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PubMedDate not supplied

The history of beta-thalassemia in Turkey.

The first two patients with beta-thalassemia major in Turkey, were reported in 1941. However, the importance of beta-thalassemia as a health problem was brought to the attention of physicians only after 1950. In Turkey, the clinical and hematological pictures of beta thalassemia were found to be mostly heterogenous. Hematological data of patients with mild disease (beta-thalassemia intermedia) severe beta-thalassemia (beta-thalassemia major) and heterozygotes indicate that patients can be grouped according to the content of Hb F, Hb A2 and red cell indices.

Humans↗
PubMed1990

The molecular basis of beta-thalassemia in Thailand: application to prenatal diagnosis.

To enable the prenatal diagnosis of beta-thalassemia by direct detection of the mutant beta-globin genes, we have determined the spectrum of mutations causing this disease in Thailand. The techniques employed included a combination of synthetic oligonucleotide probe hybridization, direct sequencing of genomic DNA enzymatically amplified by the polymerase chain reaction, and cloning and sequencing of the beta-globin genes. A total of 116 beta-thalassemia genes from 78 Hb E/beta-thalassemia patients and from 19 homozygous beta-thalassemia patients were analyzed, and the mutation was characterized in 112/116 (97%) of them. Eleven mutations were found, of which four (-CTTT in codon 41/42, AAG----TAG in codon 17, C----T in position 654 of the IVS-2 region, and A----G in position -28 upstream of the beta-globin gene) accounted for 83%; two previously undescribed mutations have been identified. The spectrum of beta-thalassemia mutations is similar to that reported among the Chinese. However, within the Thai population itself, patients with homozygous beta-thalassemia show a wider spread of mutations in comparison with the Hb E/beta-thalassemia group, in whom the frameshift 41/42 mutation predominates at a frequency of 62%. This difference in distribution may reflect the difference in ethnic origin of the two groups. Characterization of these mutations should aid the planning of a prenatal diagnosis program for beta-thalassemia in Thailand.

Base Sequence↗
PubMed1989

Decreased erythrocyte phosphoribosylpyrophosphate synthetase activity and impaired formation in thalassemia minor: a mechanism for decreased adenine nucleotide content.

Adenosine triphosphate (ATP) and adenosine diphosphate levels are decreased in erythrocytes from individuals with beta-thalassemia minor. Because 5-phosphoribosyl-1-pyrophosphate (PRPP) is an essential precurosr of adenine nucleotides, we tested the hypothesis that impaired PRPP synthesis is a mechanism for the decreased adenine nucleotide content. Erythrocyte PRPP synthetase activity was significantly decreased, and the Michaelis-Menten constant (Km) for ribose-5-phosphate (R5P) was significantly increased in individuals with alpha-thalassemia minor and those with beta-thalassemia minor. Intact erythrocytes from individuals with alpha-thalassemia and those with beta-thalassemia minor also had an impaired rate of PRPP formation. Both the decrease in PRPP synthetase activity and the impaired PRPP formation were also found in erythrocytes with microcytosis resulting from iron deficiency, indicating that these phenomena may not be specific to thalassemia minor. In all individuals examined, the rate of PRPP formation correlated with ATP content, suggesting that either (1) PRPP synthetase activity is a determinant of ATP content or (2) ATP content is a determinant of PRPP synthetase activity. The depletion of ATP from normal erythrocytes did not affect PRPP synthetase activity, suggesting that ATP content is not a determinant of PRPP synthetase activity. However, a decrease in PRPP synthetase activity did cause an impairment in the rate of adenine nucleotide synthesis, suggesting that PRPP synthetase activity is a determinant of ATP content. Taken together, our results suggest that the decrease in PRPP synthetase activity and the resulting impairment in the rate of PRPP formation are mechanisms for the decreased adenine nucleotide content in thalassemic erythrocytes.

Adenine Nucleotides↗
PubMed1989

Structural analysis of the alpha-globin gene cluster in two Chinese families with alpha-thalassemias.

The inheritance of alpha-thalassemia is determined by restriction endonuclease mapping in the members of two Chinese families with history of Hb H disease. One family carries the South East Asia (SEA) deletion in alpha-thalassemia-1 determinant and the nondeletion mutation in alpha-thalassemia-2 determinant. The other family carries the SEA deletion in alpha-thalassemia-1 determinant and the leftward deletion in alpha-thalassemia-2 determinant. Direct analysis of the genetic defects by gene mapping technique is the most reliable method for detecting minor forms of alpha-thalassemia and provides valuable information for genetic conseling in affected families.

Asian People↗
PubMed1988

[Screening for alpha-thalassemia using DNA analysis].

alpha-thalassemia was sought by gene mapping in 258 subjects selected on the basis of origin (25%), microcytosis (7%), or origin and microcytosis combined (64%). Abnormal fragments (Xba I/probe alpha) were found in 58 cases (22.5%). Using other restriction enzymes it was possible to determine the genotype alpha-/aa in 39 patients and the genotype alpha-/alpha- in 13 patients; 2 patients also exhibited hemoglobin H (alpha-/--) disease. alpha triplication anti-3.7 kb was found in 2 subjects and zeta-thalassemia in 2 other samples. 57 out of 58 patients originated from the thalassemia belt or from Africa. alpha-thalassemia is the most frequent hemoglobinopathy (21% of patients at risk) and hematologically is characterized by microcytosis. The Hb A2 level is decreased only in the alpha-/-- form of the disease. The main advantage of diagnosing zeta-thalassemias and alpha triplications lies in the possible clinical implications in the event of association with other hemoglobinopathies or beta-thalassemia.

Diagnosis, Differential↗
PubMed1988

Frequency of deletional types of alpha-thalassemia in Kampuchea.

The frequency of deletional types of alpha-thalassemias in the Khmer population of Kampuchea (Cambodia) was estimated using DNA techniques. Among 58 healthy adult Kampucheans from rural areas, 17 had alpha-globin gene anomalies. There were 14 heterozygotes and two homozygotes for alpha(+)-thalassemia; the remaining test subject carried a deletion of both alpha-globin genes (alpha(0) -thalassemia of the Southeast Asian type) on one chromosome 16, and triple alpha-globin genes on the other. All of the 18 alpha(+)-thalassemia deletions were of the -alpha 3.7 type (17 subtype I, 1 subtype II). The restriction pattern obtained with the enzyme RsaI and comparison of the intensity of hybridization with alpha-globin and beta-globin gene probes yielded no evidence of total deletion of the alpha-gene complex. The prevalence of deletional alpha(+)-thalassemia in Kampuchea is higher, and that of alpha(0)-thalassemia is lower than in neighbouring Thailand.

Blotting, Southern↗
PubMed1988

Delineation of specific beta-thalassemia mutations in high-risk areas of Italy: a prerequisite for prenatal diagnosis.

In this study, we defined by haplotype characterization combined with oligonucleotide hybridization or direct restriction endonuclease analysis the specific beta-thalassemia mutations in a representative sample of beta-thalassemia chromosomes from patients with homozygous beta-thalassemia originating from different parts of Italy. We characterized the mutations in 90% of the thalassemia chromosomes and found that three mutations, namely the beta(+)IVS 1-110, beta (0)-39 and beta(+)IVS 1-6 are prevalent in the Italian population. Most of the patients investigated were compound heterozygotes for two beta-thalassemia mutations, and only a few were homozygotes for one mutant. On the basis of these findings, we predict that prenatal diagnosis in this population would be feasible in most cases by fetal DNA analysis with the oligonucleotide method using a limited number of oligonucleotide probes selected after screening parents for the most common beta-thalassemia mutations. We have also devised a method based on hybridization with a mixture of two oligonucleotides that allows rapid and simultaneous screening of prospective parents for the two most frequent mutations in Italians, the beta(+)IVS 1-110 and beta(0)-39 mutants. This method may be applicable to prenatal diagnosis in cases at risk for the genetic compound of these mutations.

DNA Mutational Analysis↗
PubMed1988

Antenatal screening for thalassemia minor.

This report describes the findings of a screening program of 918 obstetric patients for thalassemia minor. Patients with erythrocyte mean corpuscular volume (MCV) less than 80 fL on initial complete blood count were evaluated with serum iron, total iron binding capacity, quantitative hemoglobin electrophoresis, and trial of iron replacement. A diagnosis of thalassemia minor was made when microcytosis persisted after exclusion of iron deficiency or other causes of erythrocyte microcytosis. Twenty-six women (2.8% of those screened) had an initial MCV less than 80 fL. Three cases of previously unsuspected thalassemia minor were detected (one alpha-thalassemia, two beta-thalassemia). Of 17 well-documented cases of iron deficiency, 16 had a hemoglobin level above 11 g/dL on initial complete blood count and would not have been otherwise detected until much later in gestation. A simple screening program can effectively identify pregnant women with unrecognized thalassemia minor and can also detect patients with iron deficiency before they become anemic.

Blood Cell Count↗
PubMed1988

Indications and results for splenectomy for beta thalassemia in two hundred and twenty-one pediatric patients.

To determine the advantages and complications of splenectomy in the treatment of beta thalassemia, 221 splenectomies for thalassemia performed upon pediatric patients from 1971 to 1982 are evaluated. There were 125 boys and 96 girls with a mean age of 8.2 +/- 2.5 years at the time of the operation. Sixty-one other patients who underwent splenectomy for other diseases served as the controls. Early and late complications after splenectomy are considered with a follow-up study of ten years. Hemoglobin (Hb) value, transfusional quotients and mean of transfused blood previous to surgical treatment are matched with the same parameters evaluated during the follow-up period. The effect of treatment with salicylates and dipyridamole upon the incidence of early complications after operation is analyzed. The postoperative complications in patients with thalassemia were 43.4 versus 3.2 per cent (p less than 0.01) registered in control patients. Late complications occurred with an incidence of 10.7 per cent and were due principally to sepsis. Six patients died of sepsis during the follow-up period, but the mortality rate for sepsis in the patients we studied was significantly lower than that reported by others in 73 instances of splenectomy for beta thalassemia. Blood consumption dropped from 270 +/- 99 to 155 +/- 31 milliliters per kilogram per year postoperatively (p less than 0.01) and Hb levels rose from 9.7 +/- 1.3 to 11.2 +/- 0.7 grams per milliliter. These results suggest that, even though splenectomy for beta thalassemia causes a relevant incidence of complications and fatalities, surgical treatment permits an improvement in the quality of the lives of patients with beta thalassemia and significantly reduces blood consumption. Prophylactic antibiotic therapy can reduce the incidence of sepsis, as was observed in the patients we studied.

Aspirin↗
PubMed1988

Delineation of the molecular basis of delta- and normal HbA2 beta-thalassemia.

In this study, we used cloning and sequence analysis to define the molecular defect in two delta-thalassemia genes, one associated with reduced output of delta-globin chains (delta +thal) from a Sardinian and the other with a complete suppression of delta-chain production from the affected locus (delta zerp thal) from a Southern Italian. Sequence analysis of the delta +thal gene showed a G----T substitution at the first nucleotide of codon 27 (delta +27) which produces an amino acid change (Ala----Ser) and presumably activates a cryptic splice site located at this position. Therefore, only a fraction of the transcript is processed from this site, as indicated by the clinical phenotype of delta +thal. DNA sequencing of the delta zero thal gene revealed a T----C substitution at position 1 of IVS-1, which abolishes the splicing at this site and thus leads to complete deficiency of normal mRNA explaining the clinical phenotype of delta zero thal. Oligonucleotide analysis was used to confirm the coinheritance of the delta +27 mutation in a group of Sardinians with thalassemia like phenotype and normal HbA2 level who, on the basis of genetic criteria, were supposed to be double heterozygous for delta-thalassemia and beta-thalassemia. The definition of delta-thalassemia defects in each high-risk area facilitates identification of double heterozygotes for delta- and beta-thalassemia by DNA analysis and may thus improve genetic counseling.

Base Sequence↗
PubMed1986

[Osteoarticular manifestations of thalassemia].

Thalassemia is a genetic illness which exists every where in the world. In Black Africa, intermediary thalassemia and beta-thalassemia minor are mainly observed. The osteoarthropatic signs are caused by erythroid hyperplasia and overload iron. We mention the roentgenographic skeletal survey of intermediary thalassemia and other less frequent bone abnormalities. We analyse the publications concerning osteoarticular manifestations in beta-thalassemia minor. We report a clinical and anatomical case of intermediary thalassemia with gout complications.

Adult↗
PubMed1983

Phenotypic effect of heterozygous alpha and beta 0-thalassemia interaction.

In this study, we carried out restriction endonuclease mapping in order to characterize the alpha-globin genotype of 10 Sardinian beta 0-thalassemia heterozygotes, all of whom presented with normal red blood cell indices and increased HbA2 levels. In 8 of these subjects, we found the deletion of two alpha-globin genes (-alpha/-alpha), and in the remaining two the deletion of a single alpha-globin gene (-alpha/alpha alpha). In three of these carriers with the (-alpha/-alpha) alpha-globin genotype and in one with the (-alpha/alpha alpha) genotype, we also found the glucose-6-phosphate dehydrogenase (G6PD) defect of the Mediterranean type. On the basis of these findings, we may conclude that the interaction of heterozygous beta 0-thalassemia with alpha-thalassemia, due to the deletion of either one or two alpha-globin genes, may lead to the production of red blood cells with normal indices. The association of the G6PD defect with this thalassemia gene complex may eventually contribute to this effect. We suggest, therefore, that screening programs for heterozygous beta-thalassemia in populations where alpha-thalassemia is also prevalent, should incorporate the determination of HbA2 in the first set of tests.

DNA↗
PubMed1983

Delta +-thalassemia in Sardinia.

We have defined a new type of delta-thalassemia in which beta-globin chain synthesis is incompletely suppressed. Homozygotes have unusually low HbA2 levels, and double heterozygosity for this delta-thalassemia gene and beta-thalassemia normalizes the HbA2 level. The delta-thalassemia occurs on a chromosome that is identifiable using polymorphic restriction endonuclease sites. We call this condition delta +-thalassemia, to distinguish it from the previously described delta 0-thalassemia syndromes in which no delta-globin chain synthesis occurs.

Chromosome Mapping↗
PubMed1983

A family with segregating triplicated alpha globin loci and beta thalassemia.

In this article we report a Sardinian family, in which a beta-thalassemia gene and a triple alpha-globin loci, counterpart of the rightward deletion type alpha-thalassemia-2, were segregating. The analysis of the genotype-phenotype correlations in the different family members allowed us to give an outline of the manifestations associated with different genotype combinations. The heterozygote for the triple alpha-loci showed no consistent abnormal clinical or hematologic characteristics and presented balanced alpha/beta-globin chain synthesis. In the homozygous state for this lesion, the only phenotypic expression was a slightly imbalanced globin chain synthesis. The combination of heterozygous beta-thalassemia with the heterozygous state for the triple alpha-globin loci produced no clinical manifestations and showed a hematologic phenotype indistinguishable from that of heterozygous beta-thalassemia. On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.

Adult↗
PubMed1984

Dyserythropoiesis in iron deficiency and in beta-thalassemia.

Nuclear and cytoplasmic abnormalities were quantitated in bone marrow erythroblasts from 15 patients with iron deficient anemia, 5 beta-thalassemia homozygotes, 5 beta-thalassemia heterozygotes, 6 S/beta-thalassemia double heterozygotes and 9 controls. The frequency of dyserythropoietic changes in iron deficiency was 11.90 +/- 5.02% (mean +/- SD) which is significantly higher than 3.36 +/- 1.16% obtained for the control group. The degree of dyserythropoiesis was negatively correlated with hemoglobin level (rS = 0.757). The frequency of dyserythropoietic changes obtained for the beta-thalassemia heterozygotes (5.23 +/- 1.45%) and for S/beta-thalassemia (7.13 +/- 2.00%) was elevated compared with the controls (P less than 0.05 and P less than 0.01, respectively). The highest frequency of dyserythropoiesis (19.88 +/- 7.40%) occurred among beta-thalassemia homozygotes. In all cases studied the abnormalities were observed mainly in the late erythroblasts. In addition, a peculiar cytoplasmic inclusion was observed in Leishman-stained bone marrow or peripheral blood erythroblasts from beta-thalassemia homozygotes, which is probably the result of precipitation of excess alpha-chain. This abnormality of thalassemia erythroblasts in Leishman-stained smears had not been previously reported.

Anemia, Hypochromic↗
PubMed1978

Laboratory detection of thalassemia.

The thalassemias are a heterogeneous group of genetically determined disorders of hemoglobin synthesis and can be divided into alpha-thalassemias and beta-thalassemias. The genes for these disorders are carried as relatively harmless traits which can be detected in the laboratory by a series of tests. As there are several variant genes in each group, heterozygotes for two slightly different genes occur, and interaction of these thalassemia genes with the hemoglobinopathies is quite common. Severe clinical disease usually only occurs in homozygotes, as in Cooley's anemia. The problem for the laboratory is to distinguish thalassemia trait from other causes of microcytosis and hypochromia in an economical and efficient way. The various proposed schemes are discussed, and it is suggested that detection of these traits should be part of a comprehensive screening program for hemoglobinopathies and thalassemias.

Blood Protein Electrophoresis↗
PubMedDate not supplied

[Chelating therapy in beta-thalassemia].

The iron overload is the most common cause of death among transfusion dependent subjects affected by thalassemia major and other congenital anemias. The lesions caused by iron overload are found especially in liver, endocrine glands and heart. Among the various drugs able to remove the iron excess from the organs, desferrioxamine (DF) remains the only one used. The Authors report their experience with this drug in beta-thalassemia major and in beta-thalassemia intermedia patients. The results demonstrate that the subcutaneous administration of DF (40 mg/kg/die) is able to take the patients with thalassemia major in iron negative balance since their third year of life. No important untoward effects are reported. Periodic check with slit lamp has revealed no ocular alteration in 35 subjects. In thalassemia intermedia there is also iron overload due to increased iron absorption. It is probable that these patients too can present the same alterations observed in transfusion dependent beta-thalassemia omozygotes. In order to prevent these lesions it will be necessary to reduce iron absorption since early childhood.

Adolescent↗
PubMed1994

Carrier screening and prenatal diagnosis for alpha-thalassemia with biphasic polymerase chain reaction.

Alpha-thalassemia is the most common single gene disorder in Taiwan and Southeast China. The majority of alpha-thalassemic mutations in this area are alpha-thalassemia 1. Homozygous alpha-thalassemia 1 has been recognized as the most important cause of hydrops fetalis. To investigate the incidence of alpha-thalassemia 1 mutations and to characterize its molecular defects, cord blood electrophoresis was performed on 2,000 newborns, of which 99 (5%) cases were found to have hemoglobin (Hb) Bart's levels > 3.0%. A methodology using biphasic polymerase chain reaction (PCR) with nesting primers was developed to characterize the alpha-thalassemia 1 Southeast Asia type (SEA) deletion in the cases with detectable Hb Bart's levels. The SEA deletion was found in 92 (93%) of 99 cases. Prenatal screening was performed on couples with abnormal hematologic indices, and PCR was used to detect couples heterozygous for SEA deletion. Prenatal diagnosis was performed in 21 cases, and four cases were found to have a homozygous SEA deletion. This strategy can be applied to couples who need prenatal genetic counseling for alpha-thalassemia major in this area.

Asia, Southeastern↗