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PubMed1976

A new alkali-resistant hemoglobin alpha2J Oxford gammaF2 in a Sicilian baby girl with homozygous beta0 thalassemia.

A 10-mo-old baby girl with homozygous beta0 thalassemia and alphaJOxford, presenting the clinical picture of homozygous beta thalassemia is described. Hemoglobin electrophoresis showed three bands: the first two with the mobilities of hemoglobin Hb A2 (1%) and Hb F (69%), respectively, the third migrating a little faster than Hb A (30%). About 30% of her alpha chains were J Oxford which, bound to her gamma chains, produced a new alkali-resistant hemoglobin, alpha2 J Oxford gamma F2, which has not been described previously. Hemoglobin synthesis in vitro showed the absence of beta chain synthesis and an alpha/non-alpha ratio of 2. The patient's father was heterozygous for both the Hb J Oxford and beta0 thalassemia genes, the mother a carrier of beta0 thalassemia; four other relatives were carriers of Hb J Oxford, and one was a carrier of beta thalassemia.

Alkalies↗
PubMed1999

[Detection of beta thalassemia by the technique of refractory amplification of mutation systems (ARMS-PCR)].

beta Thalassemia (Thal) mutations were studied in DNA from 80/159 patients with hemolytic anemia and high levels of Hb A2 by the amplification refractory mutation system technique (ARMS-PCR). This method detects point mutations and insertions or deletions of just a few nucleotides in the beta globin gene by the polymerase chain reaction of allele-specific priming. In 43/80 patients with different clinical presentations of beta Thalassemia and 37/80 compound heterozygous for hemoglobinopathies and beta Thalassemia the most frequent mutation found was the -29 (of African origin), followed by the CD39 (of Mediterranean origin) and in a lower frequency also was found the -88, the IVSI-6 and the IVSI-110. We conclude that this technique is an useful approach in determining the beta thalassemia mutations in population surveys, because it allows to make a differential diagnosis between beta Thalassemia minor and individuals with high levels of Hb A2. It helps to clarify the diagnosis of patients with structural hemoglobinopathies that also presents high levels of Hb A2.

Base Sequence↗
PubMed1998

[Distribution of beta-thalassemia CD17 mutant(A-->T) in Shanxi, Gansu and Xinjiang along the "Silk Road"].

OBJECTIVE: To explore the distribution of beta-thalassemia CD17 mutant along the "Silk Road". METHOD: Polymerase chain reaction in combination with dot-blot hybridization of allele-specific oligonucleotide probes(PCR/ASO) was used. RESULTS: Twenty-four cases of beta-thalassemia with CD17 mutant(A-->T) including 3 cases in Shanxi, 20 cases in Gansu and 1 in Xinjiang, were found among 85 probands of beta-thalassemia. CONCLUSION: According to distribution characteristics of beta-thalassemia CD17 along the "Silk Road" of China, the CD17 mutant of beta-thalassemia might probably originate from the "Silk Road" in Longxi district of Gansu.

Adolescent↗
PubMed1999

[Direct genotyping of an hereditary persistence of fetal hemoglobin deletion and rapid prenatal diagnosis of the fetus at-risk for compound heterozygote of this defect with beta-thalassemia in a Chinese family].

OBJECTIVE: To investigate the relationship between genotype and phenotype of a deletional hereditary persistence of fetal hemoglobin(HPFH) found in a Chinese family and explore an approach to rapid prenatal diagnosis for compound heterozygote of HPFH defects with beta-thalassemia. METHODS: By using the PCR-based method with three primers bridging a HPFH breakpoint and reverse dot blot (RDB) for detecting beta-thalassemia mutations, a Chinese family who had a propositus of six years old with intermediate thalassemia and requested prenatal diagnosis for the second pregnancy were screened. RESULTS: The propositus carried the HPFH deletion determinant inherited from her mother, and a codons 14-15 (+G) frameshift mutation causing beta-thalassemia from her father. Of six members in this family screened for this type of HPFH deletion, four were positive. Prenatal diagnosis of the fetus showed the same results as that of the propositus. An advice of termination of pregnancy was given and the result of prenatal diagnosis was confirmed in the DNA samples obtained after abortion. CONCLUSIONS: This is the first time to have performed prenatal diagnosis of Chinese family at-risk for compound heterozygotes for beta-thalassemia and HPFH in mainland China. The PCR assay for directly detecting the HPFH deletion is rapid and inexpensive and can be used as a routine in HPFH carrier screening and prenatal diagnosis.

Adult↗
PubMed2002

H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers.

BACKGROUND AND OBJECTIVES: Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism. The HFE gene implicated in this disorder has been identified on chromosome 6 (6p21.3). The most prevalent mutation in HH patients changes the 282 cysteine residue to tyrosine (C282Y). The role of a second mutation which changes the 63 histidine to aspartic acid (H63D) in iron overload has been controversial. The aim of this study was to evaluate the effect of the H63D mutation on the ferritin levels of beta-thalassemia carriers. DESIGN AND METHODS: beta-thalassemia carriers have a tendency to increase iron absorption because of mild anemia and slightly increased erythropoiesis. Differences in ferritin levels between homozygotes for H63D and wild type may indicate a modulator effect of the HFE mutation on iron absorption. We studied 152 healthy males, heterozygous for beta-thalassemia. Serum ferritin was measured by chemiluminescence. H63D genotypes were determined by digestion of polymerase chain reaction (PCR) products with MboI restriction enzyme. RESULTS: Forty-five subjects were H63D heterozygotes and four subjects were H63D homozygotes. Ferritin levels were (mean +/- SD): 250 +/- 138 microg/L in homozygotes for the wild type H/H; 295 +/- 186 microg/L in H/D heterozygotes; and 389 +/- 75 microg/L in homozygotes for the mutation D/D. The difference in ferritin values between H/H and D/D is statistically significant (p=0.022). INTERPRETATION AND CONCLUSIONS: beta-thalassemia carriers who are homozygotes for the H63D mutation have higher ferritin levels than beta-thalassemia carriers with the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron absorption.

Ferritins↗
PubMed2001

[Umbilical cord blood transplantation (UCBT) in thalassemia children].

OBJECTIVE: To evaluate the efficacy of allo-UCBT in thalassemia children. METHODS: Five patients with beta-thalassemia major (genotypes were homozygote of beta41-42, beta654 and double heterozygosities of beta41-42/beta654, beta41-42/-28, beta654/-28, respectively) were treated by allo-UCBT. The median age was 3 year and ten month old (31/2 - 7 2/12). Four donor-recipient pairs were HLA-identical and one 1 locus mismatch. The patients received a median UCB nucleated cells (NC) of 5.5 x 10(7)/kg body weight [range (4.7 - 7.7) x 10(7)/kg] and CD(34)(+)CD(38)(-) cells 2.8 x 10(5)/kg [range (0.6 - 4.5) x 10(5)/kg] and CFU-GM 1.09 x 10(5)/kg [range (0.24 - 230.00) x 10(5)/kg]. The conditioning regimen consisted ofbusalphan 16 - 20 mg/kg, cyclophosphamide 180 - 200 mg/kg, horse antithymocyte globulin (ATG) 90 mg/kg or rabbit anti-lymphocyte globulin (ALG) 25 mg/kg and melphalan of 90 mg/m(2) was added to four cases. Cyclosporine A (CsA) alone was administered in 3 cases, and a combination of CsA and methotrexate in the other 2 cases. RESULTS: Four cases were engrafted, but one rejected and recurred thalassemia state at day 60 past UCBT. One case had autologous reconstitution. The reconstitutions were found in all patients with neutrophils 0.5 x 10(9)/L at day 19 (14 - 22), platelets > 20 x 10(9)/L at day 37 (21 - 63). Two cases developed grade I and II acute GVHD respectively. None developed chronic GVHD. Three patients survived disease-freely (survival with ex-thalassemia state). The median follow-up was 18 months, the probability of survival was 100%. CONCLUSION: Allo-UCBT could reconstitute hematopoiesis with low frequency and mild grade of GVHD. It is an effective treatment for thalassemia.

Child↗
PubMed1975

Mild beta-thalassemia in black subjects.

In two American black families with beta-thalassemia, globin chain synthesis was investigated in vitro. The resultant alpha/beta and alpha/non-alpha labelling ratios were expressed in terms of both specific activity and total counts. In one family, two brothers with clinical presentations compatible with thalassemia intermedia had apparently each inherited two different beta-thalassemia alleles. Thus, they are compound heterozygotes. Their alpha/beta (or alpha/non-alpha) ratios were in the same range as those found in Caucasian subjects with severe Cooley's anemia. In addition, alpha/beta ratios in heterozygotes in this study were the same as those found in Caucasian heterozygotes. A difference in degree of chain imbalance measured by our present method cannot explain the relative lack of severe clinical manifestations of beta-thalassemia in blacks. Further family studies are indicated to discover other genetic or environmental factors modifying the effects of beta-thalassemia.

Adolescent↗
PubMed2002

[Beta-thalassemia major in children and adolescents in Denmark].

INTRODUCTION: Beta-thalassemia major occurs with increasing frequency among Danish children as a result of immigration. The aim of the study was to estimate the occurrence of beta-thalassemia major in Denmark, analyse the treatment and organ functions, and identify areas for an improved treatment strategy. MATERIAL AND METHODS: During 1998-99 all Danish pediatric departments were contacted for identification of children aged 0-18 years with beta-thalassemia major. Blood transfusions and chelation therapy were registered, and for Eastern Denmark clinical, endocrine, cardiac, and serologic parameters were performed. RESULTS: Twenty-six children had beta-thalassemia major. Out of these, 20 received blood transfusions, and 17 patients were chelated. Eight patients were not chelated owing to previous bone marrow transplantation, treatment with hydroxyurea or ferritin < 2000 micrograms/l and young age. One patient had died. The body height was between 1.5 and -5.4 SDS (median -1.7) and the sitting height was -0.6 to -5.6 SDS (median -2.3). The bone age was delayed 1-5 years (median -2.5) in six out of ten examined patients, and puberty delayed in four out of five. A dilated left ventricle was documented in one out of eight patients examined. All patients were HIV and hepatitis C negative. For 75% of the children, the parents were related. DISCUSSION: Children and adolescents with beta-thalassemia major in Denmark experience major heterogenicity with regard to treatment and late effects. An earlier and more effective iron chelation therapy together with improved patient support may reduce growth disturbances and endocrine and cardiac late effects.

Adolescent↗
PubMed2003

Pathogenetic aspects of immune deficiency associated with beta-thalassemia.

Infectious complications constitute the second most common cause of mortality and a main cause of morbidity in beta-thalassemia. Besides the high risk of blood-borne infections associated with multiple transfusions, the increased susceptibility of these patients to infectious diseases has been attributed to a coexistent immune deficiency. Immune abnormalities have also been held responsible for the frequent occurrence of malignancies in beta-thalassemia, especially leukemia and lymphomas. Recent studies on immune competence in beta-thalassemia have revealed numerous quantitative and functional defects, involving T and B lymphocytes, immunoglobulin production, neutrophils and macrophages, chemotaxis, and phagocytosis, as well as the complement system. Regarding pathogenesis, iron overload, a primary complication of both thalassemia itself and transfusion therapy, is thought to be the main precipitating mechanism, due to the important immunoregulatory properties of iron and its binding proteins; iron excess may derange the immune balance in favor of the growth of infectious organisms. Other factors include multiple transfusions, associated with constant allo-antigenic stimulation, as well as with transmission of immunosuppressive viruses; splenectomy, resulting in increased susceptibility to infections by encapsulated bacteria and to immune system modifications; low levels of zinc, another immune regulator; iron chelation therapy, which predisposes to serious infections by yersinia species; and the circulation of abnormal native thalassemic erythrocytes, forming another permanent immune stimulus. Thus surveillance for infections in patients with beta-thalassemia is crucial, while further studies are warranted on immune function abnormalities and the implicated mechanisms.

Humans↗
PubMed2003

Growth and puberty in thalassemia major.

Present transfusional regimen protocols increase the life expectancy of patients with beta-thalassemia major, but cause a progressive iron overload that can be prevented or limited only by appropriate iron chelation. Siderosis is responsible for the clinical complications of the disease. Short stature and hypogonadism are extremely frequent in patients with thalassemia. Many factors are responsible for short stature in patients with thalassemia, the most important of which are dysfunction of the GH-IGF-I axis and desferoxamine (DFX)-induced bone dysplasia. Hypogonadism is the most frequent endocrine complication, mostly due to gonadotrophins deficiency secondary to iron overload. Sex steroid treatment for induction of puberty and/or maintenance of sexual characteristics is necessary. Both short stature and hypogonadism are present in a significant percentage of bone marrow transplanted patients with thalassemia. Factors responsible for short stature are previous iron overload, liver impairment, DFX treatment, and toxicity of chemotherapeutic agents. In some patients absence of pubertal development is due to gonadotropin insufficiency, probably secondary to previous iron overload; other patients exhibit hypergonadotrophic hypogonadism due to the toxic effect of chemotherapeutic agents on the gonads. Both groups need hormonal replacement therapy. These data support the need for vigilant follow-up of patients with thalassemia before and after transplantation, in order to treat endocrine dysfunctions at the appropriate age.

Body Height↗
PubMed2003

[Preimplantation genetic diagnosis for beta-thalassemia].

OBJECTIVE: To investigate the effect of in vitro fertilization and embryo transfer (IVF-ET) and preimplantation genetic diagnosis (PGD) for the couples at risk of having children with beta-thalassemia. METHODS: Four couples carrying different thalassemia mutations received standard IVF treatment. Embryo biopsy was conducted. Single blastomeres were genotyped by a protocol involving primer extension preamplification, nested polymerase chain reaction and reverse dot-blot analysis. Only the unaffected embryos were transferred to the uterus. RESULTS: A total of 97 oocytes were retrieved from the four female carriers. Among them, 83% showed two pronuclei. Embryo biopsy was performed on 47 of these embryos. The amplification efficiency was 84.8%. The average ADO rate was 14.9%. Ten unaffected embryos were transferred. A twin pregnancy with one blighted ovum was confirmed at 7 weeks' gestation by ultrasonography and one normal baby and one carrier of thalassemia mutation were born finally. CONCLUSION: This unaffected pregnancy resulting from PGD for beta-thalassemia demonstrates that PGD technique can be a powerful diagnostic tool for couples carrying beta-thalassemia mutations who desire a healthy child and wish to avoid abortion of an affected fetus.

Biopsy↗
PubMed2003

[Beta-thalassemia in metropolitan France].

OBJECTIVES: Update the data collected in 1990 in order to assess the distribution and management of thalassemic patients presently living in Metropolitan France. METHODS: A survey conducted in France in the clinical and biological departments of haematology permitted collection of epidemiological, clinical and biological data in a population of thalassemic patients followed-up in metropolitan France. RESULTS: Analysis of the replies revealed a total of 362 thalassemia with 249 beta-thalassemia major, 81 beta-thalassemia intermedia and 32 E-beta thalassemia. These patients predominated in the East of France and in the large cities. The total number of patients has remained stable over the last decade and new cases are decreasing. Among the 249 patients presenting with a ss-thalassemia major, 42 had received a bone marrow graft, whereas 207 were systematically transfused and 189 regularly underwent iron chelating. COMMENTS: Management is standardised and efficient but could be improved on with regard to iron chelating therapy.

Adolescent↗
PubMed2003

Recurrent transient ischemic attacks in a 15-year-old boy with beta-thalassemia minor and thrombophilia. Contribution of perfusion SPECT to clinical diagnosis.

beta-Thalassemic patients exhibit an increased frequency of thrombotic events but most patients with heterozygous beta-thalassemia minor are asymptomatic and no single case with beta-thalassemia minor and concurrent stroke was reported. We present a 15-year-old boy with heterozygous beta-thalassemia minor who developed recurrent transient ischemic attacks as documented with repeated brain SPECTs whereas structural neuro-imaging was not contributory. The patient exhibited resistance to activated protein C due to heterozygosity for factor V Leiden as well as slightly decreased plasma levels of protein C and S. This unique association of risk factors might have caused clinically significant thrombophilia resulting in recurrent cerebrovascular events. This case report underlines the thrombogenic risk of heterozygous beta-thalassemia minor in children heterozygous for factor V Leiden mutation. We therefore suggest to screen for thrombophilia in children with beta-thalassemia minor when thromboembolism-related phenomena occur. This case also demonstrates that brain perfusion SPECT is a useful and sensitive tool for detecting cerebrovascular events in patients with hemoglobinopathies.

Adolescent↗
PubMed2003

[Rapid diagnosis of non-deletion alpha-thalassemias by reverse dot blot].

OBJECTIVE: To establish a rapid and convenient method of reverse dot blot (RDB) analysis for detecting the point mutations of non-deletion alpha-thalassemia in Chinese. METHODS: Label biotin to primers and amplify human alpha2 globin gene selectively, then hybridize PCR products with a set of oligonucleotide probes immobilized on strips, and develop colour to detect non-deletion alpha-thalassemia defects. RESULTS: The PCR system using biotin-labeled primers could specifically amplify a 1085 bp fragment of human alpha2 globin gene which encompasses all six alpha-thalassemia mutations. After being hybridized with sequence-specific oligonucleotide probes and colour development, it could simultaneously identify all six types of non-deletion alpha-thalassemias encountered in Chinese. CONCLUSION: This method does not need semi-nested PCR, and the products amplified by biotinylated primers can be used directly to hybridize with the probes on strips under the identical conditions of hybridization. So, it is a specific and multiplex detection assay for screening non-deletion alpha-thalassemia defects in Chinese.

Humans↗
PubMed1992

Screening for alpha-thalassemia. Correlation of hemoglobin H inclusion bodies with DNA-determined genotype.

We evaluated potential screening protocols for alpha-thalassemia in a group of 80 patients whose genotypes were determined by Southern blot analysis with alpha- and zeta-globin DNA probes. Erythrocyte inclusion bodies were measured by a modified brilliant cresyl blue test. Erythrocyte indices and iron status were also measured. The brilliant cresyl blue test reliably detects couples at risk for hemoglobin Bart's hydrops fetalis. Measurement of the number of inclusion bodies differentiates the alpha-thalassemia genotypes in the absence of a coincident beta-chain synthesis deficiency, such as hemoglobin E or beta-thalassemia. The test appears to identify patients, such as those with the Thai and Filipino deletion variants, whose alpha-thalassemia cannot be definitively characterized by DNA testing when only alpha- and zeta-globin probes are used in the analysis. We also found evidence of elevated serum ferritin levels in many patients with deletion of two or three alpha-globin genes. This study shows that most routine screening for alpha-thalassemia can be performed with three simple tests: (1) the brilliant cresyl blue inclusion study, (2) erythrocyte indices, and (3) iron studies. Analysis with DNA probes is needed in only some circumstances.

Blotting, Southern↗
PubMed2003

[Diagnostic values of serum levels of HA, PC III, C IV and LN to the liver fibrosis in children with beta-thalassemia major].

OBJECTIVE: The presence of liver fibrosis in patients with beta-thalassemia major has been demonstrated to be an important negative prognostic factor. Identification of liver fibrosis in early stage would be of great value. Hyaluronic acid (HA), type III pre-collagen (PC III), collagen IV (C IV) and laminin (LN) as serum markers were widely used in the diagnosis of liver fibrosis in patients with chronic viral infections or alcoholic liver diseases. However, their values in thalassemic liver fibrosis have not been studied. This work was to determine the serum HA, PC III, C IV and LN levels in children with beta-thalassemia major and evaluate the diagnostic utility. METHOD: Serum HA, PC III, C IV and LN in 49 hospitalized children with beta-thalassemia major (aged 1 - 15 years with the media age of 6.27 years) and 41 healthy children served as controls (aged 1 - 13 years with media age of 6.40 years) were detected by radioimmunoassay (RIA). Forty-five of 49 cases were performed percutaneous liver biopsies, and the histopathological fibrosis was compared with the four serum markers. The correlation and discriminate analysis were used. RESULTS: All the serum levels of HA, PC III, C IV and LN in beta-thalassemia were significantly higher than those in controls (P < 0.01). In 36 of 45 cases, the histopathology showed liver fibrosis including stage I and stage II by biopsies with a positive rate of 80%. The serum levels of four markers increased successively with the aggravation of liver fibrosis from stage 0 to stage II, and significant correlation was observed between the level of HA or PC III and the stage of fibrosis (HA, r = 0.379, P = 0.017; PC III, r = 0.455, P = 0.04). While there was no difference between the level of C IV or LN and fibrosis (C IV, r = 0.312, P = 0.053; LN, r = 0.310, P = 0.055). Using discriminate analysis, the discriminate function of co-detection of the four markers for the diagnosis of fibrosis was 0.002 HA + 0.003 PC III + 0.002 C IV + 0.006 LN-1.859, which had a sensitivity of 93.88%, specificity of 68.29%, predictive value of positive test and negative test of 77.97% and 90.32%, respectively. Moreover, there was a significant correlation between the serum level of HA or PC III and the liver iron concentration (HA, r = 0.318, P = 0.035; PC III, r = 0.305, P = 0.044). CONCLUSION: The results suggest that, in beta-thalassemia major with chronic liver disease, HA and PC III showed more practical value in diagnosing liver fibrosis than the levels of C IV and LN. The combination of the four serum markers could improve the accuracy and reliability of the diagnosis. A validation study is necessary before introducing into the prediction function during the clinical practice.

Adolescent↗
PubMed2004

[Methemoglobin level and its comparison with levels of globins and membrane proteins in erythrocytes of patients with beta-thalassemia].

On the basis of conducted biological-and-chemical research, the clinical-and-genetic forms of beta-thalassemia were revealed, as well as fractions and the quantity of globin chains and membrane proteins were defined. The methods of electrophoresis and of isoelectrofocusing were made use of within the case study to separate between the globin chains and the membrane proteins. Samples of venous blood obtained from one hundred and one children with beta-thalassemia and from 45 donors were tested. Higher and lower values for different globin chains were found in investigating the quantitative ratios of various globin chains in patients with beta+, beta 0- and heterozygote variations of beta-thalassemia. Reliable changes in the quantitative content of main membrane proteins were observed in patients with heterozygote beta-thalassemia. The final study data denote that an excessive accumulation of alpha-globin chains in heterozygote beta-thalassemia is accompanied by a higher level of methemoglobin and by changed quantities of globin chains and membrane proteins.

Child↗
PubMed2004

Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients.

BACKGROUND AND OBJECTIVES: Hydroxyurea (HU) is known to increase gamma-globin chain expression in postnatal life. The efficacy of HU treatment in thalassemia patients is still unclear. The aim of this study was to monitor treatment of a large cohort of patients with beta-thalassemia major in order to establish the response to HU and the associated elements. DESIGN AND METHODS: HU therapy was started in 133 patients diagnosed with transfusion-dependent beta-thalassemia in 1999. The molecular background of the disease, the polymorphisms of the promoter region of the genes, the haplotype of the beta-globin gene cluster, the alpha-gene deletions and the HS2 polymorphism at the locus control region (LCR) of the beta-globin gene cluster were studied. RESULTS: We were able to classify three categories of response: a good response (61%) in patients who shifted from monthly blood transfusion dependency to a stable transfusion-free condition at an average Hb level of more than 10 gm/dL; a moderate response (23%) in patients who remained transfusion dependent but at longer intervals (6 months or more), and non response in patients who, after one year of treatment, remained at the same level of transfusion dependency. The correlations with the molecular defects were found to be secondary to the presence of the (C-->T) at -158 of the Ggamma gene (XmnI polymorphism). The T allele, in linkage to the haplotype I (+----) and to the internal beta-globin gene framework 2, was the most significant modulating factor involved. INTERPRETATION AND CONCLUSIONS: The good response to HU treatment that a significant number of southwest Iranian patients with beta-thalassemia patients had seems to correlate with particular haplotypes. This indicates that HU treatment is a sensible option for transfusion-dependent beta-thalassemia patients with a favorable molecular background.

Adolescent↗