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PubMed1985

Alpha zero- and beta zero-thalassemia in a Thai family: unusually mild homozygous beta zero-thalassemia without alpha-globin gene deletion.

Alpha-globin genes were analyzed by the direct method of DNA mapping using alpha- and zeta-globin specific probes in a Thai family in which the proposita was an unusually mild beta zero-thalassemia homozygote. alpha zero-Thalassemia was found to be segregating in the family, inherited from the proposita's father by one of her younger sisters. However, alpha zero-thalassemia was not detected by this DNA mapping in the proposita. The mild homozygous beta zero-thalassemia in this family may result from interactions of a non-deletion alpha-thalassemia, a gene responsible for high proteolytic activity permitting more balanced globin-chain levels, or from an unusually active hemoglobin F production in the proposita.

Chromosome Deletion↗
PubMed2004

Cardiac involvement in beta-thalassemia major and beta-thalassemia intermedia.

The forms and severity of cardiac complications were investigated in patients with asymptomatic thalassemia intermedia and thalassemia major by M-mode, bi-dimensional echocardiography (ECHO) and echo-Doppler. Twenty-eight patients of both sexes with beta-thalassemia intermedia (beta-TI), mean age 23.2 +/- 6.3 years, untransfused or minimally transfused, were compared to 42 age- and sex-matched subjects with thalassemia major, who were regularly treated with hemotransfusive therapy [pre-transfusion hemoglobin (Hb) values 9.5 +/- 0.9 g/dL] and iron chelation. All patients were splenectomized. Age and sex matched healthy control subjects were randomly selected. beta-Thalassemia major (beta-TM) patients showed a marked reduction in contractile state and a milder left ventricular (LV) enlargement than beta-TI patients. Cardiac output (CO) and cardiac index (CI) were increased in both groups of patients but appeared significantly higher in beta-TI patients with consequent altered LV diastolic function indices. In addition, beta-TI patients had reduced indices of pulmonary artery flow related to long-term chronic anemia rather than iron overload. The progressive rise in CO and CI casts doubts on the current management of beta-TI syndromes.

Adolescent↗
PubMed1988

Thai (delta beta)0-thalassemia and its interaction with gamma-thalassemia.

A variant of Southern Italian (delta beta)0-thalassemia is described in a women of Thai origin. The 3' breakpoint in Thai (delta beta)0-thalassemia is located about 1 kb upstream to that in Southern Italian (delta beta)0-thalassemia and produces a smaller deletion of approximately equal to 12.5 kb. Hematological phenotype, particularly Hb F output, is similar to that found in G gamma A gamma(delta beta)0-thalassemia despite the presence of a coexistent gamma-thalassemia effect.

Chromosome Deletion↗
PubMed2001

Short stature and truncal shortening in transfusion dependent thalassemia patients: results from a thalassemia center in Malaysia.

One of the major complications in patients with transfusion dependent thalassemia is growth impairment secondary to iron overload. We studied the growth status in 66 patients with beta-thalassemia major and HbE-beta thalassemia who were transfusion dependent, aged from 2 to 24 years, and 66 controls matched for sex and age. The prevalence of short stature in transfusion-dependent thalassemics was 54.5% compared to 4.5% in control group (p<0.001). Short stature was more prevalent in those above the age of 10 years in this study group (83.3% vs 16.7%). Transfusion dependent thalassemics with short stature were found to have significantly lower mean standing height standard deviation scores (SDS), sitting height SDS and subischial leg length SDS values (p<0.001). There was also a significant difference between the mean sitting height SDS and the mean subischial leg length SDS in our thalassemics with short stature, suggesting that the short stature was due to disproportionate truncal shortening. Serum ferritin levels were significantly higher in transfusion dependent thalassemics who were short compared to those who were of normal height (p = 0.002). However, the mean pre-transfusion hemoglobin levels did not differ significantly between patients with short stature and those with normal height (p = 0.216). The prevalence of short stature also did not differ significantly between those with beta-thalassemia major and those with HbE-beta thalassemia (p = 0.32). This study highlighted the importance of providing optimal treatment in these patients, including monitoring of growth parameters and optimizing iron chelation therapy.

Adolescent↗
PubMed1989

Interaction between deletion delta-thalassemia and beta zero-thalassemia (codon 39 nonsense mutation) in a Sardinian family.

This paper describes individuals of Sardinian descent with heterozygous normal-Hb A2 beta-thalassemia who have a chromosome with a 7.2 Kb deletion in the psi beta/delta globin intergenic region and a chromosome with the codon 39 nonsense mutation. The propositus has the typical thalassemia-like red cell indices with a relatively high Hb level (13.4 g/dl) for a beta-thalassemia carrier, indicating a normal function of the beta-globin gene in cis to the 7.2 Kb deletion. The deletion starts between the psi beta and delta genes and ends in the IVS-2 of the delta-gene. His breakpoints are identical to a previously described deletion detected in the homozygous state in a patient with thalassemia intermedia, homozygous for G-greater than A mutation at position 5 of IVS-1. Because the mutation herein described silences the delta-globin gene and leaves intact the function of the in cis beta-globin gene we propose the definition of deletion delta zero-thalassemia.

Chromosome Deletion↗
PubMedDate not supplied

The effect of the beta thalassemia mutation on the clinical severity of the sickle beta thalassemia syndrome.

In this study, we have defined the beta thalassemia mutation and characterized the beta globin haplotype and the alpha globin gene arrangement in a group of patients of Sicilian descent with beta (s)/beta thalassemia. We found that those patients carrying a beta(+) thalassemia mutation associated with a moderate reduction of beta chain synthesis (beta(+) IVS-1 nt 6) have normal or reduced Hb levels and mild to moderate clinical manifestations, as defined by the number of hospital admission and sickle cell crises per year. Those patients carrying a beta(+) thalassemia mutation associated with a severe reduction of beta chain synthesis (beta(+) IVS-1 nt 110) have a disease of moderate severity. In those carrying a beta(0) thalassemia gene the disease was clinically very heterogeneous, ranging in severity from mild to severe with no difference related to the type of mutation [beta(0) 39, beta(0) IVS-1 nt 1, beta(0) IVS-2 nt 1, beta(0) 6 (-1bp)]. In this last group of patients part of the clinical variability may be attributed to the HbF levels, which were higher in those with mild to moderate clinical severity.

Anemia, Sickle Cell↗
PubMed1981

Clinical presentation of thalassemia major due to homozygous beta (0)-thalassemia.

This study concerns the clinical presentation of all thalassemia major or intermedia in children admitted to out genetics department from January 1978 to December 1979. At electrophoresis and/or globin chain synthesis analysis on column chromatography. All these patients were shown to have homozygous beta(0)-thalassemia. The clinical severity was highly variable, dependent on age at presentation and when the patient first became dependent on transfusions. On the main reasons for this variability may be associated with thalassemia 1 or alpha-thalassemia 2 which have an incidence figure of 13 % in our population and hence also in these patients. Remarkable findings of the clinical and hematological picture were: (a) early spleen enlargement and growth deficiency; (b) MCV and MCH values intermediate between normals and beta-thalassemia heterozygotes; (c) normal mean hemoglobin A2 percentage and corpuscular concentration; (d) frequently increased transferrin saturation and ferritin levels; (e) presentation at age greater than 2 with hemoglobin levels about 9 g/dl usually associated with a milder course.

Adolescent↗
PubMed2003

Thalassemia intermedia as a result of heterozygosis for beta 0 -thalassemia and alpha alpha alpha anti-3,7 genotype in a Brazilian patient.

We report a case in which the interaction of heterozygosis for both the 0-IVS-II-1 (G->A) mutation and the alpha alpha alpha anti-3,7 allele was the probable cause for the clinical occurrence of thalassemia intermedia. The propositus, a 6-year-old Caucasian Brazilian boy of Portuguese descent, showed a moderately severe chronic anemia in spite of having the -thalassemia trait. Investigation of the alpha-globin gene status revealed heterozygosis for alpha-gene triplication (alpha alpha alpha / alpha alpha). The patient's father, also presenting mild microcytic and hypochromic anemia, had the same alpha and genotypes as his son, while the mother, not related to the father and hematologically normal, was also a carrier of the alpha alpha alpha anti-3,7 allele. The present case emphasizes the need for considering the possibility of alpha-gene triplication in -thalassemia heterozygotes who display an unexpected severe phenotype. The -thalassemia mutation found here is being described for the first time in Brazil.

Alleles↗
PubMed1993

[The first case of thalassemia intermedia in Spain due to the interaction of 3 alpha genes with beta-thalassemia minor].

We have identified the case of a 9-months-old girl with heterozygotic thalassemia and triplication of alpha genes of globin (alpha alpha alpha 3.7). Molecular defect of thalassemia was a mutation without sense of 39 codon. Patient's phenotype was an intermediate thalassemia with moderate splenomegaly and marked unbalance on the globin chains. This is the first case of intermediate thalassemia, through this mechanism, described in Spain.

Female↗
PubMed1998

Heterozygous beta-thalassemia with thalassemia intermedia phenotype.

In this study we investigated the molecular bases of the beta-thalassemia intermedia phenotype in six patients belonging to two unrelated families of Sardinian descent. Sequence analysis of the beta globin gene from these patients detected, as the sole abnormality, the heterozygosity for the codon 39 nonsense mutation. The A gamma and Ggamma promoters as well as the HS2 and HS3 core sequences of the beta globin LCR from these patients, did not show any non-polymorphic nucleotide variation from the consensus sequence. One of the parents was heterozygous for codon 39 nonsense mutation but showed the beta-thalassemia carrier phenotype; the other was hematologically normal and had an entirely normal beta globin gene sequence. In both families, other members showed the typical hematological phenotype, clinically silent, of heterozygous beta thalassemia. To explain the thalassemia intermedia phenotype, we postulated the presence of an unknown molecular defect interacting with the beta globin gene mutation. Haplotype analysis excluded that this postulated defect lies in the beta globin gene cluster.

Adolescent↗
PubMed2006

Impact of a national beta-thalassemia carrier screening program on the birth rate of thalassemia major.

BACKGROUND: In Taiwan, the prevalence of beta-thalassemia trait is at least 1.1%. The Taiwan government initiated a National Screening Program in 1993. Herein we examine the differences before and after the initiation of this program. PROCEDURE: Data consisting of the total number of patients and the birth prevalence beta-thalassemia major were collected. Ninety-one patients with transfusion-dependent thalassemia treated in our hospitals were included for analysis. DNA analysis was performed for 86 patients. RESULTS: In Taiwan 361 patients exist. The birth prevalence of per 100,000 births was 5.6% in 1994 and declined to 1.21 in 2002. Fourteen patients were born after the program's initiation. DNA analysis of them revealed a new mutation (IVS-1-5 (G-C)), which was introduced through an inter-racial marriage. Otherwise, the remainder was the common beta-thalassemia mutations found in Taiwan. CONCLUSIONS: Despite how successful the National Screening Program is, a few doctors still failed to detect parents at risk. In addition, we are concerned about the emerging problem of the increase of interracial marriages where parents may not have appropriate screening. Hence, postgraduate education programs for physicians, health education for the general population, and timely screening of inter-racial marriage should become a priority.

Child↗
PubMed1985

Thalassemia in southeast Asia: determination of different degrees of severity of anemia in thalassemia.

beta (0)-Thalassemia/Hb E in Southeast Asia varies greatly in severity, with hemoglobin levels ranging from 2.5 to 13.5 g/dl, averaging 7.7 g/dl. Results of systematic investigations to find out what determines different levels of severity are reviewed. Concomitant inheritance of alpha-thalassemia significantly decreases the severity. Different degrees of severity in the majority of cases, however, is not due to alpha-thalassemia. Concordance of hemoglobin levels among patients who are sibs prevails, suggesting polygenic factor determinants. Potential factors ruled out as determinants for different levels of severity are discriminating fetal hemoglobin production, erythrocyte superoxide dismutase activity, reticulo-endothelial function, and failure of erythropoiesis compensation. Red cell survival and globin synthesis studies indicate that different degrees of excess of alpha-chains leading to different red cell pathology and survival are responsible for variable severity. Degrees of excess of alpha-chains in this circumstance are probably mainly determined by erythrocyte proteolytic activity. The relationship between the hemoglobin levels and erythrocyte cytosol proteolytic activity in 15 beta(0) -thalassemia/Hb E disease patients in whom a deletional type of alpha-thalassemia had been ruled out by DNA mapping is striking, with a correlation coefficient of 0.78. This finding suggests that modulation of erythrocyte proteolysis is another approach for treatment of thalassemia.

Asia, Southeastern↗
PubMed1989

Beta-thalassemia intermedia in two Turkish families is caused by the interaction of Hb Knossos [beta 27(B9)Ala----Ser] and of Hb City of Hope [beta 69(E13)Gly----ser] with beta (0)-thalassemia.

We have studied a few members of two Turkish families, who had a beta-thalassemia of the intermediate type. An abnormal hemoglobin was found in both families, which when present in association with beta(0)-thalassemia was considered to be the primary cause for the increased severity of the disease. In the first family this variant was Hb Knossos [beta 27(B9)Ala----Ser] which occurred together with the frameshift in codon #8 type of beta(0)-thalassemia. This compound heterozygosity, observed for the first time in the Turkish population was characterized by a considerable increase in Hb F production, mainly of the G gamma type, as expected for a chromosome with haplotype IV. In the second family, the variant was Hb City of Hope [beta 69(E13)Gly----Ser] which was present in combination with an unknown type of beta-thalassemia. The increase in Hb F production in the compound heterozygote was minimal. Reversed phase high performance liquid chromatography and the DNA amplification-synthetic oligonucleotide probe procedure were major tools in identifying the different abnormalities.

Adult↗
PubMed1992

Determination of hemoglobin Bart's in alpha thalassemia traits by two-site immunoradiometric assay. II. Detection of hemoglobin Bart's in alpha thalassemia traits.

A sensitive method for the determination of minute amounts of Hb Bart's in hemolysate of alpha thalassemia-1 and alpha thalassemia-2 was carried out by two-site immunoradiometric assay. This technique is very sensitive and is able to detect minute amounts of substances. When this method is used with specific anti-Hb Bart's derived from affinity column chromatography, then labelled with radioactive 125I, the two-site immunoradiometric assay will contain both the sensitivity and specificity for the determination of Hb Bart's. In this study, parents of fetus with Hb Bart's hydrops fetalis contained high levels of Hb Bart's 0.73-1.11 per cent (mean +/- S.D. = 0.86 +/- 0.12%). Parents of Hb H diseases had Hb Bart's in two groups. The first group contained high levels of Hb Bart's of 0.73-1.20 per cent (mean +/- S.D. = 0.88 +/- 0.14%), while the second group had levels of 0.39-0.45 per cent (mean +/- S.D. = 0.42 +/- 0.02%). Mothers of patients with Hb H disease contained Hb Bart's of 0.42 +/- 0.48 per cent (mean +/- S.D. = 0.45 +/- 0.02%). Eight out of ten normal subjects contained low levels of Hb Bart's of 0.17-0.26 per cent (mean +/- S.D. = 0.22 +/- 0.04%), while two contained high levels of Hb Bart's of 0.46 and 0.43 per cent respectively. The two-site immunoradiometric assay was able to differentiate the level of Hb Bart's among alpha thalassemia-1, alpha thalassemia-2 and normal subjects.

Hemoglobins, Abnormal↗
PubMed1992

Thalassemia in the outpatient department of the Yangon Children's Hospital in Myanmar: knowledge, attitudes and practice in relation to thalassemia.

A maternal knowledge, attitudes and practice (KAP) study concerning the nature and prevention of thalassemia was carried out at the Yangon Children's Hospital in Myanmar. The KAP information was collected using a pretested schedule. Only 18 to 28% of the mothers knew at least one of the statements: thalassemia is a genetic disorder; both parents of thalassemic children carry abnormal genes; there is a 25% chance of recurrence in each subsequent pregnancy. Eighty-two per cent of the respondents decided not to have a further pregnancy for fear of recurrence and of these 62% were currently practising contraception. Oral contraception was the most commonly used method (56%). The median scores as well as the percent responses in favor of the three attitude scales relating to limiting thalassemic children, prenatal diagnosis and termination of pregnancy were high. Although there is a need to increase the community awareness of thalassemia in Myanmar, there is a possibility that prenatal diagnosis and pregnancy termination will be accepted for the prevention of thalassemia.

Abortion, Induced↗
PubMed2004

High frequency of deletional alpha-thalassemia in beta-thalassemia trait: implications for genetic counseling.

Thalassemias are a group of genetic hemolytic disorders with varying phenotypes. In this study, the frequency of alpha globin gene deletions was studied in the beta-thalassemia trait, the mildest form of the disorder. Eleven out of 33 (33%) individuals were positive for alpha(-3.7 kb) deletions. None of the subjects was positive for the Southeast Asian deletion. Such a high frequency for alpha deletions has not been reported earlier in thalassemia minor. Hematological parameters are compared, and implications of this finding for genetic counseling are discussed.

Adolescent↗
PubMed1983

Unusual combination of genetic defects in a Sicilian boy: G gamma delta beta thalassemia, G gamma A gamma heterocellular HPFH, beta (0) thalassemia, and albinism.

We describe the clinical and hematological findings in a 5-year-old boy with G gamma A gamma delta beta thalassemia, a G gamma A gamma heterocellular form of HPFH, beta(0) thalassemia, and albinism. Clinically he manifested only the characteristics of beta-thalassemia trait and not the typical picture of doubly heterozygous beta thal/delta beta thal. The simultaneous presence of heterocellular HPFH improves gamma chain synthesis, thus reducing the alpha chain excess. It is also possible that gene expression can be modified by the presence of other genetic anomalies.

Albinism↗
PubMedDate not supplied

Targeted correction of the point mutations of beta-thalassemia and targeted mutagenesis of the nucleotide associated with HPFH by RNA/DNA oligonucleotides: potential for beta-thalassemia gene therapy.

An RNA/DNA chimeric oligonucleotide was found to be effective in the targeted correction of point mutations in Escherichia coli, plant, and mammalian genomes. This strategy, named chimeraplasty, has the potential for gene therapy of many genetic diseases caused by point mutations. beta-Thalassemia is a very common human genetic disease and in most cases it is caused by point mutations. To test whether the chimeraplasty can be used to correct the point mutations responsible for beta-thalassemia, we introduced one mutated beta-globin gene, betaE, into MEL cells and successfully corrected the point mutation of the betaE gene with the highest correction efficiency of 1.9%. Furthermore, a targeted -202 C-->G mutation of the Ggamma-globin gene, which is associated with the elevated Ggamma-globin gene expression in the adult stage, was introduced into HeLa and CMK cells by an RNA/DNA oligonucleotide. These results indicated that the chimeraplasty has potential for human beta-thalassemia gene therapy.

Animals↗