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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of beta-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of deltabeta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of alpha-thal trait is 1.5%, of which alpha-thal-2 is 1.45% and alpha-thal-1 is 0.05%. The molecular basis of the different forms of beta-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 beta-thal chromosomes have been studied. Fifteen different beta-thal mutations have been detected, four of which [IVS-I-110 (G-->A), IVS-I-6 (T-->C), IVS-I-1 (G-->A), codon 39 (C-->T)] account for 85% of all beta-thal chromosomes. Among the Albanians, 48 beta-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, -30 (T-->A), IVS-I-110, IVS-I-1] account for 85% of all beta-thal chromosomes. Four new mutations [-101 (C-->A), -87 (C-->G), -30, polyadenylation signal (poly A) (AATAAA-->AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with deltabeta-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of deltabeta-thal) was discovered. Molecular analyses of alpha-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA-->AATGAA), and Hb Icaria [alpha142, Term-->Lys, TAA-->AAA (alpha2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different alpha chain variants among 10 families, seven different beta chain variants among 33 families, two gamma chain variants in two newborns, one variant with an extended alpha chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.
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PMID:Thalassemias and other hemoglobinopathies in the Republic of Macedonia. 1736

Modifier genes are defined as inherited genetic variation that leads to a qualitative or quantitative difference in disease phenotype. This has made the prediction of the phenotype based upon the genotype more difficult. Beta-thalassemia phenotype is modified by co-existent other genetic alterations. Changes alpha/beta-globin ratio can either ameliorate the disease phenotype or increase the severity of the disease in beta-thalassemia. Primary modifiers primarily affecting the clinical presentation include alpha gene changes, XmnI polymorphism and hereditary persistence of fetal hemoglobin (HPFH) variants. 'Thalassemia intermedia' is a heterogenous group with interplay of several genetic factors. The nature of the beta-genotype as well as the knowledge of the presence or absence of alleviating factors help the physician to decide on commencement of a regular transfusion regime or other lines of management including hydroxyurea therapy. The secondary modifiers affect the severity of jaundice, bone disease, cardiac and thrombotic complications. The present review gives a concise discussion of various modifying genes and the influence on the phenotype of beta-thalassemia.
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PMID:Genetic determinants of phenotype in beta-thalassemia. 1879 52

delta beta-Thalassemia (delta beta-thal) and hereditary persistence of fetal hemoglobin (HPFH) are heterogeneous disorders characterized by elevated levels of Hb F in adult life. The two disorders should not be considered as unambiguously separate entities but rather as a group of disorders with a variety of partially overlapping phenotypes. This study was undertaken to determine the hematological and molecular characteristics of high Hb F determinants among Indians. A gap-polymerase chain reaction (gap-PCR)-based approach was used for molecular characterization of high Hb F phenotypes. Fifty-five unrelated individuals were studied. The molecular findings were correlated with the hematological data. DNA analysis identified the deletion-inversion (G)gamma((A)gamma delta beta)(0)-thal in 15 cases (27%) and the HPFH-3 (Indian deletion) determinant in 26 cases (47.2%) and the Vietnamese/Chinese determinant (27 kb deletion) in five cases (9%), which is being reported for the first time from India; 16% (nine cases) of the samples remained uncharacterized. This study emphasizes that delta beta-thal and HPFH determinants are common in India. Molecular analysis will aid in understanding genotype-phenotype correlations and will facilitate prevention and control programs of thalassemia and hemoglobinopathies in this region.
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PMID:Molecular characterization of delta beta-thalassemia and hereditary persistence of fetal hemoglobin in the Indian population. 1893 66

The objective of this review is to present examples of lead compounds identified from biological material (fungi, plant extracts and agro-industry material) and of possible interest in the field of a pharmacological approach to the therapy of beta-thalassemia using molecules able to stimulate production of fetal hemoglobin (HbF) in adults. Concerning the employment of HbF inducers as potential drugs for pharmacological treatment of beta-thalassemia, the following conclusions can be reached: (i) this therapeutic approach is reasonable, on the basis of the clinical parameters exhibited by hereditary persistence of fetal hemoglobin patients, (ii) clinical trials (even if still limited) employing HbF inducers were effective in ameliorating the symptoms of beta-thalassemia patients, (iii) good correlation of in vivo and in vitro results of HbF synthesis and gamma-globin mRNA accumulation indicates that in vitro testing might be predictive of in vivo responses and (iv) combined use of different inducers might be useful to maximize HbF, both in vitro and in vivo. In this review, we present three examples of HbF inducers from the natural world: (i) angelicin and linear psoralens, contained in plant extracts from Angelica arcangelica and Aegle marmelos, (ii) resveratrol, a polyphenol found in grapes and several plant extracts and (iii) rapamycin, isolated from Streptomyces hygroscopicus.
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PMID:Fetal Hemoglobin Inducers from the Natural World: A Novel Approach for Identification of Drugs for the Treatment of {beta}-Thalassemia and Sickle-Cell Anemia. 1895 91

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3' end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Ggamma-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T beta-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases.
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PMID:The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter. 1905 Aug 90

Phenotype studies still occupy a key position in the diagnosis of hemoglobin (Hb) disorders. An additional dimension to the methods for diagnosis of Hb disorders which are mostly based on difference in charge of the Hb molecules may be brought by studying some properties of the globin chains. Among the methods proposed, reversed-phase liquid-chromatography (RP-LC) reveals differences in hydrophobicity allowing to discriminate between variants displaying identical charges. Thus, abnormal Hbs responsible for hematological disorders, such as chronic hemolytic anemia, erythrocytosis, or thalassemia like presentation, but with a charge similar to HbA or to that of a common variant may be revealed. Also RP-LC, which discriminates between the two types of gamma chains, may be of interest for diagnosis of hereditary persistence of fetal hemoglobin (HPFH) or for suggesting a haplotype in the case of sickle cell anemia.
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PMID:Globin chain analysis: an important tool in phenotype study of hemoglobin disorders. 1950 May 61

Large deletions of the beta-globin gene cluster are problematic to diagnose, and consequently the frequency and range of these mutations in the UK is unknown. Here we present a study evaluating the efficacy of the recently available technique of multiplex ligation-dependent prob amplification (MLPA) to determine the range and frequency of these deletions in the UK population. The results revealed a large deletion mutation in 75 of 316 patient samples collected over a 3-year period. Of these, 52 had a common (deltabeta)(0)-thalassemia [(deltabeta)(0)-thal] or hereditary persistence of fetal hemoglobin (HPFH) allele and 23 had rare or novel deletions resulting in (epsilon(G)gamma(A)gammadeltabeta)(0)-thal, (G)gamma(A)gamma(deltabeta)(0)-thal and beta(0)-thal. A total of 17 different deletions were found, 10 of which were rare and four were most likely novel [Asian Indian (epsilon(G)gamma(A)gammadeltabeta)(0)-thal, African (deltabeta)(0)-thal, African beta(0)-thal and Afghanistani beta(0)-thal]. The MLPA technique detected examples from all four categories of beta-globin gene deletions and demonstrated the wide molecular basis of deletional beta-thal/HPFH in UK patients.
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PMID:Multiplex ligation-dependent probe amplification identification of 17 different beta-globin gene deletions (including four novel mutations) in the UK population. 1995 85

Hereditary persistence of fetal hemoglobin (HPFH) is characterized by increased levels of Hb F during adult life. Nondeletional forms of HPFH are characterized by single base mutations in the (A)gamma and (G)gamma promoters, resulting in an increase of Hb F ranging from 3 to 20% in heterozygotes. Many point mutations in this region have been described, including the (A)gamma -195 (C>G) mutation that causes the Brazilian type of HPFH (HPFH-B). To better understand this mechanism, we have developed HPFH-B transgenic mice. mRNA levels of human gamma-globin of -195 transgenic mice were clearly higher when compared with control transgenic mice bearing a wild type sequence of the gamma promoter. Thus, our data indicate that the -195 mutation is the unique cause of elevation of Hb F in Brazilian HPFH. These results could provide us with an opportunity to study the modifying effects of the Hb F in the phenotype of sickle cell disease and beta-thalassemia (beta-thal).
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PMID:High levels of human gamma-globin are expressed in adult mice carrying a transgene of the Brazilian type of hereditary persistence of fetal hemoglobin ((A)gamma -195). 1995 89

Hemoglobin (Hb) Q-Thailand, Hb E, and other forms of thalassemia are prevalent in Southeast Asia including China. We report a hitherto undescribed condition in which four forms of Hb defects co-segregate. The proband was a 20-year-old Chinese man who presented with moderate hypochromic microcytosis with Hb 73 g/l, hematocrit (Hct) 27.0%, mean corpuscular volume 57.6 fl, mean corpuscular hemoglobin 15.5 pg, and mean corpuscular hemoglobin concentration (MCHC) 268.0 g/l. Both Hb electrophoresis and high-performance liquid chromatography analysis revealed abnormal Hbs. DNA analysis demonstrated that the proband was a double heterozygote of Hb Q-Thailand and Hb E in combination with alpha(0)-thalassemia and Southeast Asian-type hereditary persistence of fetal hemoglobin (SEA-HPFH). Family study identified that her father was a double heterozygote for Hb Q-Thailand and Hb E, whereas her mother was a heterozygote for SEA-HPFH with alpha(0)-thalassemia. Moreover, his brother was a classical Hb QH disease patient. The genotype-phenotype relationship observed in this Chinese family with complex thalassemia syndromes is presented. This work will provide some clinical implications for molecular diagnosis for complex hemoglobinopathies.
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PMID:Complex interaction of Hb Q-Thailand and Hb E with alpha(0)-thalassemia and hereditary persistence of fetal hemoglobin in a Chinese family. 2033 23

Hereditary persistence of fetal hemoglobin (HPFH), often associated with mutations in the beta-globin gene cluster, is normally benign, but a person carrying both HPFH and another beta-thalassemia (beta-thal) mutation will develop serious anemia. These people might be erroneously diagnosed as having homozygous beta-thal with common reverse dot-blot methods. Here we report a 5-year old boy with thalassemia intermedia, who is a compound heterozygote for the rare HPFH-6 deletion with codons 41/42 (-TCTT) beta(0)-thal, who inherited the deletion from his mother and the beta(41/42) mutation from his father.
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PMID:Molecular characterization of a Chinese pedigree with beta-thalassemia intermedia. 2035 56


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