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1.
Int J Lab Hematol ; 41(2): 218-226, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30489691

RESUMO

INTRODUCTION: The hemoglobinopathies pose a significant health burden in India. Apart from the ß thalassemias and sickle cell disorders, α thalassemias and structural hemoglobin variants are also common. Here we have reviewed the phenotypic and molecular diversity of hemoglobinopathies encountered at a referral center in western India over a period of 15 years. MATERIALS AND METHODS: Screening for hemoglobinopathies was done using HPLC and cellulose acetate electrophoresis. Molecular characterization was done using Covalent Reverse Dot Blot Hybridization (CRDB), Amplification Refractory Mutation System (ARMS), GAP PCR and direct DNA sequencing. RESULTS: The study includes 31 075 individuals who were referred for diagnosis of hemoglobinopathies and prenatal diagnosis. Of these 14 423 individuals showed various hemoglobin abnormalities. Beta genotyping in 5615 individuals showed the presence of 49 ß thalassemia mutations. 143 ß thalassemia heterozygotes had normal or borderline HbA2 levels. We identified three δ gene mutations (HbA2 Pellendri, HbA2 St.George, HbA2 Saurashtra) in ß thalassemia heterozygotes leading to normal HbA2 levels. The commonest defects among the raised Hb F determinants were Gγ(Αγδß)0 Indian inversion and the HPFH-3 Indian deletion. A total of 312 individuals showed the presence of α thalassemia, of which 12.0% had a single α gene deletion (-α/αα). HbH disease was identified in 29 cases with 10 different genotypes. Alpha globin gene triplication was seen in 2.1% of ß thalassemia heterozygotes with a thalassemia intermedia phenotype. Seven unusual α chain variants and eight uncommon ß chain variants were identified. CONCLUSION: The repertoire of molecular defects seen in the different globin genes will be valuable for management and control of these disorders both in India as well as in other countries where there is a huge influx of migrant populations from India.


Assuntos
Hemoglobinas/genética , Mutação , Talassemia beta/genética , Feminino , Humanos , Índia/epidemiologia , Masculino , Estudos Retrospectivos , Talassemia beta/epidemiologia
2.
Hemoglobin ; 36(2): 114-23, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22296681

RESUMO

We report the problems in diagnosis faced by two families referred for prenatal diagnosis of thalassemia where cordocentesis and fetal blood analysis by high performance liquid chromatography (HPLC) had to be done. The Hb A levels of the fetal blood measured by HPLC on the VARIANT™ Hemoglobin Testing System were 1.2 and 6.7%, respectively, suggestive of a heterozygous ß-thalassemia (ß-thal) fetus in the first case and a normal fetus in the second case. In one family, one of the parents had a borderline Hb A(2) level and in the other, one parent had normal RBC indices. However, DNA sequencing, done later, showed that in the first case the fetus was a compound heterozygote for the IVS-I-5 (G>C) and the polyadenylation signal site [poly A (T>C)] mutation, while in the second case, the fetus was homozygous for the poly A mutation. This emphasizes that characterization of ß-thal mutations must be done whenever one of the parents has a borderline Hb A(2) level or normal RBC indices, and one should not rely on fetal blood analysis by HPLC for prenatal diagnosis of ß-thal so as to avoid misdiagnosis.


Assuntos
Erros de Diagnóstico , Hemoglobina A2/genética , Poli A/genética , Talassemia beta/diagnóstico , Sequência de Bases , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Cordocentese , Análise Mutacional de DNA , Feminino , Sangue Fetal/química , Hemoglobina A2/análise , Heterozigoto , Homozigoto , Humanos , Dados de Sequência Molecular , Mutação , Poli A/sangue , Gravidez , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal , Talassemia beta/sangue , Talassemia beta/genética
3.
Clin Biochem ; 43(16-17): 1329-32, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20709051

RESUMO

OBJECTIVES: Hydroxyurea is known to reduce ineffective erythropoiesis and thereby hemolysis leading to a reduction in bilirubin levels in patients with hemoglobinopathies. However, the effect of hydroxyurea on hyperbilirubinemia in relation to the UGT1A1 gene promoter polymorphism is not known in Indian patients with different hemoglobinopathies. DESIGN AND METHODS: We studied 112 patients (77 sickle cell anemia, 22 ß-thalassemia intermedia and 13 HbE-ß-thalassemia) who were on hydroxyurea therapy for 2 years for their response towards hyperbilirubinemia associated with UGT1A1 promoter polymorphism. RESULTS: The patients with (TA)(7)/(TA)(7) repeats had significantly higher serum bilirubin levels than those with (TA)(6)/(TA)(6) repeats in all the groups and the reduction in serum bilirubin after hydroxyurea therapy was still higher among patients with (TA)(7)/(TA)(7) repeats when compared with (TA)(6)/(TA)(6) repeats. CONCLUSIONS: Higher bilirubin levels were associated with the (TA)(7)/(TA)(7) sequence however they did not come down to normal levels after hydroxyurea therapy.


Assuntos
Bilirrubina/sangue , Glucuronosiltransferase/genética , Hemoglobinopatias/tratamento farmacológico , Hemoglobinopatias/genética , Hidroxiureia/uso terapêutico , Polimorfismo Genético , Regiões Promotoras Genéticas , Adolescente , Adulto , Criança , Deleção de Genes , Hemoglobinopatias/sangue , Humanos , Sequências Repetitivas de Ácido Nucleico/genética , Adulto Jovem
4.
J Clin Pathol ; 63(2): 147-50, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20154037

RESUMO

BACKGROUND: Haemoglobin E (HbE)-beta-thalassaemia has a very variable clinical presentation. The management of severe cases that are often transfusion dependent is similar to that of cases of beta-thalassaemia major; however, this is often not possible in India because of its high cost and the lack of availability of safe blood at many places. Thus there was a need for a drug such as hydroxyurea, which is known to reduce the transfusion requirements of patients with thalassaemia intermedia. This study was undertaken to evaluate the response of Indian patients with HbE-beta-thalassaemia to hydroxyurea. MATERIALS AND METHODS: 11 patients with HbE-beta-thalassaemia receiving regular transfusion plus two less frequently transfused patients were selected for hydroxyurea therapy. Clinical and haematological evaluation was performed before and after treatment for 2 years. Molecular studies included beta-globin genotype, beta-globin gene haplotype, Xmn I polymorphism and alpha-genotyping. RESULTS: Four clinically severe patients became transfusion independent (responders) after hydroxyurea therapy, four patients showed a reduction in their transfusion requirements (partial responders), and three patients were non-responders. Responders showed a statistically significant increase in Hb, mean corpuscular volume, mean cell Hb, fetal Hb and F cells with a reduction in their transfusion requirements. A reduction in serum ferritin concentration was also seen in responders and non-responders. CONCLUSIONS: Genetic markers such as Xmn I polymorphism and alpha-gene deletions were not always beneficial for the response to hydroxyurea therapy. Thus many more markers and a larger cohort need to be studied to predict the response in these patients.


Assuntos
Transfusão de Sangue , Hemoglobina E/análise , Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Adolescente , Adulto , Criança , Terapia Combinada , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Ferritinas/sangue , Genótipo , Humanos , Mutação , Polimorfismo Genético , Resultado do Tratamento , Adulto Jovem , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/terapia
5.
Am J Clin Pathol ; 133(3): 491-4, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20154289

RESUMO

This study was undertaken to evaluate the variable clinical expression of hemoglobin (Hb) H disease in India. For the study, alpha genotyping was done in 8 patients with Hb H disease using multiplex polymerase chain reaction and DNA sequencing. The study revealed that 4 genotypes (- -(SEA)/ -alpha(3.7), - -(SA)/-alpha(3.7), - -(SEA)/-alpha(3.7 Sallanches), - -alpha(3.7)/-alpha(3.7 Sallanches)) were responsible for Hb H disease, the alpha+ thalassemia mutation (-alpha(3.7) deletion) being the most common defect. The nondeletional mutation Hb Sallanches (alpha 2 codon 104 G --> A) was seen in 3 cases. Two unique and novel genotypes leading to Hb H disease were characterized (- -(SEA)/-alpha(3.7 Sallanches) and -alpha(3.7)/-alpha(3.7 Sallanches)). Because a majority of patients with Hb H disease do not have severe manifestations, prenatal diagnosis is usually unwarranted in India.


Assuntos
Mutação/genética , Talassemia alfa/genética , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Talassemia alfa/diagnóstico
7.
Clin Chim Acta ; 407(1-2): 10-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19545554

RESUMO

BACKGROUND: The clinical and hematological response to hydroxyurea was evaluated in beta thalassemia patients in western India with variable clinical severity and correlated with genetic factors. MATERIALS AND METHODS: Seventy-nine patients-[38-beta thalassemia intermedia-(group I), 41-beta thalassemia major-(group II)] on hydroxyurea therapy were followed-up for 20-24months. RESULTS: Among the frequently transfused patients in group I, 58% became transfusion independent and 16% showed a 50% reduction in transfusions after therapy which correlated with a higher mean fold increase in HbF and gamma mRNA expression levels. Forty-one percent of patients in group I had associated alpha-thalassemia and 72.7% were XmnI (+/+). beta thalassemia chromosomes among the responders of group I (41%) were linked to haplotype (- + + - + + - - +) as against haplotype (+ - - - - - - - +) being more common among the non-responders. Response was not linked to the beta thalassemia mutations. Thirty-two percent of group II patients showed a 50% reduction in their transfusion requirements after therapy which also correlated with a higher mean fold increase in HbF and gamma mRNA expression levels. A significant decrease in serum ferritin was seen in both groups. 19% of patients could not tolerate the drug. CONCLUSIONS: In group I, clinical response to hydroxyurea was better in patients with alpha-thalassemia, XmnI (+/+) and a higher mean fold increase in gamma mRNA expression. In group II, only one-third of patients showed a partial response.


Assuntos
Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Talassemia beta/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Haplótipos , Hematologia , Humanos , Hidroxiureia/farmacologia , Índia , Masculino , Mutação , Polimorfismo Genético , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Repetitivas de Ácido Nucleico , Resultado do Tratamento , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/genética
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