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PubMed1995

The great heterogeneity of thalassemia molecular defects in Sicily.

This paper reports the results of 1428 beta-thalassemia chromosomes studied in Sicily during a hemoglobinopathy control program starting in 1983. Molecular screening was performed by direct restriction enzyme analysis, allele specific oligonucleotide (ASO) hybridization, reverse dot blot analysis (RDB) and, for the rare or new mutations, by direct sequencing of polymerase chain reaction (PCR) products. Using these approaches 1410 (98.7%) out of 1428 beta-globin gene defects were characterized, involving 22 different beta-thalassemia mutations. Three of these were present at high frequency (beta(0)39, IVS1, 110 and IVS1,6); the other beta-globin gene defects were found at lower frequency. In the latter, we found a smaller group of mutations at a frequency lower than 10% (IVS1, 1, IVS2, 745, beta S) and a larger one at a frequency lower than 2% [-87, IVS1,2, IVS2,1, fr 6, fr 8 (-AA), fr 44, fr 76, -101, IVS1, 116, IVS1, 3'end G-C, IVS1,5 G-A, IVS1,5 G-C, cod 30, Lepore, delta beta, beta C]. The possible origin of this very large number of mutations is discussed, taking into account the historical point of view. Moreover, this approach has made a first trimester prenatal diagnosis program possible in our region in practically all cases, with a great improvement in general thalassemia management.

DNA↗
PubMed1987

Population structure of Sicily: beta-thalassemia and HbS.

The population structure of two alleles with similar characteristics, HbS and beta-thalassemia, was studied in the same area in Sicily. It was observed that beta-thalassemia has uniform frequencies over the island, and that HbS shows a South-North cline. A singularity exists for HbS in the town of Butera, where the frequency of the S gene is six times higher than the island average. It was suggested that HbS entered Sicily from Greece (or directly from North Africa) when the beta-thalassemia allele was already established in the Island.

Alleles↗
PubMed1989

Autosomal dominant polycystic kidney disease and alpha -4.2 thalassemia in a Caucasian family.

We describe the first known association between autosomal dominant polycystic kidney disease (ADPKD) and alpha-4.2 thalassemia in a Caucasian family. Linkage studies have been carried out using two probes (3'HVR and 24-1) linked to ADPKD on locus PKD1 and two probes (alpha 1-PstI and BamH-I/EcoRI-zeta 2 fragment) allowing detection of alpha-thalassemia with either a 3.7-kb deletion or a 4.2-kb deletion. Our results show that to avoid misinterpretation it is important to investigate the occurrence of an alpha-gene deletion when polymorphisms situated in the alpha-globin locus are used for linkage studies on ADPKD. The studied family is one of the rare cases of leftward deletional thalassemia described in a non-Asian population.

Chromosome Deletion↗
PubMed1989

A novel delta zero-thalassemia arising from a frameshift insertion, detected by direct sequencing of enzymatically amplified DNA.

We describe a novel mutation in the delta globin gene of a compound heterozygote for delta o thalassemia and a deletion type G gamma + (A gamma delta beta) zero thalassemia. The delta was amplified using the polymerase chain reaction (PCR), and the amplified material was used in a direct sequencing experiment. The nucleotide sequence of the mutant delta gene showed that the insertion of an extra nucleotide at the third position of codon 91 in the second exon, which gives rise to a premature stop codon at position 94, leads to the silencing of this gene. The presence of the mutation in the carriers of delta-thalassemia in this family was confirmed by dot blot hybridization. A possible model for the insertion of the extra nucleotide is discussed.

Base Sequence↗
PubMed1983

Alpha-globin loci in homozygous beta-thalassemia intermedia.

Homozygous beta-thalassemia intermediate (TI) differs from thalassemia major (TM) in being less severe clinically. Associated alpha-thalassemia could account for the TI phenotype by reducing the alpha/non-alpha chain imbalance. We have analyzed the alpha loci of 9 TI and 11 TM patients by restriction endonuclease mapping. All the TM and 7 of the TI patients have the normal complement of four alpha-globin genes (alpha alpha/alpha alpha). One TI patient has three alpha-globin genes (alpha alpha/-alpha), and another TI patient has five alpha genes (alpha alpha/alpha alpha alpha).

Adolescent↗
PubMed1985

Heterogeneity of the alpha-globin gene defects in German alpha-thalassemia affected families.

Analysis of alpha-thalassemia syndromes in several German families revealed DNA deletion as well as non-deletion forms as the molecular basis for the defects. Thus, the alpha-thalassemia haplotype was identified as the (-alpha)3.7 rightward deletion form, and the region of the putative recombination process generating such a deletion was further characterized. In addition three different alpha(0)-thalassemia haplotypes, (--)MED, (--) > 26, and (alpha alpha)T, could be detected using alpha- and zeta-globin gene-specific probes.

Chromosome Deletion↗
PubMed1984

Heterocellular hereditary persistence of fetal hemoglobin (HPFH). Molecular mechanisms of abnormal gamma-gene expression in association with beta thalassemia and linkage relationship with the beta-globin gene cluster.

We report a study of four families of Italian origin in which heterocellular HPFH is inherited linked to beta thalassemia over two or three generations. The HPFH + beta thalassemia carriers showed thalassemic blood pictures and elevated HbF and F-cell number without increase in the HbF/F-cell content. Association of this gene complex with a second beta thalassemia trait gives rise to a mild clinical picture characterized by 9-12 g/dl of mainly HbF in peripheral blood and no transfusion requirement. In two families, independent segregation of the HPFH or beta-thal trait was observed, and in one case the study of the DNA polymorphisms within the gamma delta beta gene cluster indicated that the HPFH mutation lies outside that DNA region. In one family the coexistence of a polymorphic variant of the A gamma chain (the A gamma T chain) allowed us to demonstrate that the increased gamma chain synthesis caused by the heterocellular HPFH determinant is directed by both chromosomes.

Adolescent↗
PubMed1983

Four new haplotypes observed in Algerian beta-thalassemia patients.

beta-Thalassemia, a heterogeneous group of human anemias affecting the expression of beta-globin, is caused by a number of molecular defects. Restriction endonuclease mapping of ethnic populations has revealed many polymorphisms within and around the beta-like globin genes, combinations of which are assigned as haplotypes. Several haplotypes appear to be strongly linked with the molecular defects causing thalassemia in Greek and Italian patients (Orkin et al. 1982). We describe here haplotypes from 40 Algerian beta-thalassemic patients and eight normals determined by restriction endonuclease mapping at seven polymorphic sites. Four haplotypes previously unreported were observed in these thalassemic patients; this argues the existence in this population of undescribed beta-thalassemia alleles. The knowledge of the haplotypes in thalassemic families could be used for prenatal diagnosis of homozygote forms.

Algeria↗
PubMed1988

Molecular basis of beta thalassemia in south China. Strategy for DNA analysis.

The phenotype of beta thalassemia can be caused by over 40 different mutations. To set up a prenatal diagnosis program using DNA analysis, it is important to determine the type and frequency of mutation in a particular geographic area. We have delineated the molecular lesions that cause beta thalassemia in the Guangdong province of China, and found six mutations in four different haplotypes. The surprising finding that five of these mutations each occur in two different haplotypes suggests the occurrence of crossing over or gene conversion events at the beta-globin locus. The delineation of the haplotypes and mutations will permit the choice of the appropriate probes for prenatal detection of beta thalassemia in this part of China.

China↗
PubMed1985

alpha alpha alpha anti-4.2 Haplotype and heterozygous beta null thalassemia in a Sicilian family.

The presence of the alpha alpha alpha anti-4.2 haplotype and heterozygous beta null thalassemia in a Sicilian family is described. These findings confirm the presence in Italy of a leftward deletion (-alpha 4.2) and indicate that this may not be rare. Furthermore, although the beta thalassemia determinant in this family has a severe expression, the interaction with the triplicated alpha gene does not necessarily express itself as thalassemia intermedia.

Adult↗
PubMed1987

Premature epiphyseal fusion and extramedullary hematopoiesis in thalassemia.

The main skeletal abnormalities in beta-thalassemia are widening of medullary spaces, rarefaction of bone trabeculae, thinning of cortical bone, and perpendicular periosteal spiculation. Premature epiphyseal fusion (PEF) and extramedullary hematopoiesis (EH) are found, though more rarely. The incidence of PEF and EH in 64 patients affected by beta-thalassemia is reported. The different incidence of such complications in thalassemia major and intermedia is reported, and a possible correlation with transfusion regimen is also considered.

Adolescent↗
PubMed1981

Iron overload and desferrioxamine chelation therapy in beta-thalassemia intermedia.

This study on serum ferritin levels in urinary iron excretion after 12h subcutaneous infusion of desferrioxamine in 10 thalassemia intermedia patients shows that even nontransfusion-dependent patients may have positive iron balance resulting in iron overload from 5 years of age. However, the iron overload found in these patients appears to be much lower than in age matched patients with transfusion-dependent thalassemia major. Iron overload increases with advancing age, as shown by increasing serum ferritin levels and desferrioxamine-induced urinary iron elimination. After a six month trial of 12h continuous subcutaneous desferrioxamine administration there was a significant decline in serum ferritin levels. From this study it seems that iron chelation is indicated in thalassemia intermedia patients over 5 years of age in order to prevent iron accumulation. However, the appropriate treatment schedule should be tailored to the individual needs of each patients, established by close monitoring of serum ferritin levels and desferrioxamine-induced urinary iron elimination.

Adolescent↗
PubMed1979

Interaction of alpha-thalassemia genes with each other and with HbC in an American black family.

The relative rates of in vitro synthesis of hemoglobin chains have been studied in an American black family in which the mother is doubly heterozygous for alpha-thalassemia and HbC and the father is heterozygous for alpha-thalassemia. The alpha/non-alpha synthetic ratio was equally unbalanced in both the bone marrow and the peripheral blood of the mother. Although HbC comprised 35% of her hemoglobin (compared to 42.2 +/- 2.2 in individuals with HbC trait and balanced globin synthesis), synthetic data showed that the newly synthesized beta C chain was 44% of the total newly synthesized beta chains. Isolated membranes contained more newly synthesized beta C than beta A chains. Three of the offspring were within the normal range, and the remaining three had alpha-thalassemia. There were two spontaneous abortions during the second trimester of pregnancy. Hydrops fetalis did not occur, and none of the children had HbH disease or HbC trait.

Anemia↗
PubMed1993

Molecular characterization of beta-thalassemia in Hungary.

We have identified seven different beta-thalassemia mutations and one delta beta-thalassemia determinant (the Sicilian type) in 32 members of 17 Hungarian families. The most common mutation is the IVS-I-1 (G-->A) change; its high frequency is comparable to that observed in neighboring Czechoslovakia. Additional mutations are of Mediterranean origin. One rare mutation (initiation codon ATG-->GTG) was identified as an independent mutation because of the absence of known polymorphisms in the beta-globin gene. One new frameshift at codon 51 (-C) was observed in a single individual; hematological data were as expected for a beta zero-thalassemia heterozygosity.

Amino Acid Sequence↗
PubMed1979

Prenatal diagnosis of beta-thalassemia.

Prenatal diagnosis was attempted in 14 fetuses at risk for homozygous beta-thalassemia, gestational age 18-22 weeks. In 4 cases the placenta was entirely anterior, placental aspiration under ultrasonic control only had to be used for fetal blood sampling. In 10 fetuses fetoscopy was used for puncture of a chorionic blood vessel. Diagnoses were based on the rate of in vitro synthesis of beta-globin related to total non-alphaglobin synthesis. With the aid of fetoscopy, nearly pure fetal blood was obtained in general. Placental aspiration resulted in samples which contained a low percentage of fetal and a high percentage of maternal cells. The attempt of fetal blood sampling resulted in fetal loss in two cases. In 2 aspiration cases no diagnosis could be made because the samples were inadequate. In 2 cases the diagnosis was established in spite of low fetal cell content through determination of the specific radioactivity in the placental and pure maternal blood. Until now 6 children have been born in whom prenatal diagnosis had been attempted, none of them has homozygous thalassemia. Present efforts are directed toward improving the safety of fetal blood sampling and the biochemical methods for the diagnosis in placental samples with low fetal cell content. Although the prenatal diagnosis of beta-thalassemia is possible, the procedure has still to be considered experimental.

Female↗
PubMed1975

Sea-blue histiocytosis and beta-thalassemia in the same family.

Among 5 families with SBH of Neapolitan origin, herediatry glyco-lipidosis was accompanied in one by beta-thalassemia. All 10 members of this family, namely parents and 8 siblings, were investigated. The mother and two children were found to be carriers of both SBH and beta-thalassemia, while three other siblings were carriers of SBH alone. None of the six patients conformed the classic clinical picture often observed in genotypical SBH. The present state of genotypic transmission of the stigma is discussed on the basis of the author's experience as well as the data in the literature. As for the combination SBH-thalassemia in the same individual it may be concluded that the two genes are most likely independent and certainly not linked.

Adult↗
PubMed1993

BamH1 polymorphism in the Chinese, Malays, and Indians in Singapore and its application in the prenatal diagnosis of beta-thalassemia.

The distribution of restriction fragment length polymorphism (RFLP) at the BamH1 site of the beta-globin gene was investigated in the Chinese, Indian, and Malay race in Singapore. The sample comprised of 183 normal individuals and 35 beta-thalassemia carriers in which 13 were couples with at least one beta-major child. The results from this study indicate that BamH1 polymorphism will be informative in 22% of pregnancies at risk for beta-thalassemia major in Chinese, 19% in Malays and 7% in Indians. In prenatal diagnosis using BamH1 polymorphism for one beta-major affected family, the fetus was diagnosed to be normal or beta-carrier. The validity of BamH1 polymorphism in the exclusion of beta-thalassemia major was subsequently confirmed at birth by globin chain biosynthesis.

Child↗
PubMed1980

The relations between G-6-PD deficiency, thalassemia and malaria. Further analysis of data from Sardinia and the Po Valley.

Discriminant analysis carried out on a set of environmental and sociocultural variables in the Sardinian population suggests that G-6-PD deficiency and thalassemia move along 2 dimensions partially independent of each other. Partial correlation analysis also suggests that malaria, by itself, may exert opposite effects on thalassemia and G-6-PD selection. The present results support the hypothesis that thalassemia may be the primary genetic factor selected by malaria, whereas G-6-PD selection may be a secondary adaptation phenomenon strongly dependent on other genetic and environmental variables.

Consanguinity↗