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1.
Ann Hematol ; 99(9): 2019-2026, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32676731

RESUMO

Hyperbilirubinemia and pigment gallstones are frequent complications in transfusion-dependent ß-thalassemia (TDßT) patients. Bilirubin production and clearance are determined by genetic as well as environmental variables like ineffective erythropoiesis, hemolysis, infection-induced hepatic injury, and drug- or iron-related toxicities. We studied the frequency of the Gilbert syndrome (GS), a common hereditary cause of hyperbilirubinemia in 102 TDßT patients aged 13-43 years (median 26 years). Total and unconjugated hyperbilirubinemia were frequent (81.4% and 84.3% patients respectively). Twenty (19.6%) patients showed total bilirubin > 3.0 mg/dL; 53 (51.9%) had an elevation of either alanine or aspartate aminotransferase, or alkaline phosphatase liver enzymes. Nineteen (18.6% of the 92 tested) were positive for hepatitis B or C, or HIV. The mean total and unconjugated bilirubin levels and AST, ALT, and ALP levels in patients positive for hepatitis B or C were not significantly different from negative cases. Eighteen patients (17.7%) had GS: homozygous (TA)7/7 UGT1A1 promoter motif (the *28/*28 genotype), 48 (47.1%) were heterozygous (TA)6/7. Total + unconjugated bilirubin rose significantly with the (TA)7 allele dose. Fourteen (13.7%) patients had gallstones. There was no significant difference in total/unconjugated bilirubin in patients with/without gallstones and no significant differences in frequencies of gallstones within the three UGT1A1 genotypes. This largest study in Indian TDßT patients suggests that GS should be excluded in TDßT cases where jaundice remains unexplained after treatable causes like infections, chelator toxicity, or transfusion-related hemolysis are excluded. GS was not associated with gallstones, possibly due to a lower incidence of cholelithiasis overall, a younger age cohort, or other environmental factors.


Assuntos
Grupo com Ancestrais do Continente Asiático , Colelitíase/epidemiologia , Doença de Gilbert/epidemiologia , Glucuronosiltransferase , Hiperbilirrubinemia/epidemiologia , Talassemia beta/epidemiologia , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Transfusão de Sangue/tendências , Colelitíase/genética , Feminino , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia/genética , Índia/epidemiologia , Masculino , Estudos Prospectivos , Adulto Jovem , Talassemia beta/genética , Talassemia beta/terapia
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 918-926, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552958

RESUMO

OBJECTIVE: To investigation the types and frequencies of thalassemia gene mutations in pregnant population in Nanping area of Fujian Province, so as to provide a basis for prevention and control of birth children with moderate and severe thalassaemia in this area. METHODS: The genotyping of α and ß thalassemia was performed using the gap-PCR (gap-PCR) technique combined with reverse dot blot (RDB). The genotyping test was performed by Gap-PCR for three rare deficient thalassemia. The cases with negative detection were further detected by Sanger sequencing method, so as to identify rare α or ß thalassemia mutation. RESULTS: 1120 specimens were genotyped for thalassemia, out of them 547 thalassemia genes were determined. The detection rate was 48.8% (547/1120). 340 specimens were diagnosed as α thalassemia, and the detection rate was 30.6%, including 266 cases of --SEA/αα, 44 cases of -α3.7/αα, 12 cases of -α4.2/αα, 8 cases of ααQS/αα,. 3 cases of Hb H disease ( 2 cases of --SEA/-α3.7, 1 case of --SEA/-α4.2), 2 cases of ααCS/αα, 2 cases of ααWS/αα, 1 case of -α3.7/-α3.7, and 1 case of -α3.7/ααQS. Also, they contain 11 cases of rare α thalassemia, 8 kinds of rare types of α thalassemia mutations in combination, such as 4 cases of ααIVS-II-55 (T→G) in α1/αα, 1 case of ααIVS-I-62 (C→T) in α1/αα, 1 case of ααCD106(CTG→GTG)in α2/αα, 1 case of ααHBA2:c.-24C>G/αα, 1 case of ααIVS-II-55 (T→G) in α1/ααIVS-II-55 (T→G) in α1, 1 case of ααIVS-II-55 (T→G) in α1/ααIVS-II-119 (G;+CTCGGCCC) in α2, 1 case of ααIVS-II-88 (G→A) in α2/αα, and 1 case of --THAI/αα. Among them, 5 α mutation sites were first reported, namely ααIVS-I-62 (C→T) in α1, ααIVS-II-55 (T→G) in α1, ααIVS-II-119 (G; +CTCGGCCC ) in α2, ααIVS-II-88 (G→A) in α2 and ααCD106 (CTG→GTG) in α2; 2 α thalassemia mutation sites: ααHBA2: c.-24C>G and --THAI were detected again in the Chinese population, respectively. 188 specimens were diagnosed as ß thalassemia with a detection rate of 16.8%. Among them, 68 cases of ßIVS-II-654/ßN, 47 cases of ßCD41-42/ßN, 20 cases of ßCD17/ßN, 17 cases of ß-28/ßN, 7 cases of ßCD27-28/ßN, 7 cases of ßE/ßN, 3 cases of ßCD71-72/ßN and 2 cases of ßCD43/ßN. And 17 cases were diagnosed as rare ß thalassemia, 8 kinds of rare types were ß thalassemia mutations in combination. There were 4 cases of ßIVS-II-81 (C→T)/ßN, 3 cases of ßHb J-Bangkok/ßN, 3 cases of ßHb New York/ßN, 2 cases of ß-96 (G→T)/ßN, 2 cases of ßIVS-II-806 (G→C)/ßN, 1 case of ßCodons 8/9/ßN, 1 case of ßHb G-Coushatta/ßN, 1 case of ßIVS-II-827 (A→T)/ßN. Among them, 3 ß thalassemia mutation sites were reported for the first time, namely ß-96 (G→T), ßIVS-II-806 (G→C) and ßIVS-II-827 (A→T); it was found that in the Chinese population as ßCodons 8/9, ßHb G-Coushatta, ßHb J-Bangkok, ßHb New York, and ßIVS-II-81 (C→T), respectively. 19 cases were diagnosed as αß-complex thalassemia, out of which 15 types of thalassemia mutation combinations were detected. They contain 2 cases of rare αß-complex thalassemia, which are ααIVS-II-55 (T→G)/αα complex ßIVS-II-81 (C→T)/ßN, ααIVS-II-65 (G→A) in α1/αα complex ßHb G-Coushatta/ßN. CONCLUSION: The types of thalassemia gene mutations in Nanping area of Fujian province are genetically heterogeneous. The prevention and control strategies of thalassaemia in this area should be based on the prevention and treatment of common α thalassemia and ß thalassaemia. And the attention should be paid to the types of rare and unknown gene mutations using screening and testing method.


Assuntos
Talassemia alfa , Talassemia beta , China , Feminino , Genótipo , Humanos , Mutação , Gravidez , Tailândia , Talassemia alfa/genética , Talassemia beta/genética
3.
Ann Hematol ; 99(9): 2027-2036, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567028

RESUMO

Increased expression of fetal hemoglobin (HbF) improves the clinical severity of ß-thalassemia patients. EHMT1/2 histone methyltransferases are epigenetic modifying enzymes that are responsible for catalyzing addition of the repressive histone mark H3K9me2 at silenced genes, including the γ-globin genes. UNC0638, a chemical inhibitor of EHMT1/2, has been shown to induce HbF expression in human erythroid progenitor cell cultures. Here, we report the HbF-inducing activity of UNC0638 in erythroid progenitor cells from ß-thalassemia/HbE patients. UNC0638 treatment led to significant increases in γ-globin mRNA, HbF expression, and HbF-containing cells in the absence of significant cytotoxicity. Moreover, UNC0638 showed additive effects on HbF induction in combination with the immunomodulatory drug pomalidomide and the DNMT1 inhibitor decitabine. These studies provide a scientific proof of concept that a small molecule targeting EHMT1/2 epigenetic enzymes, used alone or in combination with pomalidomide or decitabine, is a potential therapeutic approach for HbF induction. Further development of structural analogs of UNC0638 with similar biological effects but improved pharmacokinetic properties may lead to promising therapies and possible clinical application for the treatment of ß-thalassemia.


Assuntos
Células Precursoras Eritroides/metabolismo , Hemoglobina Fetal/biossíntese , Hemoglobina E/metabolismo , Quinazolinas/farmacologia , Talassemia beta/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células Precursoras Eritroides/efeitos dos fármacos , Hemoglobina Fetal/genética , Expressão Gênica , Humanos , Talassemia beta/genética
4.
Ann Hematol ; 99(7): 1475-1483, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32524201

RESUMO

Large deletions in the ß-globin gene cluster lead to increased HbF levels by delaying the γ- to ß-globin switch process. However, these deletions when inherited as a homozygous condition or when co-inherited with ß-thalassemia result in variable clinical phenotypes. Individuals or families with a clinically presenting child, where the parents had HbF levels ≥ 10%, were further screened for the presence of large ß-globin cluster deletions. Six deletions in the ß-globin gene cluster were screened by GAP-PCR, and the uncharacterized deletions were further analyzed by gene dosage or by multiplex ligation-dependent probe amplification (MLPA). Among 192 individuals suspected for the inheritance of large deletions, 138 were heterozygous for large deletions, 45 were compound heterozygous of a large ß-globin cluster deletion and ß-thalassemia, and 9 were found to be homozygous for deletions. Among the heterozygotes, the Asian Indian inversion-deletion was found to be the most common deletion (39.9%), followed by the HPFH-3 deletion (30.0%). Other deletions 49.3 kb, δß-thalassemia (21.2%), and 32.6 kb deletion (4.4%) were also found to be prevalent in our population. Patients compound heterozygous or homozygous for HPFH-3 and 32.6 kb deletions showed a milder clinical presentation, as compared with the patients compound heterozygous or homozygous for the Asian Indian inversion-deletion and 49.3 kb δß-thalassemia. This comprehensive study highlights the mutation spectrum of large ß-globin cluster deletions and the clinical heterogeneity in the patients homozygous or compound heterozygous with ß-thalassemia, thus asserting the need for molecular characterization of these deletions.


Assuntos
Hemoglobina Fetal/genética , Estudos de Associação Genética , Heterogeneidade Genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia delta/epidemiologia , Talassemia delta/genética , Idade de Início , Criança , Mortalidade da Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/análise , Estudos de Associação Genética/estatística & dados numéricos , Humanos , Índia/epidemiologia , Lactente , Padrões de Herança/genética , Masculino , Talassemia beta/sangue , Talassemia beta/mortalidade , Talassemia delta/sangue , Talassemia delta/mortalidade
5.
Cochrane Database Syst Rev ; 5: CD012284, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32463488

RESUMO

BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. This review on the role of growth hormone was originally published in September 2017 and updated in April 2020. OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 14 November 2019. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Date of latest search: 06 January 2020. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The certainty of the evidence was assessed using GRADE criteria. MAIN RESULTS: We included one parallel trial conducted in Turkey. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The certainty of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate-certainty evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate-certainty evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period. AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate certainty that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Talassemia beta/complicações , Adolescente , Criança , Intervalos de Confiança , Feminino , Crescimento/fisiologia , Transtornos do Crescimento/etiologia , Homozigoto , Humanos , Masculino , Talassemia beta/genética
6.
BMC Med Genet ; 21(1): 75, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32268883

RESUMO

BACKGROUND: ß Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A > G, c.-443C > T, and c.-153C > T, with iron overload in ß-thalassemia major patients. METHODS: A total of 102 samples from ß thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher's exact test. RESULTS: A total of 102 adult ß-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin > 1000 ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A > G variant (p = 0.02). For c.-443C > T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p = 0.058). All samples were homozygous for allele C of c.-153C > T. CONCLUSIONS: Despite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A > G polymorphism as a key component of iron homeostasis in these patients.


Assuntos
Hepcidinas/genética , Quelantes de Ferro/uso terapêutico , Polimorfismo de Nucleotídeo Único , Talassemia beta/tratamento farmacológico , Talassemia beta/genética , Adulto , Estudos de Coortes , Feminino , Homeostase/genética , Humanos , Irã (Geográfico) , Ferro/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/genética , Masculino , Regiões Promotoras Genéticas/genética , Falha de Tratamento , Talassemia beta/sangue
7.
Am J Physiol Gastrointest Liver Physiol ; 318(5): G966-G979, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308038

RESUMO

Iron overload induces intestinal-permeability defect (gut leakage), and gut translocation of organismal molecules might enhance systemic inflammation and sepsis severity in patients with thalassemia (Thal). Hence, iron administration in Hbbth3/+ mice, heterozygous ß-globin-deficient Thal mice, was explored. Oral iron administration induced more severe secondary hemochromatosis and gut leakage in Thal mice compared with wild-type (WT) mice. Gut leakage was determined by 1) FITC-dextran assay, 2) spontaneous serum elevation of endotoxin (LPS) and (1→3)-ß-d-glucan (BG), molecular structures of gut-organisms, and 3) reduction of tight-junction molecules with increased enterocyte apoptosis (activated caspase-3) by immunofluorescent staining. Iron overload also enhanced serum cytokines and increased Bacteroides spp. (gram-negative bacteria) in feces as analyzed by microbiome analysis. LPS injection in iron-overloaded Thal mice produced higher mortality and prominent cytokine responses. Additionally, stimulation with LPS plus iron in macrophage from Thal mice induced higher cytokines production with lower ß-globin gene expression compared with WT. Furthermore, possible gut leakage as determined by elevated LPS or BG (>60 pg/mL) in serum without systemic infection was demonstrated in 18 out of 41 patients with ß-thalassemia major. Finally, enhanced LPS-induced cytokine responses of mononuclear cells from these patients compared with cells from healthy volunteers were demonstrated. In conclusion, oral iron administration in Thal mice induced more severe gut leakage and increased fecal gram-negative bacteria, resulting in higher levels of endotoxemia and serum inflammatory cytokines compared with WT. Preexisting hyperinflammatory cytokines in iron-overloaded Thal enhanced susceptibility toward infection.NEW & NOTEWORTHY Although the impact of iron accumulation in several organs of patients with thalassemia is well known, the adverse effect of iron accumulation in gut is not frequently mentioned. Here, we demonstrated iron-induced gut-permeability defect, impact of organismal molecules from gut translocation of, and macrophage functional defect upon the increased sepsis susceptibility in thalassemia mice.


Assuntos
Citocinas/metabolismo , Duodeno/metabolismo , Microbioma Gastrointestinal , Hemocromatose/metabolismo , Mediadores da Inflamação/metabolismo , Ferro/metabolismo , Macrófagos/metabolismo , Sepse/metabolismo , Talassemia beta/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Duodeno/imunologia , Duodeno/microbiologia , Feminino , Óxido de Ferro Sacarado , Hemocromatose/induzido quimicamente , Hemocromatose/imunologia , Hemocromatose/microbiologia , Heterozigoto , Humanos , Lipopolissacarídeos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Sepse/induzido quimicamente , Sepse/imunologia , Sepse/microbiologia , Adulto Jovem , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/imunologia , Talassemia beta/microbiologia
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 378-383, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219817

RESUMO

OBJECTIVE: To determine the composition and distribution of beta-thalassemia-associated genotypes in Liuzhou area of Guangxi, China. METHODS: From January to December 2017, 13 847 individuals who came for premarital examination, maternity examination or health check were recruited with informed consent. The subjects were analyzed by reverse dot blotting (RDB) for 17 common beta-thalassemia-associated variants among the Chinese population. Individuals with inconsistent results by blood test, electrophoresis, and RDB were subjected to Sanger sequencing to detect rare variants of the beta globin gene. RESULTS: In total 2098 individuals were found to harbor beta-thalassemia-associated variants, which included 2075 heterozygotes (98.90%), 12 compound heterozygotes (0.57%) and 11 homozygotes (0.52%). CD41-42 (48.43%) and CD17 (31.45%) were the most common variants. Three hundred and thirty eight-individuals were found to also carry heterozygous variants of the alpha globin gene, with the most common types being --SEA/aa, -a3.7/aa, aCSa/aa, -a4.2/aa. Through Sanger sequencing, rare genotypes such as beta-32/betaN, betaCD41-42/betaIVS-II-5 and betaCD30/betaN were detected. CONCLUSION: Liuzhou area has a high incidence of beta-thalassemia, but with a complex variant spectrum and clinical phenotypes different from other regions. Genetic counseling and prenatal diagnosis for the carrier population is crucial for the reduction of the related birth defects. Our result may provide valuable information for the prevention and control of beta-thalassemia in this area.


Assuntos
Genótipo , Globinas beta/genética , Talassemia beta/genética , China , Feminino , Aconselhamento Genético , Variação Genética , Humanos , Mutação , Gravidez , Diagnóstico Pré-Natal , alfa-Globinas/genética , Talassemia beta/diagnóstico
10.
Gene ; 741: 144544, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32165295

RESUMO

The Maldives is an archipelago of 407,660 people according to population census of 2014, made up of 20 atolls, which has one of the highest prevalence of ß-thalassemia worldwide. However, there is a dearth of studies related to ß-thalassemia in the Maldives; therefore, in this study, we aimed to investigate the genetic epidemiology of ß-thalassemia in Maldives. Blood samples were collected from 110,504 participants (1992-2015). Hemoglobin and RBC indices were measured on automated hematology analyzers. The quantitation of hemoglobin, HbA2, Hb F, and other abnormal Hb variants were assessed by HPLC. Molecular analysis was performed for the most common mutations in Southeast Asia for only 874 individuals either heterozygous or homozygous for these mutations using reverse dot blot hybridization. We screened 110,504 individuals for ß-thalassemia between 1992 and 2015, which is ~ 30% of the entire population. The ß-thalassemia carrier frequency was estimated to be 16.2%. Molecular diagnosis of 874 ß-thalassemia carriers/major was performed for the most common seven mutations in Southeast Asia; of these, 139 patients were diagnosed as ß-thalassemia major. This analysis showed that the most common mutations were IVS1 + 5G > C, (678; 77.6%), followed by the CD 30 (136; 15.6%). The least frequent mutation was FS8/9, (1, 0.001%), followed by IVS1 + 1G > T and CD15 (2; 0.2%). The frequency of ß-thalassemia varies significantly among the 20 different atolls in Maldives. This study is expected to improve genetic counseling, creating awareness, enhance premarital screening, and customize the prevention and treatment strategies based on the needs of each atoll.


Assuntos
Aconselhamento Genético , Epidemiologia Molecular , Globinas beta/genética , Talassemia beta/genética , Feminino , Genótipo , Hemoglobinas Anormais/genética , Heterozigoto , Humanos , Ilhas do Oceano Índico , Masculino , Programas de Rastreamento/métodos , Mutação , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia
11.
N Engl J Med ; 382(13): 1219-1231, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32212518

RESUMO

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Transfusão de Eritrócitos/estatística & dados numéricos , Hematínicos/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Talassemia beta/tratamento farmacológico , Receptores de Activinas Tipo II/efeitos adversos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Ferritinas/sangue , Hematínicos/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Análise de Intenção de Tratamento , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteínas Recombinantes de Fusão/efeitos adversos , Esplenectomia , Adulto Jovem , Talassemia beta/genética , Talassemia beta/cirurgia , Talassemia beta/terapia
12.
BMC Med Genet ; 21(1): 43, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111191

RESUMO

BACKGROUND: Individuals with δß-thalassemia/HPFH and ß-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δß-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. METHODS: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level ≥ 5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for ß-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. RESULTS: A total of 654 individuals had hemoglobin (HbF) levels≥5, and 0.12% of the couples were found to be heterozygous for HPFH/δß-thalassemia, including Chinese Gγ (Aγδß)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore-Boston-Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying ß-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the Aγ-197C-T heterozygous state. It is difficult to discriminate between Chinese Gγ (Aγδß)0-thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. CONCLUSIONS: This study is the first to describe the familial prevalence of HPFH/δß-thalassemia and the high-risk rate in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for ß-thalassemia intermedia.


Assuntos
Hemoglobina Fetal/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia delta/epidemiologia , Talassemia delta/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Cidades/epidemiologia , Família , Feminino , Hemoglobinas Anormais/genética , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Prevalência , Adulto Jovem , Globinas beta/genética , Talassemia beta/sangue , Talassemia delta/sangue
13.
Ann Biol Clin (Paris) ; 78(1): 61-69, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108581

RESUMO

Hemoglobin D-Punjab is a common hemoglobin variant in India but very rare in Morocco. Often, its presence has minimal or no clinical impact. Its heterozygous association with ß-thalassemia is exceptional. The purpose of the study is to describe the epidemiological, diagnostic and prophylactic aspects of hemoglobinosis D-Punjab from a family case study. MATERIAL AND METHODS: Case study of hemoglobinosis D-Punjab in a Moroccan family, diagnosed at the Laboratory of Biochemistry-Toxicology of the Mohammed V Military Teaching Hospital. The biological study was based on iron and hemolysis checkups, hemogram and study of hemoglobin (electrophoresis in alkaline and acid medium, high performance liquid chromatography). The index patient also benefited from sequencing by molecular biology. RESULTS: The index patient was heterozygous D-Punjab/ß0-thalassemia, confirmed by molecular biology. Two of her sisters had the same hemoglobin profile. At electrophoresis, all three had hemoglobin D-Punjab higher than 90%, hemoglobin A less than 1% and hemoglobin A2 higher than 6%. The results of the three hemograms showed similar abnormalities (pseudo-polycythemia, hypochromia, microcytosis, anisopoikilocytosis). Six other members of the family had a thalassemic trait and another three had heterozygous hemoglobinosis D-Punjab. CONCLUSION: Hemoglobin D-Punjab remains extremely rare in Morocco and very poorly documented in the literature. The number of reported cases is expected to raise due to increasing migration. Biologist advisory services require a precise diagnosis in order to give correct genetic counseling.


Assuntos
Hemoglobinas Anormais/genética , Talassemia beta/genética , Adolescente , Adulto , Criança , Família , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Linhagem , Talassemia beta/sangue
14.
J Clin Pathol ; 73(9): 593-596, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32107282

RESUMO

AIMS: ß-Thalassaemia is an inherited blood disorder caused by mutations in the ß-globin gene cluster. Molecular characterisation of ß-thalassaemia is essential for its diagnosis and management. More and more rare and novel mutations have been reported. METHODS: Two Chinese families with ß-thalassaemia from Fujian Province were recruited in this study. The phenotypes of the probands were confirmed through haematological analysis. Routine molecular analysis of thalassaemia was employed to identify the common mutations of thalassaemia. The rare and novel mutations were detected by direct DNA sequencing. RESULTS: In family 1, the proband, a Chinese woman aged 31 years, showed elevated level of haemoglobin A2 (HbA2). No common mutations associated with ß-thalassaemia were detected, whereas a rare mutation Term CD+32(HBB: c.32A>C) was identified through DNA sequencing. Subsequent investigation of the ß-thalassaemia mutation in her family showed that her mother, her brother as well as her nephew also carried this mutation. In addition, both the proband's husband and her son carrying the rare --THAI mutation exhibited decreased levels of MCH, MCH and HbA2. In family 2, the proband, a child aged 1 year, showed elevated level of HbA2, but had no common mutations of ß-thalassaemia. The proband was identified carrying the mutation Term CD+32(HBB: c.32A>C), which was inherited from his mother. CONCLUSIONS: In this study, we first report a rare ß-thalassaemia mutation in Fujian Province, Southeast China. Moreover, our study also identified this rare mutation in humans. This finding has helped broaden the spectrum of ß-thalassaemia mutations in our region and suggested that this rare mutation may be more prevalent in the Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hemoglobina A2/genética , Talassemia beta/genética , Adulto , China , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , Análise de Sequência de DNA , Globinas beta/genética , Talassemia beta/patologia
16.
Ann Hematol ; 99(4): 729-735, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078010

RESUMO

HbE/Beta thalassemia (HbE/ß-thalassemia) is one of the common genetic disorders in South East Asia. It is heterogeneous in its clinical presentation and molecular defects. There are genetic modifiers which have been reported to influence the disease severity of this disorder. The aim of this study was to determine the genetic polymorphisms which were responsible for the disease clinical diversity. A case-control study was conducted among Malay transfusion-dependent HbE/ß-thalassemia patients. Patients who were confirmed HbE/ß-thalassemia were recruited and genotyping study was performed on these subjects. Ninety-eight patients were selected and divided into moderate and severe groups based on clinical parameters using Sripichai scoring system (based on hemoglobin level, spleen size, growth development, the age of first transfusion and age of disease presentation). Forty-three (44.9%) and 55 (56.1%) patients were found to have moderate and severe clinical presentation, respectively. Genotyping analysis was performed using Affymetrix 6.0 microarray platform. The SNPs were filtered using PLINK and Manhattan plot by R software. From the GWAS results, 20 most significant SNPs were selected based on disease severity when compared between moderate and severe groups. The significant SNPs found in this study were mostly related to thalassemia complications such as rs7372408, associated with KCNMB2-AS1 and SNPs associated with disease severity. These findings could be used as genetic predictors in managing patients with HbE/ß-thalassemia and served as platform for future study.


Assuntos
Hemoglobina E/genética , Hemoglobinúria/genética , Polimorfismo de Nucleotídeo Único , Globinas beta/genética , Talassemia beta/genética , Estudos de Casos e Controles , Criança , Grupos Étnicos/genética , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Malásia , Masculino , Fenótipo , Índice de Gravidade de Doença
17.
J Clin Pathol ; 73(8): 488-492, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31980563

RESUMO

AIMS: Thalassaemia is one of the most common genetics disorders in the world, especially in southern China. The aim of the present study was to investigate the feasibility of combining the gap-PCR and next-generation sequencing (NGS) for thalassaemia carrier screening in the Chinese population. METHODS: Blood samples were obtained from 944 prepregnancy couples; thalassaemia carrier screening was performed by using a routine haematological method and a combination of gap-PCR and NGS method. RESULTS: We found that the α thalassaemia carrier rate was 11% (207/1888); the ß thalassaemia carrier rate was 3.7% (70/1888); the composite α thalassaemia and ß thalassaemia carrier rate was 0.4% (8/1888). We also identified seven novel mutations, including HBA1: c.412A>G, -50 (G>A), HBB: c.*+129T>A, HBB: c.-64G>C, HBB: c.-180G>C, HBB: c.*+5G>A and HBB: c.-113A>G. By comparing the combined gap-PCR and NGS method, the MCV+MCH and HbA2 detection strategy showed a lower sensitivity of 61.05% (105/172) and a higher missed diagnosis ratio of 38.95% (67/172) for α thalassaemia mutations. The sensitivity was improved with the MCV+MCH and HbA2 detection screen when compared with MCV+MCH detection for ß thalassaemia (98.51% vs 85.90%). CONCLUSIONS: Our study suggests the combined gap-PCR and NGS method is a cost-effective method for the thalassaemia carrier screening, particularly for the α thalassaemia mutation carriers.


Assuntos
Talassemia alfa/genética , Talassemia beta/genética , Adulto , China , Feminino , Triagem de Portadores Genéticos/métodos , Triagem de Portadores Genéticos/normas , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Cuidado Pré-Concepcional , Sensibilidade e Especificidade , Adulto Jovem , alfa-Globinas/genética , Globinas beta/genética
18.
BMC Med Genet ; 21(1): 6, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906886

RESUMO

BACKGROUND: Thalassemia is a group of inherited hemoglobic disorders resulting from defects in the synthesis of one or more of the hemoglobin chains, which is one of the most prevalent inherited disorders in southern China. Only few studies reported the molecular characterization of α- and ß-Thalassemia in Hubei Province in the central of China. METHODS: A total of 4889 clinically suspected cases of thalassemia were analyzed by Gap-PCR, PCR-based reverse dot blot (RDB). RESULTS: 1706 (33.8%) subjects harbored thalassemia mutations, including 539 (11.0%) subjects with α-thalassemia, 1140 (23.3%) subjects with ß-thalassemia mutations, and 25 (0.51%) subjects with both α- and ß-thalassemia mutations. Seven genotypes of α-thalassemia mutations and 29 genotypes of ß-thalassemia mutations were characterized. --SEA/αα (66.05%), -α3.7/αα (24.12%), and -α4.2/αα (3.71%) accounted for 93.88% of the α-thalassemia mutations. ßIVS-II-654/ßN, ßCD41-42/ßN, ßCD17/ßN, ßCD27-28/ßN, ßCD71-72/ßN, ß - 28/ßN, ß - 29/ßN, ßCD43/ßN, ßE/ßN, accounting for 96.40% of all ß-thalassemia genotypes. Furthermore, mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) were sensitive markers for both ß-thalassemia and α-thalassemia with --SEA/αα, but not -α3.7/αα and -α4.2/αα. CONCLUSIONS: Our data indicated great heterogeneity and extensive spectrum of thalassemias in Hubei province of China.


Assuntos
Genética Populacional , Hemoglobinas/genética , Talassemia alfa/genética , Talassemia beta/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China , Feminino , Heterogeneidade Genética , Genótipo , Hemoglobinas/biossíntese , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem , Talassemia alfa/epidemiologia , Talassemia beta/sangue , Talassemia beta/epidemiologia
20.
Int J Hematol ; 111(3): 352-359, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31894534

RESUMO

Hemoglobin (Hb) is an iron-containing metalloprotein that transports oxygen molecules from the lungs to the rest of the human body. Among the different variants of Hb, HbA1 is the most common and is composed of two alpha (αHb) and two beta globin chains (ßHb) constructing a heterotetrameric protein complex (α2ß2). Due to the higher number of AHSP genes, there is a tendency to produce approximately twice as much of α subunit as ß subunit. Therefore, there is a chance of presenting excess α subunit leftover in human blood plasma; excess subunits subsequently bind with each other and aggregates ß-thalassemia occurs due to lack of or reduced numbers of ßHb subunit. Alpha-hemoglobin-stabilizing protein (AHSP) is a scavenger protein which acts as a molecular chaperon by reversibly binding with free αHb forming a complex (AHSP-αHb) that prevents aggregation and precipitation preventing deleterious effects towards developing serious human diseases including ß-thalassemia. Clinical severity worsens if mutations in AHSP gene co-occur in patients with ß-thalassemia. Considering the mechanism of action of AHSP and its contribution to ameliorating ß-thalassemia severity, it could potentially be used as a modulatory agent in the treatment of ß-thalassemia.


Assuntos
Proteínas Sanguíneas/genética , Proteínas Sanguíneas/fisiologia , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiologia , Talassemia beta/genética , Humanos
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