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

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
Blood Cells Mol Dis
PMID:Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. 1463 44

Reactivation of fetal hemoglobin (HbF) expression using pharmacological agents represents a potential strategy for the therapy of beta-thalassemia, sickle cell disease, HbE and other beta-hemoglobinopathies. However, the drugs currently available have low efficacy and specificity and are associated with high toxicity. We describe the development of stable cellular genomic reporter assays (GRAs) based on the green fluorescence protein (EGFP) gene under the Ggamma-globin promoter in the intact human beta-globin locus. We show that human erythroleukemic cell lines stably transfected with a Ggamma-EGFP beta-globin locus construct can maintain a uniform basal level of EGFP expression over long periods of continuous culture and that induction of EGFP expression parallels the induction of the endogenous globin genes. We compared the EGFP-induction potency of a number of chemotherapeutic agents, including histone deacetylase inhibitors and DNA-binding agents. We show that hydroxyurea and butyrate result in moderate levels of induction (70-80%) but with an additive inductive effect. Among the DNA-binding agents tested, cisplatin was the most potent inducer of HbF expression, (442+/-32%), a level which is comparable to hemin (764+/-145%). These results indicate that cellular GRAs containing Ggamma-EGFP-modified beta-globin locus constructs can be used to develop novel inducers of HbF synthesis for the therapy of beta-hemoglobinopathies.
Hum Mol Genet 2004 Jan 15
PMID:Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin. 1464 8

Abnormal globin chain biosynthesis may result in deficient quantity (thalassemia) or structural variation (abnormal hemoglobins) and traditionally, they represent two phenotypically distinct groups of disorders. However, the phenotypic expression of unstable hemoglobin variants often combine features of thalassemia together with variable peripheral hemolysis. To achieve definitive diagnosis in a child presenting with hemolytic anemia along with features associated with thalassemia intermedia, we evaluated clinical, hematological, biochemical, globin biosynthetic and molecular data. Definitive diagnosis was achieved by DNA analysis which characterized the proband to be a compound heterozygote for a common alpha-thalassemia-2 deletion (3.7 kb) and Hb Questembert (alpha131[H14] Ser>Pro) caused by a C>T mutation in codon 131 of the alpha1 globin gene in trans. The phenotype of thalassemia intermedia with marked dyserythropoiesis, found in patients inheriting alpha-thalassemia mutations along with unstable alpha-globin variants (i.e., alpha-thalassemic hemoglobinopathies), represents a distinct type of thalassemic syndrome. The proband in this study additionally had variable peripheral hemolysis, presumably related to characteristics of the unstable Hb Questembert. There is minimal experience for the management of such atypical cases and this case illustrates that it is probably insufficient to monitor clinical status in patients with such hemoglobinopathies based only on the levels of hemoglobin.
Blood Cells Mol Dis
PMID:Rare thalassemic syndrome caused by interaction of Hb Questembert (alpha1 codon 131, TCT>CCT, Ser>Pro) with an alpha-thalassemia-2 deletion: implications for diagnosis and management. 1475 25

Adeno-associated viral (AAV) vectors are derived from a nonpathogenic, replication-deficient virus with a small (~4.7-kb) single-stranded DNA genome. AAV vectors are devoid of viral-coding sequences and may efficiently transfer genes to nondividing cells such as muscle fibers or hepatocytes following in vivo transduction. Recombinant AAV can be administered to skeletal muscle of experimental animals and, as recently documented in a Phase I clinical trial, to humans at high vector doses without local or systemic toxicity (8,9). The potential of the vector to activate cytotoxic T lymphocytes is greatly reduced compared with some other viral vectors, thereby reducing the risk of inflammation at the site of gene transfer (7,10,11). Sustained expression of therapeutic transgenes such as coagulation factor IX (F.IX), erythropoietin, leptin, insulin-like growth factor (IGF), sarcoglycans, mini-dystrophin genes, alpha1-antitrypsin, and others have been demonstrated (2,12-18). Efficient gene transfer to myofibers by intramuscular (im) injection has been shown in several species including mice, hamsters, dogs, and nonhuman primates (6-8,13,19). These studies resulted in various levels of correction of the disease phenoypes in small and large animal models of hemophilia B (F.IX deficiency), muscular dystrophy, obesity, age-related atrophy, and beta-thalassemia (8,12,13,15,17,18,20-25).
Methods Mol Biol 2004
PMID:AAV-mediated gene transfer to skeletal muscle. 1497 May 92

The coinheritance of beta-thalassemia major with the genotype of Hb H disease is extremely rare, with few reported cases. We investigated the hematological, biochemical, biosynthetic, molecular and pathophysiological parameters to evaluate a rare male patient with this compound syndrome. The patient was studied at first diagnosis during hospitalization at 50 years of age and subsequently followed up for more than a year. Examinations included full hematological, biochemical, biosynthetic, molecular, pathophysiological and clinical parameters. Besides standard parameters, we additionally measured reticulocyte hemoglobin content (CHr), erythropoietin (Epo), soluble transferrin receptors (sTfR), oxygen pressure at 50% hemoglobin saturation (P50), 2,3-bisphosphoglycerate (2,3-BPG), total glutathione (GSHt), oxidized glutathione (GSSG), malonyldialdehyde (MDA), nontransferrin-bound iron (NTBI), vitamins A and E. The male patient was first hospitalized for a 2-day period at 50 years of age, following the finding of marked anemia (hematocrit 20%) during a blood test to investigate the cause of fatigue in the absence of weight-loss or other notable symptomatology. He had never been transfused, maintaining Hb 85-95 g/l. Definitive diagnosis was achieved through DNA studies, which showed coexistence of beta-thalassemia major (IVSI-6 T > C/IVSI-I G > A) with Hb H disease (-alpha(3.7)/-(Med)). Alpha/non-alpha globin chain biosynthesis was completely balanced. Parameters demonstrated a well-compensated anemia with ineffective erythropoiesis and oxidative stress, which was ameliorated following splenectomy. In conclusion, this case is a remarkable example that the coinheritance of severe forms of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to almost complete balance the symptoms of classic thalassemia syndromes.
Blood Cells Mol Dis
PMID:A rare example that coinheritance of a severe form of beta-thalassemia and alpha-thalassemia interact in a "synergistic" manner to balance the phenotype of classic thalassemic syndromes. 1500 25

Preimplantation HLA matching has recently emerged as a tool for couples desiring to conceive a potential donor progeny for transplantation in a sibling with a life-threatening disorder. In this paper we describe a strategy optimized for preimplantation genetic diagnosis (PGD) of haemoglobinopathies combined with HLA matching. This procedure involves a minisequencing-based genotyping of HLA regions A, B, C and DRB combined with mutation analysis of the gene regions involved by mutation. Analysis of at least eight polymorphic short tandem repeat (STR) markers scattered through the HLA complex has also been included to detect potential contamination and crossing-over occurrences between HLA genes. The above assay can also be used for preimplantation HLA matching as a primary indication. The strategy was clinically applied for HLA matching in 17 cycles (14 for beta-thalassaemia, one for Wiscott-Aldrich syndrome and two for leukaemia). A reliable HLA genotype was achieved in 255/266 (95.9%) of the blastomeres. In total, 22 (14.8%) embryos were obtained that were HLA-matched with the affected siblings, 14 (9.4%) of which were unaffected and transferred back to the patients. Four clinical pregnancies were obtained, three of which (one twin, two singletons) are ongoing and were confirmed as healthy and HLA-identical with the affected children. Minisequencing-based HLA typing combined with HLA STR haplotyping has been shown to be a reliable strategy for preimplantation HLA matching. The major advantage of this approach is that the validation of a single assay can be done once and then used for the majority of the patients, reducing notably time needed for preclinical set-up of each case.
Mol Hum Reprod 2004 Jun
PMID:Development and clinical application of a strategy for preimplantation genetic diagnosis of single gene disorders combined with HLA matching. 1504 7

alpha-Thalassemia is among the world's most common single gene disorders, which is most prevalent in the malaria belt. This geographic distribution has been attributed to a selective advantage of heterozygotes against this disease. Unexpectedly, we have found a high frequency of heterozygosity for deletional alpha-thalassemia (-alpha3.7) in Ashkenazi Jews (carrier frequency of 7.9%, allele frequency of 0.04). This population has resided in temperate climates for many centuries and was therefore not subjected to malarial selection pressure. In comparison, heterozygosity for beta-thalassemia, which is highly subject to malarial selection pressure, is very low (estimated <0.1%) in this group. It is possible that founder effect and genetic drift have contributed to the high frequency of deletional alpha-thalassemia in Ashkenazim, as may occur in closed populations. Alternatively, we hypothesize that positive selection pressure for an as yet unknown linked allele on chromosome 16 may be a significant factor leading to this high frequency.
Blood Cells Mol Dis
PMID:An unexpectedly high frequency of heterozygosity for alpha-thalassemia in Ashkenazi Jews. 1522 3

Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease, and thalassemia. It has been demonstrated recently that 4-PBA can act as a chemical chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling, and apoptosis and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eukaryotic initiation factor 2alpha phosphorylation, CCAAT/enhancer-binding protein homologous protein induction, and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation, and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric-oxide synthase and tumor necrosis factor-alpha in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia, and its use as a chemical chaperone would provide a novel approach for the treatment of stroke.
Mol Pharmacol 2004 Oct
PMID:Sodium 4-phenylbutyrate protects against cerebral ischemic injury. 1522 15

Beta-thalassemia is uncommon (0.5%) in the Romanian population, but it must be considered in the differential diagnosis of hypochromic anemia. The molecular characterization of beta-thalassemia is absolutely necessary for molecular diagnosis, as well as any genetic epidemiological study in this region. Molecular analyses consist of mutation detection by molecular scanning of beta-globin gene. This gene has 3 exons and 2 introns, involved in beta-thalassemic pathogenesis. Clinical application of DNA analysis on beta-thalassemic chromosomes allowed characterization of 29 persons with different beta-thalassemia mutations among 58 patients with anemia. The experimental strategy was based on sequential PCR amplification of most of the beta-globin gene and running on denaturing gradient gel electrophoresis of amplification products. Definitive characterization of mutations in samples identified with shifted DGGE patterns was performed ARMS-PCR and/or PCR-restriction enzyme analysis methods. Eight different beta-thalassemia alleles were identified, the most common being IVS I-110 (G-A) and cd 39 (C-T). Comparison of overall frequency of mutations in the neighboring countries, shows that these results are in the frame of overall distribution of these mutations in Mediterranean area, especially in Greece and in Bulgaria. Molecular diagnosis is useful for differentiating mild from severe alleles, for genetic counseling, as well as for mutation definition in carriers, identified by hematological analysis necessary for prenatal testing and genetic counseling.
J Cell Mol Med
PMID:Scanning of beta-globin gene for identification of beta-thalassemia mutation in Romanian population. 1525 71

The beta thalassemias are one of the commonest group of autosomal recessive disorders in India. Although majority of patients are severe and transfusion-dependent, about 10-15% of cases have a milder phenotype. We evaluated the role of beta gene mutations in modulating the clinical presentation of 342 beta thalassemia patients which included 278 severe thalassemia major (TM) and 64 thalassemia intermedia (TI) cases (severe TI: 27; mild TI: 37) from this region. Thirteen beta thalassemia mutations were characterized by reverse dot blot hybridization or amplification refractory mutation system (ARMS); denaturing gradient gel electrophoresis (DGGE) analysis and DNA sequencing helped to characterize the remaining nine mutations. Majority of the patients in the thalassemia major and thalassemia intermedia groups had severe beta+ or beta0 mutations. IVS 1-5 (G-->C) was the commonest mutation in the three groups. The six severe and common Indian mutations [(IVS 1-5 (G-->C), 619 bp deletion, IVS 1-1 (G-->T), codons 8/9 (+G), codon 15 (G-->A), codons 41/42 (-CTTT)] accounted for 92.0% of molecular lesions in the thalassemia major group, 86.8% in the severe TI group, and 72.9% in the mild TI group. IVS 1-1 (G-->T) and codon 30 (G-->C) were significantly more common in thalassemia intermedia cases. The mild capsite +1 (A-->C) mutation was present in both severe and mild cases. Three other mild beta+ mutations, poly A (T-->C), -28 (A-->G), and -88 (C-->T), were seen only in the thalassemia intermedia cases. These four mild mutations in combination with other severe beta+ or beta0 mutations resulted in a very variable clinical presentation. This study reveals that, in majority of Indian patients, the beta genotype cannot predict the phenotype.
Blood Cells Mol Dis
PMID:Impact of beta globin gene mutations on the clinical phenotype of beta thalassemia in India. 1531 95


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