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PubMed1972

-thalassemia in the American Negro.

In Italian and Chinese patients with the alpha-thalassemia syndromes the production of alpha-chain of normal hemoglobin is decreased relative to that of beta-chain in reticulocytes. In this study the relative rates of alpha- and beta-chain synthesis were determined in members of three Negro families with alpha-thalassemia. Two of the families had members with hemoglobin H disease and alpha-thalassemia trait, while the mother of several children with alpha-thalassemia trait in the third family was doubly heterozygous for alpha-thalassemia and an alpha-chain mutant. The alpha/beta ratios of globin synthesis in the patients with hemoglobin H disease and alpha-thalassemia trait indicated less severe biochemical defects in the peripheral blood than those previously determined in Italian and Chinese patients. In the third family, there was a heterogeneity of expression of the gene for alpha-thalassemia, including patients with normal red cell indices and synthesis ratios. These findings differ from those previously described in patients with alpha-thalassemia from other racial groups. Hydrops fetalis due to homozygous alpha-thalassemia may not occur in the Negro because of the relatively mild thalassemic defect.

Adolescent↗

PubMed2005

A novel molecular basis for beta thalassemia intermedia poses new questions about its pathophysiology.

During a study of the molecular basis for severe forms of beta thalassemia in Sri Lanka, 2 patients were found to be heterozygous for beta thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated alpha globin genes in combination with heterozygous beta thalassemia. The other is homozygous for a triplicated alpha globin gene arrangement and heterozygous for beta thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe beta thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended alpha globin gene interactions and in dominant beta thalassemia, raising the possibility that increased levels of HbF production in beta thalassemia may require mutations at both beta globin gene loci.

Adolescent↗

PubMed1998

Molecular basis of beta-thalassemia in the Maldives.

We have systematically analyzed beta-thalassemia genes using polymerase chain reaction-related techniques, dot-blot hybridization with oligonucleotide probes, allele specific-polymerase chain reaction, and sequencing of amplified DNA fragments from 41 unrelated patients, including 37 beta-thalassemia homozygotes, three with beta-thalassemia/Hb E, and one with beta-thalassemia/Hb S. Four different beta-thalassemia mutations were detected in 78 alleles. These are the IVS-I-5 (G-->C), codon 30 (AGG-->ACG) [also indicated as IVS-I (-1)], IVS-I-1 (G-->A), and codons 41/42 (-TTCT) mutations. The distribution of the beta-thalassemia mutations in the Maldives is 58 alleles (74.3%) with the IVS-I-5 (G-->C) mutation, 12 (15.4%) with the codon 30 (AGG-->ACG) mutation, seven (9%) with the IVS-I-1 (G-->A) mutation, and one with the codons 41/42 (-TTCT) mutation. The first three mutations account for 98.7% of the total number of beta-thalassemia chromosomes studied. These mutations are clustered in the region spanning 6 bp around the junction of exon 1 and the first intervening sequence of the beta-globin gene. These observations have significant implications for setting up a thalassemia prevention and control program in the Maldives. Analysis of haplotypes and frameworks of chromosomes bearing each beta-thalassemia mutation suggested that the origin and spread of these mutations were reflected by the historical record.

Algeria↗

PubMed1999

Comparative in vivo expression of beta(+)-thalassemia alleles.

Double heterozygotes who inherit one abnormal though stable beta-globin variant in association with a molecularly identified beta(+)-thalassaemia allele provide unique opportunities to quantify the in vivo expression of particular beta(+)-thalassemia alleles. The globin products of the two alleles can be separated, quantified and the output of the beta(+)-thalassaemia allele expressed as the MCH-beta(A) in pg beta(A)-globin/beta(+)-thalassemia allele/RBC = 0.5 MCH x Hb A%. In this communication we provide new quantitative data on the expression of five mutations as follows: the beta(+)-87 (C-->G) = 3.8 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 1); the beta(+) IVS-I-1 (G-->A) = 0.2 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 1); the beta(+) IVS-I-6 (T-->C) = 2.9 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 7); the beta(+) IVS-I-110 (G-->A) = 1.1 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 13), and the beta(+) IVS-II-745 (C-->G) = 1.74 pg beta(A)-globin/beta(+)-thalassemia allele/RBC (n = 2). The values obtained are compared with those of other beta(+)-thalassemia alleles from the literature. It can be seen that the MCH-beta(A) value may be a correct index of thalassemia severity useful for the correlation of genotype with phenotype, and for understanding the effects of mutations in beta-globin genes on pathophysiologically meaningful beta-globin gene expression.

Adolescent↗

PubMed2002

Evaluation of clinical application of gap-PCR as a routine method for alpha-thalassemia carrier detection.

OBJECTIVE: To evaluate the feasibility of using gap-PCR for routine screening of alpha-thalassemia in clinical laboratory. METHODS: A total of 382 clinical blood samples randomly collected from the population of Zhuhai city were screened for alpha-thalassemia determinants with hematological and gap-PCR method respectively in a double-blind manner. Parallel analysis with Southern blotting was performed to verify the genotyping results by PCR. RESULTS: Of the 382 samples tested, 3 common alpha-thalassemia genes with genotypes of --(SEA)/alpha alpha, -alpha(3.7)/alpha alpha and -alpha(4.2)/alpha alpha were detected in 21 (5.50%), 7 (1.83%) and 3 (0.79%) cases respectively by gap-PCR, including 7 cases with normal phenotype and 3 case of iron-deficiency anemia. The overall incidence of alpha-thalassemia was 8.12% in the population of Zhuhai city, as determined by gap-PCR, in total agreement with the results by Southern blotting. Only 21 of the 31 alpha-thalassemia cases were identified by hematological analysis (besides 2 cases with alpha-thalassemia phenotype undetermined), which had a false-negative rate of 32.3%. Seven silent alpha-thalassemia and 3 mild alpha-thalassemia cases failed to be detected by hematological analysis, resulting in a rate of 2.62% for failure of detection. CONCLUSION: Gap-PCR method is specific and feasible as a better alternative for alpha-thalassemia screening, especially advantageous in detecting silent carriers in comparison with hematological method.

DNA↗

PubMed2002

Serum erythropoietin levels in pediatric patients with beta-thalassemia/hemoglobin E.

Presently, the assays for serum erythropoietin (EPO) seem valuable tools for clinical research, but their roles in routine clinical practice remain undefined. Some studies mentioned that serum EPO measurements, which are now easily and reliably performed, should be used in monitoring the therapy of beta-thalassemia major. Here, we report our experience in the determination of serum EPO in children with beta-thalassemia/Hb E and also compared the results with those in hemoglobin E trait, beta-thalassemia/Hb E as well as healthy non-anemic controls of similar age. Fifty five transfusion-dependent beta-thalassemia/Hb E, fifteen hemoglobin E trait, five beta-thalassemia trait cases and twenty five controls were studied for their serum EPO levels. The mean (S.D.) EPO concentrations were 19.94 (17.40) U/L for the controls, 16.13 (8.47) U/L for the hemoglobin E trait, 24.40 (8.20) U/L for the beta-thalassemia trait and 372.19 (432.04) U/L for the beta-thalassemia/Hb E cases. The mean EPO concentration for the normal controls was near to that of the hemoglobin E trait (P = 0.06) and beta-thalassemia trait (P = 0.25) but eighteen times less than that for the beta-thalassemia major cases (P<0.0005).

Blood Transfusion↗

PubMedDate not supplied

Splenectomy for children with thalassemia.

Twenty-three children with thalassemia (18 with beta-thalassemia major, 3 with Hb H disease, and 2 with thalassemia intermediate) had total splenectomy (nine beta-thalassemia major patients and two thalassemia intermediate patients) or partial splenectomy (nine beta-thalassemia patients and three Hb H disease patients) as part of their management at our hospital. There were 10 males and 1 female in the total splenectomy group (mean age, 7.8 years; range, 4.5-12 years), and 4 males and 8 females in the partial splenectomy group (mean age, 6.9 years; range, 3-10 years). In all, the indication for splenectomy was hypersplenism. In the partial splenectomy group, two children with Hb H disease required no further blood transfusions. The transfusion requirements of the third patient with Hb H disease decreased from 15 to 11 transfusions per year (from 1.2 g/week Hb drop preoperatively to 0.7 g/week postoperatively), but subsequently his transfusion requirements increased as a result of an increase in the size of splenic remnant. He underwent total splenectomy 1.5 years post-partial splenectomy. For those with beta-thalassemia major who had partial splenectomy, there was a reduction in the number of blood transfusions from a preoperative mean of 15.2 transfusions per year (range, 11-22 transfusions per year) to a postoperative mean of 8.2 transfusions per year (range, 2-11 transfusions per year). Their Hb drop decreased from a preoperative mean of 1.6 g/week (range, 0.8-3.5 g/week) to a postoperative mean of 0.5 g/week (range, 0.2-0.75 g/week). Subsequently and as a result of increase in the size of splenic remnant, their transfusion requirements increased, but none of them to this point have required total splenectomy. Eleven children had total splenectomy. Their postsplenectomy transfusion requirements decreased from a preoperative mean of 17.8 transfusions per year (range, 12-23 transfusions per year) to a postoperative mean of 10 transfusions per year (range, 8-12 transfusions per year), and their Hb drop decreased from a preoperative mean of 1.8 g/week (range, 0.5-2.3 g/week) to a postoperative mean of 0.45 g/week (range, 0.3-0.65 g/week). In conclusion, total splenectomy is beneficial for children with thalassemia and hypersplenism because it reduces their transfusion requirements. Partial splenectomy may be beneficial for those with Hb H disease. However, for those with beta-thalassemia, partial splenectomy is beneficial in reducing their transfusion requirements only as a temporary measure, and it is recommended for children who are less than 5 years of age.

Blood Transfusion↗

PubMed2002

Screening for the carriers of thalassemias and abnormal hemoglobins at the community level.

Thalassemia and abnormal hemoglobins are common genetic disorders in Southeast Asia. Thalassemia is not only an important public health problem but also a socio-economic problem of many countries in the region. The approach to deal with the thalassemic problem is to prevent and control births of the new cases. This requires an accurate identification of couple at high risk to have a thalassemic child. The diagnosis of thalassemia carriers need several tests that are not practical for screening the population at large. In this study we used two simple laboratory tests to screen for potential thalassemia carriers and hemoglobin E individuals. Three-hundred pregnant women and 40 spouses were recruited in this study. The methods were the red cell osmotic fragility (OF) screening test with 0.36% NaCl and the dichlorophenolindophenol (DCIP) precipitation test to detect Hb E and unstable hemoglobins. Standard methods for red cell indices, hemoglobin analysis and detection of alpha-thalassemia by immunological method were also performed to confirm genotypes of thalassemia. The results showed that 98 women (32.7%) were carriers of thalassemias and hemoglobin E. The number of false positive by OF test was 3.2% and by DCIP test was 0.6%. Sensitivity and specificity of OF test were 89.5% and 93.3%, respectively whereas those of DCIP test were 100%. Of the 40 couples investigated, one was found to be at risk of having beta-thalassemia/Hb E fetus. Screening techniques including one tube osmotic fragility and DCIP precipitation tests are sensitive and specific for the detection of thalassemia and unstable hemoglobins such as Hb E. The techniques are also simple, economic, rapid, and give minimal false negative result.

Adult↗

PubMed2002

Using reticulocyte indices to identify alpha-thalassemia--a preliminary report.

Thalassemia poses an important public health problem in Thailand. The Ministry of Public Health of Thailand has conducted many programs for the control of thalassemia. These programs are useless if there is no effective, affordable method of screening for carriers. We report on the possibility of using an automated reticulocyte analyzer in order to identify alpha-thalassemia. Thirty-one control subjects and 14 couples, whose offsprings were affected with thalassemia H (7 alpha-thalassemia-1 and 7 alpha-thalassemia-2) were studied. We found that almost all reticulocyte parameters could be used as diagnostic marker of alpha-thalassemia-1 carriers. Unfortunately, alpha-thalassemia-2 had only 5 parameters that were significantly different when compared to normal controls. This is the report to focus attention on the use of reticulocyte parameters in the screening of alpha-thalassemia.

Case-Control Studies↗

PubMed2004

Prevention of thalassemia: experiences from Samui Island.

Thalassemia is one of the most important genetic disorders in Thailand. A model for prevention of thalassemia by combining 4 strategies including education, carrier screening, counseling and prenatal diagnosis was developed by a thalassemia task force. A thalassemia work group was formed in order to develop a mechanism to integrate the model for real use on Samui Island where thalassemia is common and a specific disease oriented program is required. 200 health professionals working on Samui Island participated in the thalassemia educational courses. The specific training courses were also provided for obstreticians, medical technologists and counselors. A team of well-trained health professionals was established to manage public education. Information booklets, posters, brochures and mass media including spot radio and newspapers were used as educational materials. For carrier screening, blood samples of pregnant women from all health care organizations on Samui Island were collected and screened for thalassemia carriers by using the osmotic fragility (OF) test/the dichlorophenol indophenol precipitation (DCIP) tests at Samui Hospital. Samples with positive results were sent to the Regional Medical Sciences Center in Surat Thani for thalassemia diagnosis. When a carrier was identified, her spouse was offered testing. For at-risk couples, details of the disorder were included in counseling to help them reach a decision that was right to them, in the context of their unique medical, moral and social situations. Amniotic fluid samples were collected for prenatal diagnosis. All patient information was registered by using computer software. After 1 year of integration by using facilities of the Ministry of Public Health service system, a wide range of problems were identified. They underlined the need for effective health service structure co-operation, adequate education of responsible health professionals, explicit policies and a clear line of responsibility at local, regional and national levels for service development and quality management. It is hoped that all information conducted in the present study will be useful to health authorities to develop an explicit policy and promote the health service structure co-operation in the country that will finally lead to successfully reducing the frequency of severe thalassemia in the future.

Endemic Diseases↗

PubMed2005

[Treatment of thalassemia major with unrelated donor bone marrow transplantation].

OBJECTIVE: Allogeneic marrow transplantation is a curative therapy for thalassemia, but no more than 30% of patients have HLA-indentical sibling marrow donor. The selection of alternative donors of unrelative marrow and the study on the probability of treating thalassemia major with unrelated donor bone marrow transplantation are of importance. METHODS: Nine children with thalassemia were included in the study, and their gene mutational type were homozygote of thalassemia and double heterozygote, respectively. All of them were finally diagnosed of thalassemia major, and treated with unrelated donor bone marrow transplantation. To high-resolution HLA typing, two patients were matched, five had one unmatched isoform and two had two unmatched isoforms. The erythrocyte blood type was not matched in six patients. The preparative regimen included busulfan (oral use, 16 mg/kg, divided for 4 days), cyclophosphamide (intravenous use, 200 mg/kg, divided for 4 days), antithymocyte immunoglobulin (intravenous use, 30 mg/kg, divided for 3 days), and fludarabine (intravenous use, 125 mg/m(2), divided for 3 days). Ciclosporin A and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. RESULTS: All patients had allergen reactions. One had hypotension. Five patients experienced I degrees approximately III degrees acute GVHD in the skin, while one had II degrees acute GVHD in liver. One patient had III degrees GVHD of intestines and gradually developed chronic GVHD in the skin, lungs and brain. One patient died of pulmonary hemorrhage. The duration when peripheral blood neutrophil count exceeded 0.5 x 10(9)/L was 12 - 26 days. The recovery time of WBC was as long as 23 - 110 days. Thrombocytes exceeded 50 x 10(9) within 61 approximately 142 days. The time when hemoglobin reached 100 g/L varied from 23 to 116 days. The last blood transfusion was on 13 - 62 days. Eight patients were fully grafted, while one was not grafted. During the 6 - 24 months of follow-up, seven patients' genotype of thalassemia major became normal. The erythrocyte blood type of five patients also changed into the same as that of donor. The hemoglobin was kept over 110 g/L without blood transfusion. CONCLUSION: The transplantation of unrelated donor bone marrow for thalassemia major was successful. Unrelated donor bone marrow transplantation could cure thalassemia major, which expanded the marrow donor source for the transplantation of thalassemia major.

ABO Blood-Group System↗

PubMed1982

Alpha-thalassemia in two Mediterranean populations.

We used restriction endonuclease analysis to determine the incidence of alpha-thalassemia in two Mediterranean islands. In a random population sample, the gene frequency of deletion-type alpha-thalassemia-2 (-alpha) was 0.18 in Sardinians and 0.07 in Greek Cypriots. All cases were the rightward crossover type. From these frequencies and the known incidence of hemoglobin-H disease in these populations, we calculated the frequency of the alpha-thalassemia-1 genotype (--) and determined that it was low. We also found that beta-thalassemia homozygotes in sardinia have a higher incidence of alpha-thalassemia than normals and beta thalassemia heterozygotes because a significantly greater number of these homozygotes are also homozygous for the alpha-thalassemia-2 lesion. These findings support the theory that coinheritance of alpha-thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.

Cyprus↗

PubMed1995

Reverse dot-blot detection of the African-American beta-thalassemia mutations.

DNA-based diagnosis of the beta thalassemias provides accuracy to newborn screening genetic counseling, and prenatal diagnosis. However, the use of polymerase chain reaction (PCR)-based methods is challenged by the great number of different-beta-thalassemia mutations that exist even within defined ethnic groups. In this regard, the reverse dot-blot method offers a means of screening for several mutations with a single hybridization reaction. We have applied the reverse dot-blot method to the detection of the beta-thalassemia mutations of African-Americans. We used two biotin-labeled primer pairs in a duplex reaction to amplify and label two beta-globin target DNA fragments that encompass all known African-American beta-thalassemia mutations. The PCR products were denatured and hybridized to polyT-tailed, membrane-fixed, allele-specific probe pairs for the hemoglobin (Hb) S, Hb C, and 14 beta-thalassemia mutations and their corresponding wild-type sequences. Seven common mutations plus Hb S and Hb C were included on one diagnostic strip, and seven less common beta-thalassemia mutations were included on another strip. Carefully controlled, high stringency hybridization allowed accurate distinction of these alleles. Reverse dot-blot diagnosis of the less common beta-thalassemia mutations precludes the need for alternative, more technically challenging methods. This method provides a rapid, accurate method for diagnosis of beta thalassemia among African-Americans and other ethnic groups in which beta thalassemia occurs.

Base Sequence↗

PubMed1997

[The association of beta zero-thalassemia and Hb D Punjab in a family of Indian origin. The second case reported in Spain].

The present report described the hematologic and molecular study of the second case of Hb D-Punjab associated with a beta zero-thalassemia found in Spain and the first case in which the mutations have been identified at molecular level. A family from India is studied, which is constituted by mother (I2) and 3 children (II1, II2 and II3). The molecular characterization of the hemoglobinopathy was made by electrophoretic and chromatographic techniques and confirmed by sequencing of the beta-globin gene. The mutation causer of the beta-thalassemia was studied by PCR-ARMS. The mother (I2) and one of her child (II2) are carriers of the gene for beta zero-thalassemia owing to the frameshift CD 8/9 mutation (+ G). Other of them (II1) is heterozygous for Hb D-Punjab without beta-thalassemia association. The third child (II3) knows a double heterozygote state for Hb D-Punjab/beta zero-thalassemia (hemoglobin D-thalassemia). In spite of the patient with hemoglobin D-thalassemia has 94.5% of Hb D, without Hb A, the hematologic picture belongs to thalassemia trait with moderate haemolytic anemia, intense microcytosis and hypochromia and numerous target cells. This hematologic picture discloses the mildness of the Hb D-Punjab, but the reliable responsible for the phenotype is the disbalance in the synthesis of globin chains, because of frameshift CD 8/9 mutation (+ G) beta zero-thalassemia mutation.

Adult↗

PubMedDate not supplied

Silent thalassemias: genotypes and phenotypes.

BACKGROUND AND OBJECTIVE: Current application of molecular biology techniques to the study of the DNA of globin genes has confirmed the existence of silent alpha and beta thalassemias; which had already been reported on the basis of red blood cell parameters and family studies. The present work was aimed at analyzing all the aspects of the phenotype of the most common varieties of silent thalassemia. MATERIALS AND METHODS: Groups of heterozygous carriers of these varieties were examined using established techniques that determined all hematologic, hemoglobin (electrophoresis and measurement of Hb A2 and Hb F levels), and globin synthesis (evaluation of the alpha/beta ratio) parameters. Furthermore, all subjects underwent a complete molecular study of the alpha and beta globin genes by means of the ARMS, SSCP, DGGE, PCR and Southern blotting techniques. RESULTS: 1) The -101 C-->T mutation of the promoter of the beta globin gene shows a normal hematological picture with the Hb A2 level often slightly raised and the alpha/beta globin synthesis ratio slightly greater than 1; 2) beta + thalassemia resulting from the IVS II 844 C-->G mutation has a phenotype that is even closer to normal; 3) -alpha 3.7 deletion type I usually has a totally silent phenotype; 4) the alpha Ncol mutation almost always gives rise to a sub-silent phenotype if it is located on gene alpha 2 and to a silent phenotype if it is found on gene alpha 1; 5) alpha + thalassemia due to the alpha 2 Hphl mutation displays a sub-silent phenotype in some cases and a silent one in others; 6) triplication of the alpha genes gives rise to a phenotype that is quite similar to that of the -101 C-->T mutation of the promoter of the beta globin gene, namely one that is very often silent. INTERPRETATION AND CONCLUSIONS: Many of these silent varieties (beta + thalassemia due to the -101 C-->T mutation; alpha + thalassemia from a deletion or point mutation of an alpha gene; alpha alpha alpha triplication) are quite frequent in the overall group of thalassemias. It is therefore important for the operators in the field of thalassemia diagnosis to possess exact knowledge of them especially in order to prevent thalassemia major.

Adolescent↗

PubMed1998

Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia?

Hemoglobin E (HbE; alpha2beta226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous beta thalassemia. Yet, when it is inherited together with a beta thalassemia allele, the resulting condition, HbE/beta thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the beta thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37 degrees C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/beta thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/beta+ thalassemia red blood cells age. Globin binding to membranes was assessed and only alpha globin chains were found, in contrast to other unstable hemoglobins in which both alpha and beta chains were present. However, in experiments performed on blood from HbE/beta thalassemics in the temperature range 39 degrees C to 41 degrees C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/beta thalassemia is primarily the result of the interaction of two beta thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia.

5'-Nucleotidase↗

PubMed1997

Prevalence and genotypes of alpha- and beta-thalassemia carriers in Hong Kong -- implications for population screening.

BACKGROUND: The thalassemias are common in southern China. We determined the prevalence of heterozygous carriers of these genetic disorders in Hong Kong and assessed the feasibility of a community-based screening program. METHODS: An educational and screening program for the thalassemias was carried out in three high schools with a total of 2420 students. Seventy-five percent of the students agreed to undergo screening, which consisted of blood counts, hemoglobin electrophoresis, serum ferritin measurements, and DNA analyses. RESULTS: Of the 1800 blood samples tested, 150 (8.3 percent) had microcytosis (mean corpuscular volume, <80 microm3). Ninety students (5.0 percent) were carriers of alpha-thalassemia, of whom 81 (4.5 percent) were carriers of the Southeast Asian type of deletion, in which both alpha-globin genes on the same chromosome 16 are deleted. Sixty-one students (3.4 percent) were carriers of either beta-thalassemia or the mutation coding for hemoglobin E. Six students were carriers of both alpha- and beta-thalassemias. On the basis of these figures, the estimated numbers of pregnancies in Hong Kong in which the fetus is at risk for homozygous alpha-thalassemia and beta-thalassemia major or intermedia are 145 and 80 per year, respectively. In Hong Kong the actual numbers of women referred for prenatal diagnoses of these disorders are approximately 95 and 40 per year, respectively. CONCLUSIONS: Despite the availability of hospital-based screening and prenatal diagnosis for many years in Hong Kong, many women carrying fetuses at risk for thalassemia are not referred for genetic counseling. A community-based program of education, screening, and counseling is needed in Hong Kong and southern China.

Adolescent↗

PubMed1996

The thalassemia syndromes: lessons from molecular medicines index case.

The thalassemia syndromes were the first of human diseases to become thoroughly examined for the underlying molecular lesions by the application of molecular genetic strategies and recombinant DNA methods. Students of thalassemia have now enjoyed over two decades of experience with this research paradigm. These experiences reveal both the awesome power and the limitations of the "reductionist, deterministic" approach of gene cloning and analysis. Incredibly precise and abundant information about the exact molecular lesions responsible for various forms of thalassemia were rapidly obtained by the use of molecular genetic approaches. The mechanisms by which these mutations deranged globin gene expression could be documented with extraordinary precision and efficiency. Precise, powerful methods for detecting disease early in fetal life were rapidly developed, made practical for field use, and disseminated widely. This resulted in a dramatic reduction in the incidence of new births of patients with homozygous beta thalassemia. These experiences demonstrate the extraordinary impact that recombinant DNA technology has upon our ability to understand disease processes, to detect disease long before its phenotypic expression is apparent, and to influence the prevalence of the abnormal alleles in the population. Experience with the antenatal diagnosis of the thalassemias also demonstrates, and should alert us to, the relative ease with which genetic information can be applied to societal and governmental initiatives to alter the reproductive behavior of individuals. While the benefits of reducing the incidence of beta thalassemia are clearcut, application of the strategies that were applied in this narrow situation to broader aspects of disease or genetic manipulation does raise concerns. The thalassemia syndromes demonstrate that genetic information does have more than a theoretical potential to have a major impact upon society. The struggles of many investigators to develop effective pharmacologic agents for the treatment of hemoglobinopathies have also revealed some of the limitations of an isolated molecular approach to the understanding of disease. The tortuous course by which a class of reagents has been identified for stimulation of HbF synthesis illustrates an important point. The application of recombinant DNA methods revealed an entirely new array of pathophysiologic facts that stimulated new hypotheses about the regulation of gene expression and opportunities to manipulate that regulation therapeutically. However, practical application and proper understanding of the molecular information were achieved only when those data were placed in the context of cell biology, tissue and organ-based clinical pathophysiology, and clinical pharmacology. Progress was possible only because of the productive interaction of talented individuals with expertise in these different fields. Our two decades of experience with the thalassemias illustrate very clearly the fact that biology and disease are extraordinarily complex, non-deterministic processes. They will be understood and treated properly only if thriving centers exist within which individuals with diverse interests, expertise, and perspectives about basic science and clinical medicine can exist, interact, and have sufficient time to employ their imaginations to the fullest benefit.

Adult↗