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PubMed1998

Prenatal and postnatal diagnoses of thalassemias and hemoglobinopathies by HPLC.

The conventional approach to qualitative and quantitative analyses of hemoglobin (Hb) molecules for the diagnoses of hemoglobinopathies requires a combination of tests. We used an automated HPLC (VARIANT) system to study alpha-thalassemia and beta-thalassemia syndromes in Thailand. The beta-thalassemia short program is applicable to the diagnosis of alpha-thalassemia and beta-thalassemia disorders, including Hb H, EA Bart's disease, and EF Bart's disease, in adults, newborns, and fetuses. The system cannot quantify accurately certain Hb molecules, such as Hb H and Hb Bart's. The alpha-thalassemia short program was therefore developed and used to quantify Hb Bart's to detect alpha-thalassemia genotypes in cord blood. This automated HPLC system is an alternative approach to the diagnosis of complicated thalassemia syndromes in Thailand and Southeast Asia.

Adult↗
PubMed1982

alpha-Thalassemia: prevalence and hematologic findings in American Blacks.

alpha-Thalassemia is common in southeast Asia and the Mediterranean, where the predominant lesion seems to be a deletion of one or more of the four gene loci responsible for alpha-globin chain production. In the United States, the prevalence of alpha-thalassemia in blacks was once thought to be low, but more recent studies show that the prevalence of alpha-thalassemia is high. We measured the globin chain synthetic rations in 144 black Americans to determine the prevalence and hematologic manifestations of alpha-thalassemia in this population. There were 120 subjects with a mean synthetic ration of 0.986 +/- 0.04, with a range of 0.90 to 1.06; these were classified as normal. Five subjects were found to have beta-thalassemia; 19 subjects had mild alpha-thalassemia. The overall gene frequency for alpha-thalassemia was estimated to be 0.07 in this population. The hemoglobin values of subjects with mild alpha-thalassemia were not statistically significantly different from normal black or white control subjects of the same sex, but there was a significant decrease in the mean corpuscular volume and in the mean corpuscular hemoglobin value.

Adult↗
PubMed1987

Clinical and molecular correlations in the sickle/beta+-thalassemia syndrome.

Sickle/beta thalassemia is a sickling disorder of varying severity which results from compound heterozygosity for sickle cell trait and beta-thalassemia trait. Clinical and genetic studies have shown an inverse correlation between the level of hemoglobin A and the severity of the disease. It has been suggested that the level of hemoglobin A may be a function of the severity of the beta-thalassemia defect. In this study, we use molecular biological techniques to test this hypothesis. We show that the interaction of the mildest of the beta+-thalassemia genes with the sickle gene results in a high level of hemoglobin A. However, the interaction in this case resulted in a severe sickling disorder in the absence of significant anemia. We hypothesize that a mild beta+-thalassemia gene may have two opposite effects on the clinical course of sickle/beta+ thalassemia: (1) A high level of hemoglobin A which probably confers a favorable antisickling effect and (2) decreased hemolysis leading to increased numbers of total circulating red cells, thereby increasing the blood viscosity and the propensity for sickling. The inheritance of heterozygous alpha thalassemia 2 in conjunction with the mild beta+-thalassemia gene and sickle gene in this patient may have further enhanced the latter effect and resulted in a severe sickling disorder.

Adult↗
PubMed1995

Genetic interactions in thalassemia intermedia: analysis of beta-mutations, alpha-genotype, gamma-promoters, and beta-LCR hypersensitive sites 2 and 4 in Italian patients.

In order to verify the genetic factors influencing the clinical expression of beta-thalassemia we have studied 292 Italian patients, 165 with thalassemia intermedia and 127 with thalassemia major. The beta-globin gene mutations were defined in all cases. The number of alpha-globin genes and the integrity of specific control regions of the beta-globin cluster--gamma promoters and beta-Locus Control Region (beta-LCR)--were studied in selected cases. Homozygosity for mild mutations (group I) accounts for 24% of the intermedia patients and it is not represented among major patients. Forty-four percent of intermedia patients had combinations of mild/severe (group II) mutations and 32% had homozygosity or double heterozygosity for severe mutations (group III). Seventy-six percent of patients with thalassemia major were classified in group III and 24% in group II. Deletion type-alpha3.7 thalassemia, assessed in a part of the cases, was found in 5% of thalassemia major and 19.5% of intermedia patients in groups II and III. Structural analysis of gamma promoters and beta-LCR HS2 and HS4 regions, carried out in order to look for alterations associated with Hb F increase, did not reveal new mutations. Only rare polymorphic changes were observed at the HS2 and HS4 level. The -158G gamma C T change was found with an increased incidence in intermedia patients in groups II and III. A subset of 10 beta-thalassemia heterozygotes with mild intermedia phenotype resulted from coinheritance of a triplicated alpha-locus. We have been unable to find a molecular basis for the benign clinical course in approximately 20% of patients with thalassemia intermedia. Other genetic or acquired factors must be hypothesized which ameliorate the clinical condition.

Adolescent↗
PubMed1999

Plasma chitotriosidase activity in patients with beta-thalassemia.

Chitotriosidase, a macrophage marker, which is extremely increased in plasma of Gaucher patients, was measured in patients with beta-thalassemia, an haematological disorder characterized by the genetic defect of beta-globin chains synthesis resulting in unproductive erythropoiesis and enormous expansion of the reticuloendothelial system. Plasma chitotriosidase was increased to a variable extent in 13 of 70 patients with beta-thalassemia major treated with the intense transfusion regimen and iron chelation therapy. It was normal in 22 and slightly elevated in 3 subjects with beta-thalassemia intermedia which were not transfused. The highest levels of plasma chitotriosidase, as high as in Gaucher patients, were found in 7 (10%) of the beta-thalassemia major patients which also had the highest degree of iron overload as judged by their serum ferritin level (> 3000 ng/ml), high SGPT level and elevated urinary iron excretion. To our knowledge, beta-thalassemia is hitherto the only disorder in which an increase of plasma chitotriosidase, comparable to that seen in Gaucher disease, may occur. The increase of plasma chitotriosidase activity in beta-thalassemia patients with high iron overload, could be related to an iron mediated damage to the lysosomal apparatus. In addition, similarly to Gaucher disease, the increased chitotriosidase production in beta-thalassemia might reflect macrophage activation probably related to the intracellular iron overload, storage of erythrocytes membrane break-down products and oxidation of excess alpha-hemoglobin subunits. Further studies are required to define the role of chitotriosidase evaluation to assess the efficacy of chelation therapy in reducing the macrophage activation due to intracellular iron overload in beta-thalassemia.

Adolescent↗
PubMed2003

Phenotype score to grade the severity of thalassemia intermedia.

OBJECTIVE: Thalassemia intermedia is an ill-defined group of thalassemia patients with severity in between thalassemia major and asymptomatic carriers. The severity of cases varies greatly. With availability of information about genetic modifiers of beta-thalassemia phenotype, attempts are being made to study genotype phenotype correlation in thalassemia intermedia. METHODS: The first important step in genotype, phenotype correlation is well-defined phenotypes. Severity of thalassemia intermedia can not be graded only on haemoglobin level and age of presentation. The authors have developed a phenotype scoring system to subclassify thalassemia intermedia patients into 3 groups, viz, mild, moderate and severe. RESULT: This phenotype scoring system appears to grade the severity correctly depending on various clinical features like age of presentation, severity of anaemia, growth retardation, bone marrow hyperplasia, need of blood transfusions and splenectomy. CONCLUSION: The classification of thalassemia intermedia will be useful for genotype phenotype correlation, to develop management guidelines for the subgroups and to try new treatment modalities like hydroxyurea, erythropoetin etc.

Adolescent↗
PubMed2002

PCR-based analysis of alpha-thalassemia in Southern Taiwan.

The Southeast Asia type deletion of alpha-thalassemia-1 (--SEA) is the most common type of alpha-thalassemia-1 in Taiwan. There are 2 less common types, Filipino type (--FIL) and Thai type (--THAI). In the current study, we screened 754 cases of alpha-thalassemia-1 in Southern Taiwan using a polymerase chain reaction (PCR)-based method. Our results show that the prevalence of the (--SEA) type is 90.6%, followed by the (--FIL) type (8.6%), the (--THAI) type (0.5%), and the (-alpha(3.7/-alpha(3.7)) type (0.3%). We also analyzed the genotypes of 96 patients with hemoglobin (Hb) H disease and 48 cases of hydrops fetalis with Hb Bart's. The frequencies of the genotypes of the alpha-thalassemia-1 allele in Hb H disease are in accordance with the results of analyses of alpha-thalassemia-1 cases. The alpha-thalassemia-2 allele includes alpha(4.2), alpha(G), alpha(CS), and alpha(QS)alpha. Forty-one cases, 6 cases, and 1 case of hydrops fetalis with Hb Bart's were caused by --SEA/--SEA, --SEA/--FIL and --SEA/--THAI respectively. The genotypes and frequencies of alpha-thalassemia in this study are different from those in previous studies in Taiwan and Hong Kong. These differences may be attributed to the diverse genetic origin among different ethnic groups and the extensive inclusion of the (--FIL) and (--THAI) alpha-thalassemia-1 types.

DNA Primers↗
PubMed1997

alpha-Thalassemia in The Netherlands: a heterogeneous spectrum of both deletions and point mutations.

In this article we describe the molecular characterization of 104 independent alpha-thalassemia patients identified by hematological analysis and family studies. During the study, another six chromosomes were identified with rearrangements of the alpha-cluster or point mutations in the alpha 2-globin gene, not associated with alpha-thalassemia, in healthy relatives of the patients. The molecular defects were established by Southern blot analysis and, if no deletions could be identified, the alpha-globin genes were investigated by denaturing gradient gel electrophoresis and single strand conformation analysis for the presence of point mutations. Following this strategy, we were able to identify the molecular basis of 131 independent alpha-thalassemia chromosomes. In two individuals, the alpha-thalassemia determinant could not be demonstrated at the molecular level. We identified eight different deletion and five non-deletion alpha-thalassemias, three rearrangements in the alpha-cluster, two alpha-chain variants, and a silent mutation in the alpha 2-globin gene not associated with alpha-thalassemia. The large heterogeneity of alpha-thalassemia mutations seen in the Dutch population might be typical for northern European countries where, besides the more common mutations introduced by migration, a variety of sporadic mutations was also found in the autochthonous population. The screening strategy as described here, capable of identifying a wide spectrum of both deletions and point mutations, identified 98% of the alpha-thalassemia determinants present in 133 chromosomes.

Blotting, Southern↗
PubMed1989

Molecular genetics of alpha thalassemia.

Linked duplicate genes in Chromosome 16 condition the production not only of alpha-globin chains in the Hemoglobin A (HbA) molecule, but also of the varied forms of alpha thalassemia in human subjects. Null allelism, not gene deletion, exists at these gene loci. Two codominant alleles occur at each locus; these are characterized as Gb and Ob at one locus, and as Gc and Oc at the second locus. Gb and Gc are genetically active alleles, and either conditions the production of alpha-globin chain. Ob and Oc are null or genetically inert alleles, and neither conditions the production of alpha-globin chain. Gb and Gc are additive in the expression of disease genotype. The number of alpha-globin chains in the HbA molecule, and the absence as well as the varied forms of alpha thalassemia are inherited quantitatively as follows: four alpha-globin chains and the absence of alpha thalassemia result from GbGbGcGc; either GbGbGcOc or GbObGcGc yields three alpha-globin chains and asymptomatic alpha thalassemia minor; any one of three genotypes, GbGbOcOc, GbObGcOc or ObObGcGc, yields two alpha-globin chains and mild alpha thalassemia minor; either GbObOcOc or ObObGcOc yields one alpha-globin chain and severe alpha thalassemia minor; ObObOcOc produces no alpha-globin chain and the fetal alpha thalassemia major. The inheritance of any combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects.

Alleles↗
PubMed2006

Thalassemia intermedia: revisited.

Thalassemia intermedia encompasses a wide clinical spectrum of beta-thalassemia phenotypes. Some thalassemia intermedia patients are asymptomatic until adult life, whereas others are symptomatic from as young as 2 years of age. A number of clinical complications commonly associated with thalassemia intermedia are rarely seen in thalassemia major, including extramedullary hematopoiesis, leg ulcers, gallstones and thrombophilia. Prevention of these complications, possibly with blood transfusion therapy, is ideal since they may be difficult to manage. Currently, many patients with thalassemia intermedia receive only occasional or no transfusions, since they are able to maintain hemoglobin levels between 7-9 g/dl; the risk of iron overload, necessitating adequate chelation therapy, is also a contributing factor. At present, there are no clear guidelines for initiating and maintaining transfusions in thalassemia intermedia for the prevention or treatment of complications. Here, we review the major clinical complications in thalassemia intermedia and suggest some therapeutic strategies based on retrospective clinical observations.

Blood Transfusion↗
PubMed2000

New trends in the treatment of beta-thalassemia.

Thalassemia is the world's most common hereditary disease, and is a paradigm of monogenic genetic diseases. Because of increased population mobility, the disease is found today throughout the world, even in places far from the tropical areas in which it arose. Therapy of thalassemia has in the past been confined to transfusion and chelation. Recently, novel modes of therapy have been developed for thalassemia, based on the pathophysiology and molecular pathology of the disease, both of which have been extensively studied. This review will discuss the therapeutic modalities currently in use for the supportive treatment of thalassemia, both those that are standard therapy and those that are in clinical trials. We will include transfusion, chelation (intravenous and oral), antioxidants and various inducers of fetal hemoglobin (hydroxyurea, erythropoietin, butyrates, hemin). Most of the newer therapies are suitable primarily for thalassemia intermedia patients. In addition, the treatment modalities currently in use for the curative treatment of thalassemia major will be discussed, including bone marrow transplantation in its various forms. Experimental therapeutic methods, such as intrauterine bone marrow transplantation and gene therapy, are included. Physicians caring for thalassemia patients have an increasing variety of treatment options available. Future clinical studies will determine the place of newer agents and modalities in improving the quality of life as well as the life expectancy of thalassemia patients.

Humans↗
PubMed2003

Distribution and frequency of beta-thalassemia mutations in northwestern and central Greece.

OBJECTIVES: Beta-Thalassemia is a common autosomal recessive disorder resulting from over 200 different mutations of the beta-globin genes. The spectrum of beta-thalassemia mutations in Greece has been previously described in the population of the capital city of Athens, or in beta-thalassemia patients having transfusion therapy. The aim of the present study was to identify the distribution of the most common beta-thalassemia mutations in the population of northwestern and central Greece. METHODS: The data for this study were derived from a total of 1,130 unrelated subjects including 46 beta-thalassemia major, three beta -thalassemia intermedia and 1,081 carriers identified in our antenatal screening program. beta-Thalassemia mutations were identified by ARMS, DGGE and Reverse Dot Blot. RESULTS: The most common mutation, IVS-I-110, is followed, in order of frequency, by the mutations Cd-39, IVS-I-1, IVS-II-1, Cd-6, IVS-I-6, IVS-I-5, IVS-II-745, Cd-5 and 44 bp del. IVS-I-110 and Cd-39 frequencies are similar with those found in other Balkan countries. Significant differences in regional distribution were observed. The results showed a clear drift of the distribution of the most frequent IVS-I-110 mutation in the south-north (29.4, 40.0, 44.6 and 61.7%) and the east-west axis (31.8 and 44.6%). CONCLUSIONS: Population screening and prenatal diagnosis are significantly facilitated by these data. Furthermore, the detailed distribution tables of beta-thalassemia mutations are essential for counseling and extraction of genetic diversity estimates for population genetic studies in other inherited disorders.

DNA Mutational Analysis↗
PubMed2004

Beta-thalassemia minor during pregnancy.

OBJECTIVE: To investigate pregnancy outcome of patients with beta-thalassemia minor. METHODS: A population-based study comparing all pregnancies of women with and without beta-thalassemia minor was conducted. Deliveries occurred during the years 1988-2002 at Soroka University Medical Center. A multivariate logistic regression model, with backward elimination, was constructed to find independent risk factors associated with maternal beta-thalassemia minor. RESULTS: During the study period there were 159,195 deliveries, of which 261 (0.2%) occurred in patients with beta-thalassemia minor. The following conditions were significantly associated with beta-thalassemia minor: oligohydramnios (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.2%, 3.7%), intrauterine growth restriction (IUGR; OR 2.4; 95% CI 1.4%, 4.2%), Jewish ethnicity (OR 1.5; 95% CI 1.2%, 1.9%), and previous cesarean delivery (OR 1.4; 95% CI 1.1%, 2.0%). No significant differences were noted between the groups regarding perinatal outcomes such as birth weight, low Apgar scores, congenital malformations, or perinatal mortality. Patients with beta-thalassemia minor were more likely to have cesarean deliveries than were the nonthalassemic parturients (16.9% and 12.2%, respectively; P =.021). However, while controlling for possible confounders such as IUGR, oligohydramnios, and previous cesarean delivery, with another multivariate analysis with cesarean delivery as the outcome variable, beta-thalassemia minor was not found as an independent risk factor for cesarean delivery (OR 1.3; 95% CI 0.9%, 1.9%). CONCLUSION: The course of pregnancy of patients with thalassemia minor, including perinatal outcomes, is favorable. Because higher rates of IUGR were found, we recommend ultrasound surveillance of fetal weight for early detection of IUGR. LEVEL OF EVIDENCE: II-2

Adult↗
PubMed1995

Detection of alpha-thalassemia-1 (Southeast Asian type) and its application for prenatal diagnosis.

A simple non-radioactive method based on the polymerase chain reaction was used to detect the Southeast Asian type of alpha-thalassemia 1 (--). Three oligonucleotide primers, one of which was adjacent to the breakpoint of the alpha-thalassemia-1 allele, were used to amplify the 570 and 194 bp DNA fragments. The 570 bp product was specific to the alpha-thalassemia-1 determinant and the 194 bp fragment was amplified from either the alpha-thalassemia-2 (-alpha) or normal alpha-globin (alpha alpha) determinants. In Hb Bart's hydrops fetalis (--/--), only the 570 bp fragment was obtained, whereas the 194 bp fragment was amplified in normal individual (alpha alpha/alpha alpha) and alpha-thalassemia-2 trait (-alpha/alpha alpha). Both 570 and 194 bp fragments were detected in alpha-thalassemia-1 trait (--/alpha alpha) and Hb H patients (--/-alpha). This procedure is useful for the rapid screening of alpha-thalassemia-1 trait and prenatal diagnosis of Hb Bart's hydrops fetalis in populations with a high frequency of the Southeast Asian Type of alpha-thalassemia-1.

Asia, Southeastern↗
PubMed2000

Premarital screening of beta-thalassemia trait in the province of Denizli, Turkey.

A premarital screening program aiming at reducing the incidence of thalassemia major was started under the auspices of the Regional Health Administration in 1995 in the city of Denizli in the Aegean region of Turkey. In this report we assessed the 4-year results of the screening program. All couples who applied for marriage procedures were screened for beta-thalassemia trait by automatic red cell indices and Hb A(2) determination. The couples at risk were counseled and offered prenatal diagnosis and termination of pregnancy in case of an affected fetus. From October 1995 to August 1999, a total of 19,804 subjects (9,902 couples) were recruited for this study. The prevalence of beta-thalassemia trait with increased Hb A(2) was found to be 2.6% (514/19,804). In addition to the thalassemia trait, 22 patients (0.11%) had sickle trait. In 15 of the 9,902 couples, both partners were found to be carriers of the beta-thalassemia trait. After genetic counseling, 2 of the 15 planned carrier marriages were canceled. Seven couples declared that they do not want to have a child at present. Prenatal diagnosis was sought by 6 couples. One fetus was found to be normal, 4 had thalassemia minor and 1 had thalassemia major; this pregnancy was terminated by elective abortion. This study indicated that premarital screening is a very useful tool for detecting carrier couples and an effective way of controlling thalassemia major.

Abortion, Induced↗
PubMed2004

Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules.

The most common single genetic disorder and a major public health issue in Greece and other Mediterranean countries is beta-thalassemia. Current therapeutic approaches for homozygous beta-thalassemia entail blood transfusions and iron chelation therapy with deferoxamine or deferiprone for preventing tissue hemosiderosis. Recently, much effort has focused on various inducers of fetal hemoglobin (HbF) such as recombinant human erythropoietin (rHuEPO), especially in beta-thalassemia intermedia. Ten adult patients, 5 with beta-thalassemia major and 5 with beta-thalassemia intermedia, received 150 IU/kg rHuEPO (epoetin-alpha) subcutaneously three times a week. Seven patients were transfused every 14-30 days and 3 with beta-thalassemia intermedia were only occasionally transfused. The minimum duration of treatment was 12 weeks in order to define if there was any response. Transfusion intervals were modified according to the rHuEPO response to maintain stable Hb values. Lower transfusion requirements were observed in 5 patients after rHuEPO treatment (p = 0.028). In the 3 non-transfused patients, Hb values increased, and the patients are still being treated and followed up for a period ranging from 14 weeks to 2 years. Two patients with thalassemia major discontinued treatment after 12 weeks, as they did not achieve any response regarding transfusion requirements or Hb values. Pretreatment serum transferrin receptor levels were higher than in controls (p < 0.001) and significantly increased following rHuEPO treatment (p = 0.027). Patients had higher serum endothelin-3, sICAM-1 and sE-selectin values before rHuEPO treatment compared to controls (p < 0.001, p < 0.001 and p = 0.016, respectively), but these values were not altered during treatment. HbF values presented a slight, non-significant increase. rHuEPO treatment has a beneficial effect in transfusion-dependent beta-thalassemia patients. Although a slight increase in HbF levels was observed, other possible mechanisms are probably involved. None of our patients experienced thrombotic complications and a rise in blood pressure.

Adolescent↗
PubMed2005

Molecular heterogeneity of beta-thalassemia in the United Arab Emirates.

The beta-thalassemia alleles in 313 national patients of the United Arab Emirates (UAE) have been characterized using PCR-based DNA-diagnostic techniques including DNA sequencing. A total of 212 patients had homozygous beta-thalassemia and the remaining 101 were compound heterozygotes. More than half of the patients were homozygous for the IVS-I-5 (G-->C) mutation followed by the sickle cell gene. The latter accounted for 25% of the chromosomes. In terms of frequency, five beta-thalassemia mutations; IVS-I-5 (G-->C), betaS, -25 bp del, Cd 8/9 (+G) and IVS-II-1 (G-->A) accounted for 83% of the alleles. In addition, 427 expatriate patients were studied: 256 with homozygous beta-thalassemia and 171 were compound heterozygotes. In both the UAE nationals and expatriates, the beta-thalassemia mutations and their frequency followed a similar trend. Our results indicate that the frequency of beta-globin gene defects including beta-thalassemia, sickle cell gene (betaS) and abnormal hemoglobins is significantly increased and poses a major public health problem in the UAE. The number of homozygous patients strongly suggests a high degree of consanguinity among the UAE nationals. With 50 different beta-thalassemia alleles, UAE is arguably the most heterogeneous population in the world. The diversity of these mutations reflects the historical admixture of genes and their migration from different areas in the region. Our data strongly suggest the need for a comprehensive thalassemia control program and provides a basis for population screening, genetic counseling and prenatal diagnosis.

DNA Mutational Analysis↗
PubMed1980

beta+ -Thalassemia intermedia. Genetic and biochemical study of a family including 3 cases.

3 cases of thalassemia intermedia have been found in the same family. The parents are not consanguineous but both come from the same town of Calabria (Italia). The mother is a heterozygote for beta-thalassemia, as well as the father whose globin chain synthesis is nevertheless balanced, thus suggesting an association with alpha-thalassemia. This hypothesis is confirmed by the fact that one of the offspring shows the typical characteristics of alpha-thalassemia heterozygosity. The 3 subjects with thalassemia intermedia are synthesizing the beta-globin chain in a proportion higher than that expected from the level of Hb A in peripheral blood. In 2 of them, the globin chain biosynthetic ratio measured in the blood reticulocytes is not significantly different from that usually observed in thalassemia major of either the beta o or beta+ type. In the third subject the globin chain synthesis is slightly less unbalanced probably because an alpha-thalassemia is also present. This suggests that factors other than a lesser imbalance in globin chain synthesis are involved in the occurrence of thalassemia intermedia. One of these factors could be a better survival of cells richer in Hb F than in Hb A, since these cells must have a lesser excess of alpha-chains.

Adolescent↗