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PubMed1991

Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan.

beta-Thalassemia is a hereditary disease caused by any of 90 different point mutations in the beta-globin gene. Specific populations generally carry a small number of mutations, the most common of which are those that are widely distributed regionally. The present study constitutes an extensive molecular characterization of this disease in a small, highly inbred ethnic group with a high incidence of beta-thalassemia--the Jews of Kurdistan. An unusual mutational diversity was observed. In 42 sibships 13 different mutations were identified, of which 3 are newly discovered: a C----A transversion at -88 to the cap site, a frameshift in codon 36/37, and an A----G transition in the polyadenylylation signal. Four of the mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews only in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant chromosomes carry the mutations unique to Kurdish Jews. We traced the origin of the mutations to specific geographic regions within Kurdistan. This information, supported by haplotype analysis, suggests that thalassemia in central Kurdistan (northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible. We conclude that several evolutionary mechanisms contributed to the evolution of beta-thalassemia in this small ethnic isolate.

Base Sequence↗

PubMed2006

Humanized beta-thalassemia mouse model containing the common IVSI-110 splicing mutation.

Splicing mutations are common causes of beta-thalassemia. Some splicing mutations permit normal splicing as well as aberrant splicing, which can give a reduced level of normal beta-globin synthesis causing mild disease (thalassemia intermedia). For other mutations, normal splicing is reduced to low levels, and patients are transfusion-dependent when homozygous for the disease. The development of therapies for beta-thalassemia will require suitable mouse models for preclinical studies. In this study, we report the generation of a humanized mouse model carrying the common IVSI-110 splicing mutation on a BAC including the human beta-globin ((hu)beta-globin) locus. We examined heterozygous murine beta-globin knock-out mice ((mu)beta(th-3/+)) carrying either the IVSI-110 or the normal (hu)beta-globin locus. Our results show a 90% decrease in (hu)beta-globin chain synthesis in the IVSI-110 mouse model compared with the mouse model carrying the normal (hu)beta-globin locus. This notable difference is attributed to aberrant splicing. The humanized IVSI-110 mouse model accurately recapitulates the splicing defect found in comparable beta-thalassemia patients. This mouse model is available as a platform for testing strategies for the restoration of normal splicing.

Alternative Splicing↗

PubMedDate not supplied

Past malaria, thalassemia and woman fertility in southern Italy.

The role of natural selection in maintaining the thalassemia polymorphism is examined in a southern Italy district, in the past affected by malaria endemia. The Haldane's hypothesis that the thalassemia heterozygotes enjoy more protection than the normal homozygotes against the risk of malaria infection, seems to be confirmed by this indirect study at population level. The higher number of children born of the women who lived in the highly endemic villages, where the highest proportion of heterozygotes occurs, supports the hypothesis that the woman fertility contributes to the thalassemia maintenance. The joint effects of the acquired and inherited immunities and of the reproductive compensation are assumed as the mechanisms through which malaria and thalassemia influence fertility.

Child↗

PubMed2006

The prevalence and spectrum of thalassemia in Shenzhen, Guangdong Province, People's Republic of China.

Thalassemia (thal) is the most common autosomal disorder in southern China. The aim of the present study was to investigate the prevalence and spectrum of thalassemia mutations in the population of Shenzhen, Guangdong Province. In total, 3,711 samples from two hospitals in Shenzhen were subjected to hematological and molecular analysis. Of these, 241 (6.49%) were carriers of thalassemias, of which 161 (4.34%) had alpha-thal, 74 (1.99%) had beta-thal, and six (0.16%) had both alpha- and beta-thal. Three deletional and one nondeletional alpha-thal mutation, and nine beta-thal mutations were identified. Compared with other areas in Guangdong Province, the prevalence of thalassemia in Shenzhen was lower, while there was no evident difference for the spectrum of mutations. These results will provide a reference for prenatal testing and genetic counseling in the area.

China↗

PubMed2006

Thalassemia treatment and prevention in Uva Province, Sri Lanka: a public opinion survey.

Due to its excessive cost thalassemia management is a major health care problem in Sri Lanka. The majority of doctors are using only desferrioxamine (DFO), in grossly inadequate doses mainly because of its unavailability. Deferiprone (L1), which is more affordable, is not used due to fear of toxicity, as previously reported. Arthropathy attributed to L1 has been observed in some patients, and has led to the discontinuation of the drug in all patients, without scientific rationale. The proposed thalassemia prevention project for Uva Province is based on prevention of marriages between carriers. This could be achieved by carrier screening and counseling of teenagers and adolescents well before they select their partners. In Sri Lanka, people find their marriage partners at their work place or universities, by themselves, or with the help of professional marriage brokers (they are called Kapuwa), through relatives and close friends. This process of finding a partner may also be helped by paper advertisements. However, in addition to the appearance and attitude of the prospective partner, the caste, social background and horoscope are major considerations in selecting a partner. Even when they select partners on their own at the work place or university, they keep these factors in the back of their minds to ensure social acceptance. Many relationships are given up due to objections and advice from parents when the caste or social background does not match. A horoscope is a written document that almost every child gets, written by a professional horoscope reader and depending on the time of birth. It is believed, according to the horoscope, that a person's attitudes, desires, future prospects of finding a suitable partner, could be predicted. It is rare to proceed with a marriage if the horoscope does not match. These customs are considered less seriously among educated people when they find their partner at the work place or university. The concept of thalassemia risk-free marriages advocates promotion of marriages where at least one partner is a non-carrier. Success of such a project could be monitored at the time of marriage. This opinion survey indicates that the public is motivated to promote carrier screening and the prevention of thalassemia.

Abortion, Eugenic↗

PubMedDate not supplied

A case with extraosseous Ewing's sarcoma: a late effect related to bone marrow transplantation for thalassemia or a component of a familial cancer syndrome?

Allogeneic bone marrow transplantation has proved to be a radical form of cure in patients with beta-thalassemia major who have a human leukocyte antigen identical donor. Although malignant neoplasms are serious late complications of bone marrow transplantation, very few reports describing the development of malignant tumors after allografting for thalassemia appeared in the literature. A case is presented here of extraosseous Ewing's sarcoma that developed 8 years after allogeneic bone marrow transplantation performed for beta-thalassemia major. The phenotypic features of the patient's family fulfill the criteria for Li-Fraumeni syndrome. The patient was treated with chemotherapy and radiotherapy and died with recurrent disease. To the authors' knowledge, this is the first case of extraosseous Ewing's sarcoma after bone marrow transplantation for thalassemia. The possible contribution of transplantation procedure and the genetic factors as well as the primary genetic hemoglobinopathy to the development of this malignant tumor are discussed.

Adult↗

PubMed2001

Gilbert syndrome associated with beta-thalassemia.

The authors investigated whether the considerable variability in serum bilirubin levels (STB) found in transfusion-dependent beta-thalassemia, beta-thal intermedia, and heterozygous beta-thalassemia individuals could be related to the coexistence of Gilbert syndrome (GS). The promoter region [A(TA)nTAA] of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) was analyzed in a total of 128 beta-thalassemia individuals (108 transfusion-dependent beta-thal patients, 20 very mild beta-thal intermedia) and in 33 beta-thal heterozygotes. The control group consisted of 70 healthy children with no history of anemia. The frequency of GS genotype (TA)7/(TA)7 did not differ significantly between the groups studied. A significant difference was observed between serum bilirubin levels (STB) and GS genotypes (TA)7/(TA)7 and (TA)6/(TA)7 and also between (TA)7/(TA)7 and (TA)6/(TA)6 for all groups examined. These results confirm that the (TA)7/(TA)7 GS genotype is one of the factors accounting for the hyperbilirubinemia observed in beta-thalassemia major, intermedia, and heterozygous individuals.

Bilirubin↗

PubMedDate not supplied

Immunological status of thalassemia syndrome.

A major cause of morbidity and mortality in thalassemic patients is infections, assumed to be the result of immunological changes. In this study immune functions of peripheral blood lymphocytes have been studied in 38 beta-thalassemia major, 12 beta-thalassemia trait, and 17 healthy children. Results show decrease in CD4+/CD8+ ratios in the beta-thalassemia major group and no difference according to absolute T-lymphocyte numbers and activated T-cell numbers. These results do not correlate with the tendency to infection. No significant difference was found in humoral immunity. The study of other factors in thalassemia is needed to detect those who are more susceptible to infections.

Adolescent↗

PubMed2006

The usefulness of glycosylated hemoglobin (HbA1C) in discriminating between iron deficiency and thalassemia.

This study assessed whether glycosylated hemoglobin could be used as an index to distinguish between iron-deficiency anemia and thalassemia minor. Glycosylated hemoglobin was measured by high-pressure liquid chromatography in 40 ss -thalassemia minor patients, 20 iron-deficiency anemia patients, and 38 healthy controls, all nondiabetic. Median glycosylated hemoglobin was lower in ss -thalassemia minor than in the iron-deficiency and control groups (p = .000). There was no difference between iron-deficiency patients and healthy controls (p = .095). Glycosylated hemoglobin was not different in iron-replete and iron-deficient traits (p > .05). A cutoff value of 5% has provided a sensitivity of 95% and specificity of 75.7% for distinguishing between these two entities. Positive and negative predictive value were 96.6 and 67.9%. These values were superior to the traditional discriminants' values calculated on the same individuals. Glycosylated hemoglobin could be useful in discriminating between iron-deficiency anemia and thalassemia minor. Further studies are needed, but the point that it can also be used when both conditions exist simultaneously seems to be clinically important.

Adolescent↗

PubMed2005

Do alpha deletions influence hydroxyurea response in thalassemia intermedia?

Thalassemia intermedia patients show variable phenotypes. Hydroxyurea (HU) may benefit some of the thalassemia intermedia cases (1), however, the parameters influencing the response to HU have not been reported. In this study, the molecular parameters, alpha-globin and beta-globin genotype and the Xmn I polymorphism, were correlated with the HU response. Twenty patients with thalassemia intermedia were given HU (10-20 mg/kg) and responses were evaluated over a one year period. Twelve patients (60%) showed a good response to therapy with a significant increase in Hb and HbF levels and with elimination of the transfusion requirement in four patients. Four out of the twelve (33%) patients were positive for -alpha(3.7) deletions whereas none of the 8 non-responders were positive for alpha deletions. One each of the responders and non-responders were positive for alpha alpha alpha(anti-3.7) triplication. Three (25%) responsive and one non-responsive patients were homozygous for the IVS1-1 (G-->T) mutation. Three of the responsive patients with alpha deletions were also homozygous positive for Xmn I polymorphism. Thus, in addition to acting in synergy with the XmnI polymorphism, alpha deletions may be an independent factor predicting good response to HU in thalassemia intermedia, although this needs to be confirmation in larger studies.

Adolescent↗

PubMedDate not supplied

Neutrophil apoptosis in patients with beta-thalassemia major.

Increased susceptibility to infection is reported in patients with beta-thalassemia major due to toxic effect of iron on neutrophil functions and reticuloendothelial system dysfunction. This study investigated the association between the neutrophil apoptosis and frequency of infection episodes, desferrioxamine treatment, and serum ferritin levels in patients with beta-thalassemia major. A total of 35 children diagnosed with beta-thalassemia major were enrolled. Group 1 consisted patients who were receiving desferrioxamine (DFO) and group 2 consisted of patients who did not start to receive DFO. A total of 15 healthy children were enrolled to serve as a control group. Frequency of infection episodes within a year was noted from hospital records. In all patients, the same method based on flow cytometry (annexin V labeled with FITC) was used to assess neutrophil apoptosis. Neutrophil count and percentage of apoptotic neutrophils did not differ significantly between the groups. When frequency of infection episodes among groups was evaluated, frequency of infection episodes of the patients who were receiving DFO was significantly higher than in the other groups. When correlation between neutrophil apoptosis and frequency of infection episodes, serum ferritin levels, and neutrophil count of the patients was analyzed according to groups, no significant correlation was found. The results indicate that high serum ferritin level and DFO use in patients with beta-thalassemia major do not enhance neutrophil apotosis in vivo and enhanced neutrophil apoptosis cannot be a possible cause for increased susceptibility to infections in these patients.

Adolescent↗

PubMed2001

Molecular analysis of beta-thalassemia in South Vietnam.

The high prevalence of beta-thalassemia in Southeast Asia is a major public health problem. Development of genetic counseling and prenatal diagnosis programs is a priority. To provide the groundwork for such programs in South Vietnam, we determined the spectrum of beta-thalassemia mutations in 35 severely affected patients and their relatives. We identified six different beta-thalassemia alleles (five beta(0) and one beta(+) mutations), in addition to the common mutation at codon 26 (GAG --> AAG) responsible for Hb E. These data provide insights into the distribution of beta-thalassemia alleles in the Vietnamese population.

Alleles↗

PubMed2001

A multi-center study in order to further define the molecular basis of beta-thalassemia in Thailand, Pakistan, Sri Lanka, Mauritius, Syria, and India, and to develop a simple molecular diagnostic strategy by amplification refractory mutation system-polymerase chain reaction.

The spectrum of the beta-thalassemia mutations of Thailand, Pakistan, India, Sri Lanka, Mauritius and Syria has been further characterized by a multi-center study of 1,235 transfusion-dependent patients, and the mutations discovered used to assess the fidelity of a simple diagnostic strategy. A total of 44 beta-thalassemia mutations were identified either by allele-specific oligonucleotide hybridization, amplification with allele-specific primers, or DNA sequencing of amplified product. The results confirm and extend earlier findings for Thailand, Pakistan, India, Mauritius and Syria. This is the first detailed report of the spectrum of mutations for Sri Lanka. Two novel mutations were identified, codon 55 (-A) and IVS-I-129 (A-->C), both found in Sri Lankan patients. Two beta-thalassemia mutations were found to coexist in one beta-globin gene: Sri Lankan patients homozygous for the beta0 codon 16 (-C) frameshift were also homozygous for the beta+ codon 10 (C-->A) mutation. Studies of Sri Lankan, Pakistani, and Indian carriers suggest the codon 10 (C-->A) mutation is just a rare polymorphism on an ancestral allele, on which the beta0 codon 16 (-C) mutation has arisen. Each country was found to have only a few common mutations accounting for 70% or more of the beta-thalassemia alleles. A panel of primers to diagnose the majority of the mutations by the amplification refractory mutation system was developed, enabling a simple molecular diagnostic strategy to be introduced for each country participating in the multi-center study.

Asia↗

PubMed1991

Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia.

In an attempt to determine the mechanism whereby thalassemia in its milder forms may protect against malaria, we have examined the expression of neoantigen at the surface of Plasmodium falciparum-parasitized thalassemic red cells. Neoantigen expression was estimated by measurement of antibody bound after incubation in serum from adults living in a malaria-endemic area, using a quantitative radiometric antiglobulin assay. We found that P. falciparum-parasitized alpha- and beta-thalassemic red cells bind greater levels of antibody from endemic serum than controls: mean binding ratios (+/- SE), respectively, for alpha- and beta-thalassemia compared with controls were 1.69 +/- 0.12 and 1.23 +/- 0.06 on a cell for cell basis, and 1.97 +/- 0.11 and 1.47 +/- 0.08 after a correction for surface area differences. Binding of antibody increased exponentially during parasite maturation. In addition, we found a small but significant degree of binding of naturally occurring antibody to parasitized red cells, the extent of which was also greater in thalassemia. The apparent protective effect of thalassemia against malaria may be related to enhanced immune recognition and hence clearance of parasitized erythrocytes.

Animals↗

PubMed1999

Plasmodium falciparum infection: influence on hemoglobin levels in alpha-thalassemia and microcytosis.

Plasmodium falciparum malaria, alpha-thalassemia, and anemia are frequent in African children. In 494 nonhospitalized Nigerian children, P. falciparum infection rates, alpha-globin genotypes, and hematologic parameters were determined. P. falciparum infection was observed in 78% of the children. The gene frequency of alpha-thalassemia was 0.28. Infection rates and parasitemia were similar for the 3 alpha-globin genotypes. In contrast to nonthalassemic and heterozygous persons, infection in children with homozygous alpha-thalassemia did not influence hemoglobin values. Because microcytosis and anemia are common features of alpha-thalassemia, their significance in P. falciparum infection was examined. Microcytosis was significantly associated with protection from hemoglobin decrease due to P. falciparum. Moreover, the rate of infection was lower in microcytic than in normocytic anemia.

Blood Volume↗

PubMed1997

Frequency of deletional alpha-thalassemia genotypes in a predominantly Asian-American population.

alpha-Thalassemia is prevalent among Asian-Americans. Most cases involve deletions of one or more alpha-globin genes. Parents with two-gene cis deletions can have offspring with hemoglobin Bart's hydrops fetalis or hemoglobin H disease. The diversity of deletions poses special challenges to laboratories that offer DNA-based testing for alpha-thalassemia. The purpose of this study was to determine both the frequency of alpha-thalassemia genotypes in a predominantly Asian-American population (n = 78) and the mutation detection rate of a comprehensive Southern blot method. The ethnic composition of the study population was similar to the major Asian-American groups that reside in the United States as a whole. Three mutations (the Southeast Asian type, --SEA; -alpha3.7; and the Filipino type, --FIL) accounted for all mutant alleles present in the Asian-American patients tested for reproductive reasons. The relative frequencies of these three mutations were 62%, 27%, and 11%, respectively. The mutation detection rate was 100%. Laboratories that perform DNA-based alpha-thalassemia testing in populations similar to the one residing in Washington State should use a testing system that allows for the unequivocal identification of the haplotypes detected in the study population, namely --SEA, -alpha3.7, and --FIL.

Anemia↗

PubMed1997

The erythrocyte cell hemoglobin distribution width segregates thalassemia traits from other nonthalassemic conditions with microcytosis.

Red cell heterogeneity, as represented by the red cell distribution width (RDW), can be used to distinguish thalassemia traits from iron deficiency. Two other indices of heterogeneity, the hemoglobin distribution width and the cell hemoglobin distribution width (CHDW), are also available. In addition, the CHDW may reflect the process of cell hemoglobinization more accurately than does the RDW. In this study, recursive partitioning methods were used to compare the ability of these three indices to discriminate between thalassemia traits and other nonthalassemic conditions among hospital patients who had microcytosis. The data indicate that the CHDW can segregate patients who have either iron replete or iron deficient nonthalassemic conditions from those who have thalassemia traits. A CHDW level of less than 3.05 correctly discriminated 78.4% of patients in a mixed hospital sample. A CHDW/RBC ratio of 0.57 improved the segregation further, with a sensitivity of 79.2% and a specificity of 88.5% for the identification of a thalassemia trait.

Anemia, Iron-Deficiency↗

PubMed1987

Screening for alpha-thalassemia in neonates. Routine erythrocyte measurements.

Alpha-thalassemia can be diagnosed in the neonate based on the level of Bart's Hemoglobin (HbB) in cord blood. This level corresponds to the degree of alpha-gene deletion. Thus, the extent of the alpha-thalassemia carrier state can be determined. This is important for genetic counseling. Because HbB is present only until a child is six months of age, and the hematologic manifestations of the carrier state may be mild, early detection is important. This study identified a logarithmic relationship between the mean corpuscular volume (MCV) and HbB. Additionally, a discrimination level of 93.5 fL. was calculated to screen for neonates that required evaluation with hemoglobin electrophoresis to identify two- and possibly three-gene deletion alpha-thalassemia. The red blood cell indices were found not to be useful in identifying patients with a one-gene deletion alpha-thalassemia.

Erythrocyte Indices↗