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PubMed1990

Mediterranean types of beta-thalassemia in the German population.

Forty beta-thalassemia genes from unrelated German heterozygotes with no known foreign ancestry were examined using the oligonucleotide technique and DNA restriction analysis, with the aim of determining the contribution of Mediterranean beta-thalassemia mutations to the prevalence of this trait in the German population. Of the 40 beta-thalassemia genes, 26 were identified as Mediterranean types (20 beta 39 nonsense, 3 IVS2 nt 110, 2 IVS2 nt1, 1 IVS1 ntl G----A). The geographic distribution of the birthplaces of the probands' grandparents revealed no difference in the proportion of Mediterranean and unidentified beta-thalassemia genes in the west and the north of Germany.

DNA↗
PubMed1980

Heterogeneity in beta 0 thalassemia from Algeria: genetic, clinical and molecular studies.

Six Algerian patients with beta 0 thalassemia are presented, in addition to the two patients already reported (Godet et al., 1977). Family studies indicate that all the patients had homozygous beta thalassemia characterized by absence of beta globin chain synthesis in peripheral blood. The clinical severity varies from one family to the other and within the same family, from typical Cooley's anemia to thalassemia intermedia and appears to be related to the child death rate observed in each family. The gamma/alpha biosynthetic ratio was 0.36-0.40 in seven patients and 0.2 in the most seriously affected patient. The mRNA beta content in peripheral reticulocytes was less than 1.5% of mRNA alpha in seven patients and 13.3% in one patient. These results indicate that Algerians homozygous for beta 0 thalassemia are heterozygous at the clinical, biochemical and molecular levels.

Adolescent↗
PubMed1981

Genetic regulation of gamma gene expression: study of the interaction of beta-thalassemia with heterocellular HPFH.

A family has been observed which a gene for heterocellular hereditary persistence of fetal hemoglobin (HPFH), probably identical to that previously described as Swiss type HPFH, has been inherited together with beta-thalassemia. The interaction of these two genes resulted in beta-thalassemia heterozygotes with unusually high levels of fetal hemoglobin (3.6-6.15), heterogeneously distributed. Globin synthesis studies showed a similar degree of chain imbalance in the heterocellular HPFH-beta thalassemia compound heterozygotes and in the heterozygous beta-thalassemia member of the family. On the basis of the pattern of genetic transmission of these two characters it can be concluded that the HPFH determinant does not behave as an allele of the gamma beta delta complex.

Adolescent↗
PubMed1988

Beta-thalassemia mutations in the Portuguese population.

In this study we have carried out haplotype analysis on the beta-globin gene cluster and characterized the beta-thalassemia mutation by oligonucleotide hybridization in 14 patients with thalassemia major and 5 with sickle cell/beta-thalassemia originating from southern Portugal. We found that three mutations, namely the beta(0)-39, beta(0) IVS-1 nt 1 and beta(+) IVS-1 nt 110 are prevalent accounting for 53%, 32% and 10% of the beta-thalassemia chromosomes respectively. In general each mutation was associated with a specific chromosomal haplotype; the beta(0)-39 mutation, however, was linked to three different haplotypes. These results indicate that three oligo-probes complementary to the most common mutations allow prenatal diagnosis by oligonucleotide analysis in 96% of the couples at risk of having offspring with thalassemia major in southern Portugal.

Genotype↗
PubMed1988

A frequent A gamma-hereditary persistence of fetal hemoglobin in northern Sardinia: its molecular basis and hematologic phenotype in heterozygotes and compound heterozygotes with beta-thalassemia.

A survey of hemoglobinopathies in northern Sardinia revealed a high frequency (0.3%) of carriers of a hematologic condition characterized by increased expression of fetal hemoglobin during adult life (hereditary persistence of fetal hemoglobin or HPFH). In spite of a normal hematologic phenotype, the heterozygous carriers for this condition display about 12% HbF, almost exclusively of the A gamma type; compound heterozygotes with beta-thalassemia have 20%-26% HbF and run a very mild clinical course. The sequence analysis of the cloned A gamma gene linked to the HPFH determinant revealed the presence of a G----A substitution at position -117 of the A gamma-globin gene promoter; the same mutation occurs also in Greek HPFH, although associated with different restriction polymorphisms. Another hereditary condition characterized by increased HbF (alpha 2 A gamma 2) level and a mild thalassemia phenotype in Sardinia is associated with the -196C----T substitution in the A gamma-globin gene promoter (Sardinian delta beta-thalassemia). Population studies using oligonucleotides complementary both to the -117 G----A and -196C----T mutations and the corresponding normal sequences confirm the presence of these mutations only in HPFH and delta beta-thalassemia chromosomes and exclude these changes being common DNA polymorphisms.

Female↗
PubMed1986

DNA polymorphisms in North Sardinian newborns and their linkage with abnormal gamma globin gene arrangements and with beta (0) -thalassemia.

Fetal hemoglobin analysis and globin gene mapping have identified one type of beta(0)-thalassemia and four different gamma globin gene arrangements among newborn babies from the northern part of Sardinia. The beta(0)-thalassemia with a nonsense mutation at codon 39 was found on two chromosomes, each with a distinct pattern of polymorphic restriction sites; one had the A gamma T (A gamma 75 Ile----Thr) mutation, while the second did not. Four closely related haplotypes were identified for chromosomes with the A gamma T mutation. The gamma-thalassemia heterozygosity with the -GA gamma- hybrid gene fell into two categories. One apparently originated through crossing-over between mismatched chromosomes characterized by the most common haplotype, while the other had polymorphisms resembling those of a less frequently occurring chromosome. Chromosomes with the -G gamma-AG gamma-A gamma- triplication had polymorphic sites to be expected for this condition, being complimentary to the -GA gamma- thalassemias. Of the two additional gamma globin gene variations the -G gamma- G gamma- arrangement was associated with the chromosome with the most commonly occurring haplotype, while the chromosome with the -A gamma-A gamma- arrangement had a haplotype characteristic for that with the A gamma T mutation, which identified an -A gamma-A gamma T- arrangement. The incidental discovery of a silent beta-chain mutant, Hb Hamilton, with the Val----Ile substitution at position beta 11, in five newborns was also reported.

Chromosome Mapping↗
PubMed1988

Prevalence and molecular heterogeneity of alfa+ thalassemia in two tribal populations from Andhra Pradesh, India.

We describe here the screening of a small group of apparently healthy individuals belonging to the tribal communities of Koya Dora and Konda Reddi. A remarkably high incidence of deletion and nondeletion alpha + thalassemia mutants has been found with allele frequencies and distributions characteristic to each tribe. We have confirmed the strict relationship between Hb S levels and the number of alpha globin genes in double heterozygotes for the S gene and alpha thalassemia. In this population sample we did not find either heterozygous carriers of alpha 0 thalassemia (deletion of both alpha genes in "cis") or individuals showing hemolytic anemia due to inactivation of three alpha-globin genes (Hb H disease). Selection by malaria is most probably responsible for the prevalence of the various alpha + thalassemia haplotypes among the two tribal populations of Andhra Pradesh.

Ethnicity↗
PubMed1991

Thalassemia: genotypes and phenotypes.

The large degree of phenotypic heterogeneity of thalassemia can now be related to the underlying genomic defects. This information has accumulated rapidly over the last years through the recent advances in molecular technology. The list of main types of thalassemia (alpha or beta) that can be differentiated includes several gene deletions (complete or partial) and point mutations (or very short deletions). These occur within the genes or across the flanking DNA sequences and apparently interfere with the expression of these genes. From a quantitative point of view, the severity of the condition is directly related to the amount of functional globin chain mRNA which is made available to the ribosomes; this may vary from zero (gene deletions, frameshift, non-sense mutations or mutations at the splice-junction nucleotides) to very little (mostly hnRNA processing mutants) or to slightly subnormal (transcriptional mutants, mutations resulting in cryptic site activation or in defective cleavage of the poly-A tail). A few hyper-unstable globin chains also produce a thalassemic phenotype. This pattern is straightforward in the alpha-thalassemias. In the beta-thalassemias, the decreased beta-chain synthesis reflects the available mRNA, but the phenotypic expression depends also on the ability of the patient to reactivate gamma-chain synthesis and complement the red cell content with hemoglobin F.

Genotype↗
PubMedDate not supplied

Splenectomy in children with sickle cell disease and thalassemia.

A number of Saudi children (31) with sickle cell disease and thalassemia underwent splenectomy: 12 for frequent blood transfusions, 15 for chronic hypersplenism (most of whom were also the recipients of periodic blood transfusion) and 4 for splenic abscess. The mean age of splenectomy was 8.8 years (8 months-18 years). Eight patients had sickle cell disease, 14 beta-thalassemia and 9 had sickle cell thalassemia. All patients received prophylaxis against pneumococcal infection. There was one postoperative death most probably due to sepsis. Sixteen of those who required frequent preoperative blood transfusions needed no more transfusions, while in 7 the need for transfusions decreased significantly (p less than 0.05). For those with hypersplenism, there was a significant postoperative increase in total hemoglobin (P less than 0.001), RBC (P less than 0.001) and platelet counts (p less than 0.02); and a substantial decrease in reticulocyte counts (p less than 0.05). The common post splenectomy complications were chest infection and a brief episode of pyrexia, but without undue morbidity. The study establishes a definite place for splenectomy in a selected population of children with sickle cell disease and thalassemia.

Adolescent↗
PubMed2006

Psychosocial burden in thalassemia.

OBJECTIVE: To study the psychosocial life aspects of Indian adolescents suffering from transfusion dependent beta-thalassemia major. Earlier studies done in Italy, Greece and United Kingdom reported the presence of psychosocial burden associated with the disease. We aimed to determine the presence of disease burden in the psychosocial life aspects of Indian adolescents affected with thalassemia. METHODS: Structured interviews were carried out with each of the subjects using a schedule which contained questions relating to perceived burden of thalassemia in the various psychosocial life aspects of affected adolescents. RESULTS: Adverse impact of thalassemia was perceived in the domains of education (70%) and sports (72%). Most thalassemics were not satisfied with their body image. Almost all the study subjects felt that the disease did not affect their family or social relationships. The adolescents were anxious about their future health and education. Majority of the subjects (80%) did not discuss about their disease and its related problems with their friends. They mainly depended on their parents for monetary and emotional support. CONCLUSION: There is tremendous psychosocial disease burden perceived by the affected adolescents and hence it is imperative to ameliorate it by promoting a clear understanding of the disease and initiating intervention programs.

Adolescent↗
PubMed2003

Prevalence and clinical significance of hepatitis C virus infection in Thai patients with thalassemia.

Hepatitis C virus (HCV) infection is a common cause of liver disease in thalassemia major patients in Western, especially Mediterranean, countries. Its significance in thalassemic patients from Southeast Asia has not been critically evaluated. In this report, we describe our study of the prevalence of HCV infection among Thai patients with thalassemia. The relationships of the infection to blood transfusion and the infection's effects on liver function have also been determined. Of the 104 patients studied, 21 (20.2%) tested positively by enzyme immunoassay for anti-HCV antibody, whereas only 2 patients (2%) had the hepatitis B surface antigen. There was no significant relationship between the presence of anti-HCV antibodies and the number and frequency of blood transfusions. In fact, 2 patients (10%) who tested positive for anti-HCV antibodies had never received transfusions. Patients with anti-HCV antibodies had significantly abnormal liver functions, such as higher levels of serum aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) and lower levels of serum albumin, compared with patients without anti-HCV antibodies (P = .021, .017, and .004, respectively). However, there were also significant correlations between iron status as indicated by transferrin saturation or serum ferritin levels and SGOT, SGPT, and gamma-glutamyltransferase (GGT) levels. Moreover, abnormal liver function as represented by elevated levels of SGOT, SGPT, GGT, and serum alkaline phosphatase was observed more frequently in patients with iron overload than in patients with a lower degree of iron burden. The presence of HCV did not alter the effects of iron overload on liver function. The findings suggest that both HCV and iron overload are the main causes of abnormal liver function in Thai patients with thalassemia. The treatment of both problems, if coexisting in patients with thalassemia, is required to prevent progression to chronic liver disease.

Adolescent↗
PubMed2002

Carrier screening and genetic counselling in beta-thalassemia.

This paper review the most important aspects of carrier detection procedures, genetic counselling, population screening and prenatal diagnosis of beta-thalassemias. Carrier detection can be made retrospectively, following the birth of an affected child or prospectively. Several programmes, with the aim of preventing homozygous beta-thalassemia, based on carrier screening and counselling of couples at marriage; preconception or early pregnancy, are operating in several Mediterranean at-risk populations. These programmes have been very effective, as indicated by increasing knowledge on thalassemia and its prevention by the target population and by the marked decline of the incidence of thalassemia major. Carrier detection is carried out by haematological methods followed by mutation detection by DNA analysis. Prenatal diagnosis is accomplished by mutation analysis on PCR-amplified DNA from chorionic villi. Future prospects include automation of the process of mutation-detection, simplification of preconception and preimplantation diagnosis and fetal diagnosis by analysis of fetal cells in maternal circulation.

Female↗
PubMed2002

Inverse correlation of plasma leptin and soluble transferrin receptor levels in beta-thalassemia patients.

The aim of the study was to investigate the association of leptin with hematological parameters in beta-thalassemia patients in Greece. We measured plasma levels of soluble transferrin receptor (sTfR) and leptin by enzyme-linked immunosorbent assay (ELISA) in 40 beta-thalassemia patients (21 transfusion dependent and 19 not transfused or sporadically transfused), in 20 beta-thalassemia carriers, and in 30 healthy individuals (HI). The percentage of reticulocytes (RET) was measured by the NE 9500 Sysmex automated method. Body mass index (BMI) was calculated by dividing body weight (kg) by square height (m). Endocrine measurements including sex hormones were also determined. sTfR concentrations were significantly higher in both transfusion-dependent (females 10.5+/-2.9, males 9.1+/-3.1) and non-transfusion-dependent patients (females 15.8+/-5.4, males 19.8+/-13.7) as compared to carriers (females 3.1+/-2.5, males 3.8+/-1.8) and to HI (females 1.5+/-1.2, males 2.5+/-2.1). Leptin levels were lower both in female and in male transfusion-dependent patients (0.5+/-0.3 and 1.2+/-1, respectively) and in non-transfused males (1.9+/-2) compared to carriers (females 7.9+/-2.7, males 13.1+/-9.1) and HI (females 14.6+/-6, males 7.5+/-3). There was a negative correlation between leptin and sTfR levels in transfused patients (R=-0.61, p<0.05). A stronger negative correlation (R=-0.7, p=0.006) was found in hypogonadic men and women with beta-thalassemia. These findings enhance previous results indicating that leptin may play some role in hematopoiesis and could associate the pathophysiology of thalassemic patients with the triggering effect of leptin in reproductive ability.

Adult↗
PubMed2002

Molecular characterization of deletional forms of beta-thalassemia in Taiwan.

beta-Thalassemia is one of the most common genetic diseases in Taiwan. The most common mutations of beta-globin are point mutations, and six mutations account for over 90% of cases. Less than 5% of the cases with beta-globin gene deletion result in beta-thalassemia minor. The mutational type of the deletion is not clear in Taiwanese. We used polymerase chain reaction (PCR)-based methods to detect the breakpoint junctions of different deletional types of beta-thalassemia. In total, six cases of clinically suspected deletional type of beta-thalassemia were studied. The results showed that there were three types of deletions in these cases: two cases each for hereditary persistent fetal hemoglobinemia (HPFH) of the Southeast Asian (SEA) type, HPFH of the Yunnanese type, and gamma(G)+(gamma(A)deltabeta)(0)deletions, respectively. The clinical features of these deletional mutations are milder than the beta(o) types of the point mutation. The patients with compound heterozygous mutations of the point mutation and the deletional mutation are always transfusion independent.

Adolescent↗
PubMed2003

Decreased expression of membrane alpha4beta1, alpha5beta1 integrins and transferrin receptor on erythroblasts in splenectomized patients with beta-thalassemia intermedia. Parallel assessment of serum soluble transferrin receptors levels.

Dysfunction of cell membrane is a recognized consequence of the pathogenetic process underlying the beta-thalassemia syndromes and it is reasonable to hypothesize that surface structures crucial for the development of erythroid lineage may also be affected. The study included six adult splenectomized patients with beta-thalassemia intermedia. Expression of alpha4beta1 integrin (CD49d/CD29), alpha5beta1 integrin (CD49e/CD29) and transferrin receptor (CD71) on peripheral blood and bone marrow erythroblasts and on erythroid precursors grown in vitro was studied by flow cytometry and immunocytochemistry. Serum soluble transferrin receptor levels (sCD71) were also measured with enzyme-linked immunosorbent assay. In beta-thalassemic patients, significant reduction of CD49d, CD29 and CD71 expression was found in peripheral blood nucleated red cells, compared to patients presenting with erythroblasts in the circulation because of other diseases. Marrow erythroblasts were also deficient for the same molecules against the erythroblasts in iron deficiency anemia. All molecules tested were greatly diminished on erythroid precursors developed in vitro from the patients' cells. Serum sCD71 levels were much higher in thalassemic patients in comparison to both patients with iron deficiency anemia and healthy individuals. The loss of certain integrins and CD71 from erythroid precursors in beta-thalassemia intermedia could be attributed to a generalized membrane dysfunction, perhaps affecting the integrity of their transmembrane domains. The elevation of serum sCD71 levels may be the result of the increased red cell lineage turnover or, alternatively, may indicate increased shedding from the cells to prevent iron overload. In any case, further molecular study of the membrane components is warranted to provide a better understanding of the pathogenetic process in beta-thalassemia syndromes.

Adult↗
PubMed2004

Hemodynamic assessment of splenomegaly in beta-thalassemia patients undergoing splenectomy.

Splenomegaly is a common finding in beta-thalassemia; however, its hemodynamic features and its potential correlations with high output state and hepatic disorders, both also frequent in thalassemia, have not yet been assessed in these patients. Eight beta-thalassemia patients with the indication for splenectomy and no symptoms or signs of heart disease, aged 25.6+/-5.5 years, were studied. Preoperative assessment included hematological profile, liver biology, hepatitis virus serology, and echocardiography. During splenectomy, splenic artery blood flow and splenic vein pressure were directly measured and liver biopsies were taken. Preoperative echocardiographic data were compared with those of 34 healthy controls. The preoperative cardiac index was significantly elevated in patients (4.8+/-1.3 vs 3.4+/-1.1 l/min per m2 in controls, p<0.001). Splenic blood flow, although increased, was not particularly high, being 285+/-56 ml/min or 0.13+/-0.04 ml/min per g of splenic mass, representing 4.1+/-0.9% of total cardiac output (CO). Splenic vein pressure was considerably elevated (29.7+/-5.5 cmH2O). Hepatic fibrosis, iron deposition, and extramedullary foci were found in all eight biopsies. Serology was positive in five of eight cases. beta-thalassemia patients with extensive splenomegaly requiring splenectomy are characterized by high output state, increased splenic blood flow, which probably makes a limited contribution to CO elevation, and portal hypertension, manifest by increased splenic vein pressure and hepatic histopathological abnormalities.

Adolescent↗
PubMed2005

Cardiovascular effects of splenomegaly and splenectomy in beta-thalassemia.

Splenomegaly is common in beta-thalassemia, bearing some particular hemodynamic features, while splenectomy is an established therapeutic intervention in these patients. Their effects, however, on systemic hemodynamics and thalassemia heart disease have not yet been assessed. The study included 32 consecutive patients, 13 with thalassemia major (TM) and 19 with thalassemia intermedia (TI), aged 23.4+/-4.2 years, requiring splenectomy. Assessment was performed before and 6 months after splenectomy and included hematological profile and resting echocardiography; total blood volume was also measured in 10 of 32 cases. Preoperative echocardiographic data were compared with those of 34 controls. Preoperative left ventricular diameters and mass, cardiac index, and systolic pulmonary artery pressure were all significantly higher in patients compared to controls (p<0.001), but did not differ significantly between TM and TI patients. Postoperatively, the mean hemoglobin level increased from 8.1+/-0.6 to 9.1+/-0.4 g/dl (p<0.001), total blood volume index declined from 2847+/-332 to 2310+/-276 ml/m(2) (p<0.001), blood transfusions were discontinued in 80% of TI patients and mean 6-monthly transfusion requirements in TM patients were reduced from 28+/-5 to 22+/-4 units (p<0.001). However, cardiac parameters were not significantly modified. It seems that left ventricular remodeling, high output state, and increased pulmonary artery pressure characterize both TM and TI patients who require splenectomy. Although these abnormalities remain unchanged after splenectomy, the removal of the spleen may contribute to the prevention of further cardiac damage by ameliorating the patients' hematological status and reducing their transfusion needs.

Adult↗
PubMed2006

Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload.

Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major (TM). Successful iron chelation is therefore essential for the optimal management of TM. Although desferrioxamine (DFX) has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L(1)) since 1987 is useful but showed poor efficacy when used alone as compared to DFX. We therefore decided to compare DFX alone with a prospective combined therapy with DFX and L(1) in beta thalassemia major patients with iron overload. We studied 91 patients with beta thalassemia major (mean age+/-SD, 15.02+/-5.8; range 2-30 years) attending the day care unit for regular transfusional support. They received packed red cells every 3-4 weeks to maintain pretransfusion hemoglobin concentration above 9 g/dl. They had been receiving DFX at a daily dose of 40 mg kg(-1) day(-1) by subcutaneous infusion for 8-10 h on 4-5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusional iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L(1) at 75 mg kg(-1) day(-1) body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Of the 91 patients, six developed severe gastrointestinal (GI) upset, two agranulocytosis, two arthropathy, one persistently raised liver enzymes, two died owing to sepsis, and two received allogeneic bone marrow transplantation. Amongst the remaining 76 patients, 21 were found noncompliant (not taking DFX regularly, but taking L(1) regularly). Thus, in the 55 evaluable patients {6-48 months on combination therapy; mean [(+/-SD)22+/-12 months]}, the mean serum ferritin (+/-SD) fell dramatically from 3,088 (+/-1,299) ng/ml (DFX alone) to 2,051 (+/-935) ng/ml (DFX and L(1); p<0.001). It is interesting to note that there was also a significant improvement in the myocardial function as assessed by the ejection fraction (p<0.004) and fractional shortening (p<0.05) in those patients (n=42) who could be studied after being on combination therapy for a minimum of 1 year. The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L(1). Our results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in the echocardiographic parameters of myocardial performance in these patients receiving combination therapy.

Adolescent↗