7 years (17-41 years). Mean menstrual age was 31.3 +/- 4.7 weeks (22-42 weeks). All fetuses were stillborn or died very shortly after birth. The indications for sonographic examination included early onset of pre-eclampsia, large for date, decreased fetal movement and nonreactive NST, or bradycardia and premature contractions. The sonographic features found in more than 90% of cases included hepatosplenomegaly, cardiac enlargement, edematous placenta, and ascites. Other common findings were oligohydramnios (82%), subcutaneous edema (75%), decreased fetal movement (74%), cord edema (63%), and enlarged umbilical vessel (62%). Pericardial or pleural effusion was seen in only 15% of cases. None of the fetuses showed any morphological abnormality. Early findings (22-28 weeks) included evidence of a thickened placenta and/or minimal ascites and/or slight cardiomegaly. CONCLUSIONS: The sonographic characteristics of alpha-thalassemia hydrops fetalis ranged from no obvious morphological abnormalities to evidence of fluid retention. These typical abnormal findings generally did not appear until the late second trimester or early third trimester.

Adult↗
PubMed1999

Beta-thalassemia in the German population: mediterranean, Asian and novel mutations. Mutations in brief no.228. Online.

The beta-thalassemia mutations of 13 unrelated heterozygous Germans who remained unidentified in a previous study of 40 subjects were investigated at the DNA level. Two Mediterranean, one Asian and three novel mutations (CD6 -G, CDs 108 /112-12nt, CDs 130/131 + GCCT) were identified. Altogether, in 30 of the 35 subjects (86%) in which a mutation in the beta-globin gene was identified, the mutation was of Mediterranean origin. The geographical distribution suggests recent migration from the Mediterranean region as cause of the high proportion of frequent Mediterranean beta-thalassemia mutations in the German population. Our results support the notion that the majority of beta-thalassemia genes in the western and central European population are of Mediterranean origin.

DNA Mutational Analysis↗
PubMedDate not supplied

Induction of fetal hemoglobin synthesis with recombinant human erythropoietin in anemic patients with heterozygous beta-thalassemia during pregnancy.

OBJECTIVE: Recombinant human erythropoietin (rhEPO) increases fetal hemoglobin synthesis in nonpregnant thalassaemic patients. We used rhEPO in 4 pregnant patients with heterozygous beta-thalassemia and anemia to study its effect on erythropoiesis, F cell production, and HbF synthesis. METHODS: Patients were treated with a combination therapy of rhEPO and iron. The effect on HbF synthesis was assessed by the percentage of F reticulocytes, F cells, and total HbF, erythropietis by reticulocyte count, and hemoglobin measurements and iron status by ferritin levels, transferrin saturation, and percentage of hypochromic red cells. RESULTS: RhEPO caused an increase of F reticulocytes (1.5 to 10.5 fold), F cells (5.0 to 7.7 fold), and HbF (1.4 to 2.2 fold). All patients showed an increase of young, immature reticulocytes and had elevated reticulocytes at the end of therapy. Hemoglobin increased with a range from 0.3 to 1.5 g/dL. Transferrin saturation and ferritin levels were normal at the end of the study. There was an increase of the percentage of hypochromic red cells, indicating functional iron deficiency after rhEPO administration despite supplemental iron. CONCLUSIONS: RhEPO stimulates both HbF synthesis and erythropoiesis in pregnant patients with heterozygous beta-thalassemia and anemia. Since it is known that high HbF levels ameliorate thalassemia symptoms in nonpregnant patients, use of rhEPO for the treatment of severe anemia in thalassaemic patients during pregnancy might be further evaluated.

Adult↗
PubMed2002

Increased circulating activated endothelial cells, vascular endothelial growth factor, and tumor necrosis factor in thalassemia.

An increased number of circulating endothelial cells (CECs) was demonstrated in alpha- and beta-thalassemic patients, beta-thalassemia/hemoglobin E (BE), both splenectomized (BE[S]) and non-splenectomized (BE[NS]), had higher numbers of CECs than alpha-thalassemia, both HbH (alpha-thal l/alpha-thal 2; H) and HbH with hemoglobin Constant Spring (alpha-thal 1/CS; H/CS). CECs were also increased in heterozygous HbE (EA) and homozygous HbE (EE). The highest level of tumor necrosis factor-alpha (TNF-alpha) was found in HbH/CS patients, whereas the highest levels of vascular endothelial growth factor (VEGF) was observed in BE[S] patients. Significant decreases, in protein C and protein S levels were found in both alpha- and beta-thalassemia compared with normal. Good correlations between the numbers of CEC and TNF-alpha, VEGF, protein C, and protein S levels were demonstrated in this study. In addition, markers for endothelial cell activation and injury (intercellular adhesion molecule-1, ICAM-1/CD54; vascular cell adhesion molecule-1, VCAM-1/CD106; and E-selectin, ELAM-1/CD62E) were detected on the surface of isolated CECs using immunofluorescence technique. Appearance of CECs with markers for endothelial cell activation, together with increased levels of TNF-alpha and VEGF and decreased levels of protein C and protein S in the circulation, may account for the propensity of vascular perturbation in thalassemic subjects.

Adult↗
PubMed2002

Asymptomatic homozygous deletional beta(0)-thalassemia in an African individual.

Homozygosity or compound heterozygosity for beta(0)-thalassemia mutations most commonly results in a transfusion-dependent thalassemia major phenotype. In this report, we describe a 55-year-old male, from Guinea-Bissau, that had been asymptomatic and never transfused until being admitted to hospital with anemia, fever, splenomegaly, and asthenia. Following hospital admission, HIV-2 and Mycobacterium tuberculosis infections were diagnosed, and biochemical and molecular studies revealed homozygosity for beta(0)-thalassemia. At the molecular level, this is the first description of homozygosity for the beta(0)-Black 1,393-bp deletion. In this case, the complete absence of beta-globin gene expression seems to be compensated by an unusually high fetal globin gene expression (Hb F 96%). Beta-globin haplotyping results were compatible with the propositus being homozygous for the Black 2 haplotype and for the absence of the XmnI polymorphism at -158 of (G)gamma-globin gene (-/-). Co-inheritance of genetic factors usually associated with high Hb F levels was not detected. Otherwise, the propositus is a heterozygote for the alpha-globin gene 3.7-kb deletion that is a beneficial modulating factor but not sufficient to explain this extremely mild phenotype. This unusual genotype/phenotype association is discussed in terms of the mechanisms underlying hemoglobin switching during development.

Anemia↗
PubMed2003

Molecular spectrum of alpha-thalassemia in the Iranian population of Hormozgan: three novel point mutation defects.

We describe the molecular spectrum of alpha-thalassemia mutations in a population sample of newborns in the South-Iranian province of Hormozgan. Out of 660 randomly collected blood samples 218 (33%) had visibly elevated Hb Bart's. DNA was extracted from 78 samples out of this selection (n=156), of which 114 alleles were found to carry an alpha-thalassemia defect. Besides the common -alpha3.7 (79.1%), -alpha4.2 (1.7%), and alpha-5nt alpha alleles (4.3%), three novel nondeletional alpha-thalassemia mutations were found; the alpha2 cd19 (-G) frameshift mutation (12.2%), the alpha1 IVS1-148(A-->G) (0.9%) affecting the splice acceptor site consensus sequence and the cd14 (TGG-->TAG) (0.9%), which creates a premature stop codon in the first exon of the alpha1-gene. A fourth mutation in the alpha1-gene, the IVS1-38 (C-->T) (0.9%) of undetermined effect, was found in an individual heterozygous for the alpha2 cd19(-G) mutation.

Alleles↗
PubMed2003

Beta-thalassemia in association with a new delta-chain hemoglobin variant [delta116(g18)Arg-->Leu]: implications for carrier screening and prenatal diagnosis.

We describe a complicated genetic counseling and prenatal diagnostic case involving an East Indian couple that had lost two consecutive pregnancies. Hemoglobinopathy screening was conducted to investigate the possibility of Hb Bart's hydrops fetalis or Hb H hydrops fetalis. The initial work-up indicated that alpha-thalassemia was not a contributing factor, with both parents being carriers of single gene deletions (-alpha(3.7)/alphaalpha). However, the Hb electrophoresis results indicated that the couple might be at risk for having children with Hb E/Hb Lepore disease. Subsequent DNA testing demonstrated that the father carried the Hb E mutation, but failed to confirm that the mother carries the Hb Lepore deletion. Sequence analysis revealed that the mother was heterozygous for a common East Indian beta(0)-thalassemia mutation, yet had a normal level of Hb A(2). The mother also carried a previously unreported missense mutation of the delta-globin gene, in cis with the beta(0)-thalassemia mutation, which gave rise to the minor Hb variant originally misidentified as Hb Lepore. This case illustrates the importance of comprehensive molecular analyses for accurate assessment of genetic risks for hemoglobinopathy syndromes.

Abortion, Spontaneous↗
PubMed2004

Co-inheritance of Hb Pak Num Po, a novel alpha1 gene mutation, and alpha0 thalassemia associated with transfusion-dependent Hb H disease.

Hb H disease is generally associated with moderate to severe anemia but rarely requires regular blood transfusion. We recently studied two apparently unrelated patients with transfusion-dependent Hb H disease. Hemoglobin studies demonstrated Hb H and Hb Bart's without other detectable abnormal globin species. Extensive molecular analyses of the alpha globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for alpha0 thalassemia (--(SEA)) and a novel point mutation, a thymidine insertion after codon 131 of the alpha1 gene. The resulting frameshift gives rise to a highly unstable alpha globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual alpha1 globin variant clearly causes alpha thalassemia, but the unexpectedly severe phenotype suggests that this mutation may have additional effects on red cell physiology. A PCR-based (ARMS) assay was developed for rapid detection of this novel mutation, and this might be useful to study the prevalence of this novel mutation which poses potentially significant clinical consequences in populations of Southeast Asia. Detecting carriers of this mutation using the molecular diagnostic procedures described will provide the means to screen and prevent a potentially severe form of alpha thalassemia in Thailand.

Amino Acid Sequence↗
PubMed2001

Spectrum of beta-thalassemia in Jordan: identification of two novel mutations.

Two hundred and forty-four beta-thalassemia alleles were identified from 135 unrelated occasionally and periodically transfusion dependent beta- and S/beta-thalassemia patients from all regions of Jordan. Allele identification was achieved by PCR amplification of beta-globin genes, dot-blotting the amplified DNA, hybridization with allele specific synthetic probes, and direct sequencing of amplified genomic DNA. A total of 19 different mutations were detected, eight of them constituted about 86% of the Jordanian thalassemic chromosomes. These mutations were IVS1-110 (G>A) (25%), IVS2-1 (G>A) (15%), IVS2-745 (C>G) (14.2%), IVS1-1 (G>A) (10%), IVS1-6 (T>C) (8.3%), codon 37 (G>A) (6.3%), codon 39 (C>T) (4.6%), and codon 5 (-C) (3.8%). The remaining eleven mutations were rare, presented with frequencies ranging between 0.4% and 1.6%. These included two novel mutations and four others detected in Jordan for the first time. The novel mutations were the frame shift (-C) at codon 49 and the substitution (A>C) at position -29 in the TATA box. Four alleles (1.6%) remained unidentified; having no abnormalities in their beta-globin gene sequences and therefore, constituted additional defects causing beta-thalassemia in the Jordanian population. These unknown alleles are expected to be candidates for upstream or downstream mutations affecting the expression of beta-globin gene. The results provided the essential foundation for planning a national preventive program for thalassemia in Jordan and will help improving the medical services for the patients and their families by helping their clinicians and genetic counselors in evaluating their variants and designing their treatment regimens.

Alleles↗
PubMed2004

Plasma kinetics of a cholesterol-rich microemulsion in subjects with heterozygous beta-thalassemia.

Patients with beta-thalassemia trait have been reported to present lower plasma concentrations of low-density lipoprotein (LDL) and lower frequencies of acute myocardial infarction than normal subjects. In this study, the metabolism of LDL was tested in 12 patients with heterozygous beta-thalassemia trait (HBT) and 13 healthy subjects without the disease by determining the plasma kinetics of an artificially made cholesterol-rich microemulsion (LDE) that mimics the LDL metabolism and binds to LDL receptors. The emulsion was labeled with 14C-cholesterol ester and injected intravenously into the subjects. Blood samples were drawn at regular intervals over 24 hr to determine the plasma decay curve of the emulsion radioactive label and to estimate its plasma fractional clearance rate (FCR, in hr(-1)). FCR of the 14C-cholesterol ester was greater in HBT compared to controls (0.0631 +/- 0.0178 hr(-1) and 0.0501 +/- 0.0094 hr(-1), respectively; mean +/- SD, P = 0.022). No differences were found regarding LDL cholesterol plasma concentration between the two groups, but apolipoprotein B concentration was lower in HBT than in control subjects (80 +/- 44 and 96 +/- 14, respectively; mean +/- SD, P = 0.026). Our results show that LDE FCR is increased in HBT, indicating that LDL clearance is increased in patients with beta-thalassemia trait possibly due to the increased proliferation in the bone marrow of erythroid precursors.

Adult↗
PubMed2005

Compound heterozygote state for GgammaAgamma(deltabeta) degrees -thalassemia and hereditary persistence of fetal hemoglobin.

We report a hitherto undescribed interaction of a deletional (deltabeta) degrees -thalassemia and a deletional hereditary persistence of fetal hemoglobin (HPFH) in an adult Thai individual. He was a 40-year-old Thai male who had the following hematologic data: Hb 13.9 g/dL, Hct 43.8%, MCV 78.0 fL, MCH 24.7 pg, MCHC 31.6 g/dL, and RDW 17.1%. Hemoglobin analysis revealed 97% Hb F with Ggamma-globin chain predominant. Globin gene analyses demonstrated that he carried the GgammaAgamma(deltabeta) degrees -thalassemia deletion in trans to the HPFH-6. Hematologic data of the patient were compared to those of the heterozygotes for these high-Hb F determinants found in his parents and an unrelated Thai patient with a compound HPFH-6/deletion-inversion Ggamma(Agammadeltabeta) degrees -thalassemia previously described.

Adult↗