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At least 19 recordsLinked to original sources
PubMed2001

Simultaneous PCR detection of beta - thalassemia and alpha - thalassemia 1 (SEA type) in prenatal diagnosis of complex thalassemia syndrome.

OBJECTIVE: To establish a rapid PCR method for simultaneous detection of beta-thalassemia and alpha-thalassemia 1 genes for diagnosis of complex alphabeta-thalassemia syndrome. DESIGN AND METHODS: Using multiplex allele specific PCR approach, we evaluated a simultaneous detection of the SEA type alpha-thalassemia 1 and the common Southeast Asian beta-thalassemia and hemoglobin E genes. The system was tested on known cases of double heterozygote for alpha- and beta-thalassemias and in a prenatal diagnosis of complex alphabeta-thalassemia syndrome. RESULTS: Co-inheritance of alpha-thalassemia 1 (SEA type) with each of the common beta-thalassemia genes in Southeast Asian and with hemoglobin E could be identified in a single PCR reaction. A successful application of this simultaneous detection system in prenatal diagnosis of a complex thalassemia syndrome caused by an EFBart's disease was demonstrated in a Thai family. CONCLUSION: We have shown that correct diagnosis of double heterozygosity for alpha-thalassemia 1 and beta-thalassemia or hemoglobin E could be obtained using a simultaneous multiplex PCR. These rapid PCR assays would facilitate characterization and prenatal diagnosis of complex thalassemia syndromes in the regions where both alpha- and beta-thalassemias and hemoglobin E are common.

Chorionic Villi Sampling↗
PubMed1999

Interaction of an alpha(+)-thalassemia deletion with either a highly unstable alpha-globin variant (alpha2, codon 59, GGC-->GAC) or a nondeletional alpha-thalassemia mutation (AATAAA-->AATAAG): comparison of phenotypes illustrating "dominant" alpha-thalassemia.

Thalassemia syndromes and unstable hemoglobins traditionally represent two phenotypically separate disorders of hemoglobin synthesis. Highly unstable hemoglobin variants, however, often have phenotypic characteristics associated with both ineffective erythropoiesis (thalassemias) and peripheral hemolysis (unstable hemoglobins). Many highly unstable beta chain variants cause a dominant thalassemia-like phenotype, in which simple heterozygotes for such mutations have a clinical expression similar to thalassemia intermedia. The phenotypic expression of highly unstable alpha-globin variants is usually less severe, due mainly to a gene dosage effect, and they are often only characterized on interaction with other alpha-thalassemia mutations, whence they are classified as nondeletional alpha-thalassemia determinants. This study reports the clinical and hematological findings in five cases with rare alpha-thalassemia genotypes: a single patient with the thalassemic alpha2-globin gene codon 59 Gly-->Asp hemoglobin variant in trans to an alpha(+)-thalassemia deletion, and four compound heterozygotes for the nondeletional alpha-thalassemia polyadenylation mutation (alpha2 gene AATAAA-->AATAAG or alpha(T-Saudi)alpha/-alpha) and an alpha(+)-thalassemia deletion. Evaluation of the clinical and hematological features in these two analogous genotypes clearly demonstrates the more severe clinical expression associated with the alpha-thalassemic unstable hemoglobin variant. In addition, the case in this study with the codon 59 alpha chain variant provides a further example illustrating the spectrum of phenotypes associated with the alpha-thalassemic hemoglobinopathies.

Adolescent↗
PubMedDate not supplied

Effect of alpha-gene numbers on the expression of beta-thalassemia intermedia, beta-thalassemia and (delta beta)0-thalassemia traits.

The effects of variations in alpha-gene numbers on phenotypical expression of beta-thalassemia are assessed in 11 subjects of 8 families. The study indicates that coexistence of alpha-thalassemia (-alpha3.7/alpha alpha) decreases the HbF in IVSI-6 homozygote and in delta beta thalassemia trait and may ameliorate the disease in beta-thalassemia compound heterozygotes associated with one mild and one severe beta-thalassemia mutation. Coexistence of alpha-gene triplication is associated with an increase in HbF value and may increase the severity of beta-trait or beta-thalassemia intermedia. The effects of alpha-gene triplication on phenotypic expression of beta-thalassemia trait may not be uniformly observed in every subject affected with a similar genotype.

Adolescent↗
PubMed1993

Thalassemia intermedia: compound heterozygous beta zero/beta(+)-thalassemia and co-inherited heterozygous alpha(+)-thalassemia.

The relative excess of alpha- over beta-globin chains in the erythroid precursors is the chief pathophysiological factor of homozygous beta-thalassemia. The clinical picture is usually characterized by a transfusion-dependent dyserythropoietic anemia (thalassemia major). However, some patients present with moderate anemia that does not require regular blood transfusions (thalassemia intermedia). The molecular heterogeneity of beta-thalassemia mutations and changes of alpha- and gamma-globin gene expression play an important role in modifying the clinical phenotype. We report here on a female Greek patient with homozygous beta-thalassemia but normal growth and development, excellent exercise tolerance, and no need of blood transfusions. She is thus mildly affected clinically, although there is marked pallor, jaundice, and hepatosplenomegaly. These signs correspond to her marked hypochromic, microcytic anemia with erythroid hyperplasia of the bone marrow. beta-Globin genotyping shows here to be compound heterozygous for the codon 39 C-->T beta zero-nonsense mutation and for the T-->C beta(+)-mutation at position 6 of the splice consensus at the exon 1/intron 1 junction (CD39 C-->T/IVS1-6 T-->C). alpha-Globin gene mapping demonstrates the presence of a 3.7-kb alpha (+)-thalassemia deletion on one allele (-alpha 3.7/alpha alpha). Taken together, this study identifies a complex interaction of genetic factors that do not significantly alter the clinical phenotype when present alone but ameliorate the course of homozygous beta-thalassemia when inherited in combination.

Base Sequence↗
PubMed1997

Red cell parameters in alpha-thalassemia with and without beta-thalassemia trait or hemoglobin E trait.

Eighty-five patients who attended at Ramathibodi Hospital during November 1994 to June 1996 were investigated for thalassemia genotype, hemoglobin (Hb) typing and blood cell parameters. All patients were screened primarily for complete blood count using the Technicon H*3 automated hematology analyzer and Hb typing using the automated HPLC. Their genotypes were evaluated by in vitro gene amplification using primers for detection of common alpha-thalassemic genes found in the Thai population. We found 45 cases out of 85 were alpha-thalassemia trait with A2A typing, 10 were normal, 7 were alpha-thalassemia trait complicated by beta-thalassemia trait or HbE trait, 18 were HbH disease or HbH with Hb Constant Spring (HbH/CS), and 5 were AE Bart's disease. The alpha-thalassemia 1 trait had heterogeneity in red cell population as shown by increased red cell distribution width (RDW), the increased percent microcytic red cell (%Micro) and decreased mean cell volume (MCV). Red cell parameters in alpha-thalassemia 2 trait and HbCS trait were not significantly different from normal. The cases with coinheritance of alpha-thalassemia trait with beta-thalassemia trait or with HbE trait showed variation in their red cell parameters: one case showed less abnormal red cell parameters than those of uncomplicated alpha-thalassemia but the other two cases showed unimproved values. The homozygous alpha-thalassemia 2 showed similar red cell parameters to the alpha-thalassemia 1 trait. In conclusion, we can screen the alpha-thalassemia 1 trait and homozygous alpha-thalassemia 2 by using the simple red cell parameters such as the MCV and RDW; however, they must be confirmed for alpha-thalassemic genes. Unfortunately, red cell parameters of alpha-thalassemia 2 trait or HbCS trait were not different from those of normal subjects.

Erythrocytes↗
PubMed1999

MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease.

OBJECTIVE: The purpose of this study was to evaluate the spectrum of MR findings of the brain in asymptomatic patients affected with thalassemia intermedia or sickle cell-thalassemia disease to prevent brain damage by identifying patients at risk for stroke so that transfusional or pharmacologic treatment could be implemented. SUBJECTS AND METHODS: Forty-one asymptomatic patients who were younger than 50 years and were affected by minor hemoglobinopathies underwent MR imaging of the brain. Ischemic lesions were classified as small, medium, or large and as single or multifocal. Atrophic changes were graded subjectively as mild, moderate, or severe. A grade of brain damage was assigned to every patient. The frequency and severity of brain damage were correlated with the number of sickle-cell crises per year, hemoglobin level, sickling hemoglobin level, platelet count, sex, and age. RESULTS: Of the patients with thalassemia intermedia, 37.5% showed asymptomatic brain damage, and 52% of those with sickle cell-thalassemia disease showed asymptomatic brain damage. In the thalassemia intermedia group, atrophy was always mild and ischemic lesions were generally small (25%) and single (25%). Among the patients with sickle cell-thalassemia disease, 24% had small, 16% had medium, and 12% had large ischemic lesions. Multifocal lesions were twice as common in the patients with sickle cell-thalassemia disease (20%) as in those with thalassemia intermedia (12.5%). Only in the patients with thalassemia intermedia did the frequency of brain damage increase with age. Moreover, brain damage inversely correlated with hemoglobin level in patients with thalassemia intermedia but not in those with sickle cell-thalassemia disease. Brain damage was more severe in patients with sickle cell-thalassemia disease who had more crises per year. CONCLUSION: This study suggests that patients with thalassemia intermedia and those with sickle cell-thalassemia disease may have asymptomatic brain damage. Our results suggest that MR imaging is useful in identifying patients at risk for stroke so that they can be treated with transfusional or pharmacologic therapy.

Adolescent↗
PubMed1993

[Molecular-genetic characteristics of alpha, beta and delta beta-thalassemias in 139 heterozygotes in 56 unrelated Czech and Slovak families (Priority description of 3 beta-thalassemia mutations, an extensive alpha-thalassemia 2 (18+ kb) deletion and a Swiss-type nondeletion hereditary persistence of hemoglobin F)].

In 135 subjects from 54 unrelated families of Czech and Slovak families the authors identified 11 different beta-thalassaemic alleles. In 25 families they proved a IVS I-1 (G-A) mutation. Another 4 "mediterranean" mutations: IVS II-1 (G-A), IVS II-745 (C-G); IVS I-110 (G-A) and mutations in the codon 39 (C-T) were found in 18 families. Mutation IVS I-5 (G-C) found in one family is common in Asia. A frameshift at codons 82/83(-G) found in two families, was described previously only by Schwartz in one families from Azerbaijan. A rare mutation in codon 121 (C-T) is usually characterized as beta-thal. with formation of Heinz bodies. The latter were however found only in one of three families with this allele. Newly detected alleles include: mutation in codon 112 (T-A) found in one family (surprisingly also without formation of Heinz bodies); mutation in CD 115 (GCC-GAC) which results in unstable variant of Hb-Hradec Králové alpha 2 beta 2 115 (G17) Ala-Asp with formation of Heinz bodies and a frame shift in codons 38/39(-C) found in two families. In one of them there was also a new mutation of the promotor area of the G gamma gene (-110 A-C) causing the Swiss type of the disease with hereditary persistence F haemoglobin. The so-called Sicilian type of delta beta thalassaemia caused by deletion of DNA length cca 13 kb starting in IVS-II was found in one patient. alpha-thalassaemic mutations are rare in this population. In addition to common alpha-thalassaemia 2(-3,7 kb) deletion, however, also a new alpha-thalassaemia 2 was found caused by a large (18+kb) deletion involving alpha 1 and theta globin genes. alpha alpha alpha anti 3,7 triplication found in 7 beta-thal. heterozygotes led to deterioration of parameters of the red cell haemogram.

Base Sequence↗
PubMed1970

Mild thalassemia: the result of interactions of alpha and beta thalassemia genes.

Homozygous thalassemia is due to inherited unbalanced synthesis of the alpha- or beta-chains of hemoglobin. Clinical severity may be in part related to the extent of alpha:beta imbalance. Two families are presented that illustrate this concept. Thalassemia in these individuals was evaluated by clinical and genetic criteria. The relative rates of alpha- and beta-chain synthesis in their reticulocytes were estimated by the extent of incorporation of 1-leucine-U-(14)C into the chains. Unusual combinations of clinical and hematological data and biosynthetic ratios were obtained in certain individuals which indicated the presence of combinations of alpha- and beta-thalassemia genes. The propositus of the first family had mild Cooley's anemia and was believed to have one alpha- as well as two beta-thalassemia genes. Presumably the alpha-thalassemia gene interfered with alpha-chain production which lead to less accumulation of alpha-chains and a reduced rate of intramedullary and peripheral hemolysis. In the second family two individuals were believed to have an alpha-thalassemia, a "silent carrier," and a beta-thalassemia gene. Despite the fact that they appeared to have the genotype of hemoglobin H disease, their cells contained no hemoglobin H and had a normal lifespan presumably because excess beta-chain production was inhibited by the beta-thalessemia gene. These family studies suggest that the alpha:beta imbalance observed in thalassemia may be favorably influenced by combinations of alpha- and beta-thalassemia genes.

Adult↗
PubMed1991

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations.

In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the beta-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent beta-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe beta-thalassemia mutation and a beta-thalassemia mutation associated with high residual output of beta-globin chains (beta + intervening sequence [IVS]-I-nt6, beta -87, beta -101), indicating that inheritance of a mild beta-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the beta + globin gene and found three novel beta-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans beta-globin gene (The reason for the presence of clinical manifestations in a beta-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5' untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal beta-globin gene sequences at the other locus.

Adult↗
PubMed1976

Thalassemia intermedia caused by heterozygosity for both beta-thalassemia and hemoglobin Saki [beta 14 (A11) Leu replaced by Pro].

The syndrome thalassemia intermedia can be the clinical expression of heterozygosity for different tyes of thalassemia, beta-thalassemia and hereditary persistence of fetal hemoglobin, beta-thalassemia and Hb-Lepore, and in blacks it may even represent a true beta-thalassemia homozygote. This report describes thalassemia intermedia in a white male due to beta-thalassemia and an unstable hemoglobin. Chain-synthesis studies showed an excess of alpha-chain production over beta-chain production in the propositus and his mother but balanced chain synthesis in the clinically normal father, who is heterozygous for the unstable hemoglobin. The unstable hemoglobin was found to be beta14 (A11) Leu leads to Pro, which has previously been described in a clinically normal African woman, and named Hb-Saki. This hemoglobin is not distinguishable from Hb-A on routine electrophoresis at alkaline or acid pH and tests for unstable hemoglobins are necessary for its detection. The increasing list of such hemoglobin variants and previous cases of heterozygosity for beta-thalassemia and unstable hemoglobins are reviewed.

Adolescent↗
PubMed1996

Antenatal screening and fetal diagnosis of beta-thalassemia in a Chinese population: prevalence of the beta-thalassemia trait in the Guangzhou area of China.

In this paper beta-globin gene mutations were detected in 452 beta-thalassemia carriers from 13462 unselected individuals (6731 pregnant women and their husbands) who were screened for the beta-thalassemia trait in the Guangzhou area of China. The incidence of beta-thalassemia was calculated as 3.36%. This is higher than found in previous studies performed in southern China. Using reverse dot blot analysis, we found 11 types of mutations and identified the mutations in 446 (98.7%) of the 452 cases. Direct sequencing was carried out on the 6 unknown alleles, and a novel amber mutation in a beta 0-thalassemia gene (beta 37TGG --> TAG) was found in one of them. Thus, the prevalence and spectrum of beta-thalassemia mutations were obtained for this region. Twelve couples were detected at risk for thalassemia, and prenatal diagnosis was carried out in 11 of them. This is the largest number of Chinese subjects studied by DNA analysis to date and is the first report on the prospective diagnostic trial for beta-thalassemia in a Chinese population. In addition, we have performed 80 prenatal diagnoses based on screening for beta-thalassemia retrospectively.

Amino Acid Sequence↗
PubMed2002

Beta-thalassemia intermedia from southern Iran: IVS-II-1 (G-->A) is the prevalent thalassemia intermedia allele.

The preliminary results of a pilot study are reported, intended as an initiation of a research plan, focused on the prevention of beta-thalassemia in Iran. The aims of this study are: (i) to improve the knowledge of the molecular background of beta-thalassemia intermedia in Southern Iran; (ii) to verify the role of the -158 (G)gamma (C-->T) (Xmn I) polymorphism as a modulating factor in thalassemia intermedia; (iii) to test the validity of the multiplex and single mutation specific amplification refractory mutation system in analyzing the molecular defects causing beta-thalassemia in multiethnic populations; and (iv) to develop suitable strategies for the application of prevention protocols in Iran. To accomplish the task we have selected 87 beta-thalassemia intermedia patients and adapted the DNA methodology to detect the following 11 frequent mutations in Iran: codon 5 (-CT); frameshift codons (FSC) 8/9 (+G); codon 30 (G-->C); IVS-I-1 (G-->A); IVS-I-5 (G-->C); IVS-I-6 (T-->C); IVS-I-110 (G-->A); codons 36/37 (-T); codon 44 (-C); IVS-II-1 (G-->A); IVS-II-745 (C-->G). Because of the multiethnicity of the population we have also included the Indian IVS-I (25 bp deletion) and the Mediterranean IVS-I-130 (G-->C) and codon 39 (C-->T) mutations. Forty-eight patients were randomly studied for the Xmn I polymorphism together with 50 healthy volunteers as a control group. The molecular analysis conducted in Iran, identified only 31% of the alleles that were presumed to be thalassemic, revealing either a strategic or a technical insufficiency of the chosen method. However, the mutations with the highest prevalence in the country (IVS-II-1, IVS-I-110, IVS-I-1 and FSC 8/9) were found. As expected the IVS-II-1 defect, being the most frequent in south Iran, was present at the highest rate (24%). The Xmn I polymorphism was found in association with this prevalent mutation and was detected in the homozygous state in 87.5% of the patients homozygous for the IVS-II-1 (G-->A) mutation. The overall positivity for Xmn I was found in 40.6% of the thalassemic alleles vs. 14% in the non-thalassemic, confirming the hypothesis of an older event, antecedent to the IVS-II-1 mutation. In trying to assess a more suitable molecular detection method we intend to continue this study in collaboration with the European centers involved, applying more effective technologies and better defining the molecular spectrum of beta-thalassemia in the sub-populations. We also intend to verify the effect of alpha-thalassemia in the genotype/phenotype correlation of beta-thalassemia intermedia.

Case-Control Studies↗