Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 308
Filtrar
1.
Ann Hematol ; 100(4): 903-911, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33523291

RESUMO

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and ßS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and ßS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with ßS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.


Assuntos
Anemia Falciforme/sangue , Bilirrubina/sangue , Colelitíase/etiologia , Doença de Gilbert/sangue , Glucuronosiltransferase/fisiologia , Regiões Promotoras Genéticas/genética , Talassemia alfa/sangue , Adolescente , Adulto , Idoso , Alelos , Anemia Falciforme/complicações , Anemia Falciforme/enzimologia , Anemia Falciforme/genética , Criança , Pré-Escolar , Colelitíase/sangue , Colelitíase/genética , Feminino , Hemoglobina Fetal/análise , Genótipo , Doença de Gilbert/enzimologia , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Haplótipos/genética , Hemólise , Humanos , Hiperbilirrubinemia/enzimologia , Hiperbilirrubinemia/etiologia , Hiperbilirrubinemia/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia alfa/complicações , Talassemia alfa/enzimologia , Talassemia alfa/genética
2.
Ann Hematol ; 100(4): 921-931, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33586016

RESUMO

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.


Assuntos
Anemia Falciforme/complicações , Talassemia alfa/complicações , Globinas beta/genética , Adolescente , Adulto , Idoso , Anemia Falciforme/sangue , Anemia Falciforme/genética , Arteriopatias Oclusivas/epidemiologia , Arteriopatias Oclusivas/etiologia , Brasil/epidemiologia , Criança , Colelitíase/epidemiologia , Colelitíase/etiologia , Feminino , Hemoglobina Fetal/análise , Seguimentos , Haplótipos/genética , Hemólise , Humanos , Úlcera da Perna/epidemiologia , Úlcera da Perna/etiologia , Masculino , Mutação , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/genética
3.
Pediatr Blood Cancer ; 67(4): e28109, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31876111

RESUMO

BACKGROUND: Diabetes mellitus (DM) associated with iron overload has been reported among adults with transfusion-dependent thalassemia and those with non-transfusion-dependent thalassemia (NTDT), especially in ß-thalassemia disease. However, little is known about glucose metabolism and how early its dysregulation can develop in α-thalassemia hemoglobin H (Hb H) disease, which is one of the most common types of NTDT worldwide. PROCEDURE: We prospectively calculated glucose metabolism index in 40 patients (aged 10-25 years) with Hb H disease. Glucose metabolism data were compared between patients with deletional versus nondeletional Hb H, and between patients with normal versus abnormal insulin secretion/sensitivity. RESULTS: Despite normal glucose tolerance in all patients, 52.5% had abnormal insulinogenic index indicating decreased ß-cell insulin secretion. Patients with functional hemoglobin < 8 g/dL had significantly higher percentages of abnormal insulinogenic index. There was no significant difference in abnormal insulinogenic index between deletional and nondeletional Hb H. CONCLUSION: Decreased ß-cell insulin secretion is highly prevalent among children and adolescents with Hb H disease, and it is associated with levels of functional anemia at baseline, but not with the type of Hb H disease. This result warrants heightened awareness among hematologists due to potentially increased risk of DM later in life.


Assuntos
Anemia/etiologia , Secreção de Insulina , Talassemia alfa/complicações , Talassemia alfa/metabolismo , Adolescente , Adulto , Criança , Feminino , Glucose/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Adulto Jovem
4.
Ultraschall Med ; 41(2): 186-191, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29415313

RESUMO

OBJECTIVE: To assess fetal cardiac remodeling in response to anemia, by comparing the fetal cardiac dimensions and global sphericity index (GSI) of normal fetuses and fetuses with anemia using fetal Hb Bart's disease as a study model. METHODS: Fetuses at risk for Hb Bart's disease undergoing cordocentesis at 18 to 22 weeks of gestation were recruited. Fetal cardiac dimensions including GSI (cardiac length to cardiac width ratio), interventricular septum thickness (IVST), left ventricular wall thickness (LVWT) and right ventricular wall thickness (RVWT) were measured. RESULTS: 215 pregnancies at risk met the inclusion criteria, including 54 affected fetuses and 161 normal fetuses. The mean GSI was significantly lower in the affected group (1.11 ±â€Š0.06 vs. 1.26 ±â€Š0.09, p-value 0.017). The GSI of the normal group was relatively constant regardless of gestational age. The IVST and LVWT tended to increase, but not significantly, in the affected group, whereas the RVWT was minimally but significantly increased. The ROC curve for GSI had an area under curve of 0.844. The best cut-off of GSI was 1.17, giving a sensitivity of 74.1 % and a specificity of 88.2 %. CONCLUSION: Fetal cardiac remodeling in response to anemia causes a marked decrease in global GSI with minimal hypertrophy as an adaption to volume overload. Importantly, GSI is a new maker for anemia and may play a role in clinical application for early detection of fetal anemia, possibly due to any cause. Additionally, GSI measurement is simple and gestational age-independent.


Assuntos
Anemia , Hemoglobinas Anormais , Remodelação Ventricular , Talassemia alfa , Anemia/complicações , Feminino , Feto , Humanos , Gravidez , Segundo Trimestre da Gravidez , Talassemia alfa/complicações
5.
Medicine (Baltimore) ; 98(44): e17612, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689767

RESUMO

RATIONALE: Extramedullary hematopoiesis (EMH) is a rare disease characterized by the formation of hematopoietic elements outside the bone marrow driven by several hematological disease. To the best of our knowledge, EMH is relatively common in patient with beta-thalassemia or hereditary spherocytosis but rarely reported in patients with alpha-thalassemia. Here, we discuss a large intrathoracic EMH (measuring 95 mm × 66 mm) without presenting severe complications in alpha-thalassemia along with literature review. PATIENT CONCERNS: A 55-year-old Chinese female patient with alpha-thalassemia presented with ipsilateral pleural effusion and low hemoglobin level. DIAGNOSIS: Lung cancer was suspected at first and the mass was subjected to CT-guided percutaneous mediastinum biopsy and the pathology confirmed the final diagnosis of extramedullary hematopoiesis. INTERVENTIONS: Blood transfusion, thoracentesis and regular follow up were scheduled rather than surgical interventions or radiotherapy since our patient did not exhibit significant symptoms. OUTCOMES: After 6 months' regular follow up, the patient exhibited no evidence of disease progress. LESSONS: EMH is frequently misdiagnosed and should be differentiated from other masses in thoracic cavity, especially when the underlying hematological disease is discovered. Treatment methods of EMH include surgical resection, hyper-transfusion, hydroxyurea, low-dose radiation or a combination of them.


Assuntos
Hematopoese Extramedular/fisiologia , Derrame Pleural/etiologia , Talassemia alfa/complicações , Transfusão de Sangue , Feminino , Humanos , Pessoa de Meia-Idade , Derrame Pleural/terapia , Toracentese
6.
Neuropediatrics ; 50(5): 327-331, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319423

RESUMO

The X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus-dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.


Assuntos
Distúrbios Distônicos/diagnóstico , Epilepsias Mioclônicas/diagnóstico , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Puberdade Precoce/diagnóstico , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/diagnóstico , Criança , Distúrbios Distônicos/complicações , Distúrbios Distônicos/genética , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Puberdade Precoce/complicações , Puberdade Precoce/genética , Irmãos , Talassemia alfa/complicações , Talassemia alfa/genética
7.
Pediatr Blood Cancer ; 66(8): e27807, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31094093

RESUMO

BACKGROUND: The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV-exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa. METHODS: A 3-year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine sickle cell trait and disease prevalence within high-burden districts, (2) document the prevalence among HIV-exposed and nonexposed children, (3) confirm previously suggested HIV comorbidity, and (4) estimate the co-inheritance of known genetic modifiers of sickle cell disease. RESULTS: A total of 163 334 dried blood spot samples collected between April 2015 and March 2018 were analyzed, including 112 352 samples within the HIV Early Infant Diagnosis program. A high burden with >1% sickle cell disease was found within targeted East Central and Mid-Northern districts, in both HIV-exposed and nonexposed children. Based on crude birth-rate data, 236 905 sickle cell trait births and 16 695 sickle cell disease births will occur annually in Uganda. Compared to sickle cell disease without HIV, the odds ratio of having sickle cell disease plus HIV was 0.50 (95% confidence interval = 0.40-0.64, P < .0001). Alpha-thalassemia trait and G6PD deficiency were common with sickle cell disease, but with different geospatial distribution. CONCLUSIONS: High sickle cell burden and potential HIV comorbidity are confirmed in Uganda. Genetic modifiers are common and likely influence laboratory and clinical phenotypes. These prospective data document that targeted sickle cell screening is feasible and effective in Uganda, and support development of district-level comprehensive care programs.


Assuntos
Anemia Falciforme/diagnóstico , Genes Modificadores , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Talassemia alfa/diagnóstico , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Pré-Escolar , Comorbidade , Feminino , Seguimentos , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Prognóstico , Estudos Prospectivos , Talassemia alfa/complicações , Talassemia alfa/epidemiologia , Talassemia alfa/genética
9.
Lab Med ; 50(2): 168-173, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30295867

RESUMO

BACKGROUND: The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported. OBJECTIVE: To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan. METHODS: We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan. RESULTS: Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P <.05). Compared with the healthy population, the patients with HbH disease exhibited short body length, low body weight, and low body mass index (BMI). CONCLUSIONS: Patients with nondeletional HbH disease had lower Hb levels and a higher requirement for splenectomy and iron-chelation therapy than did those with deletional HbH disease. Also, growth status was compromised in patients with HbH disease.


Assuntos
Talassemia alfa , Adolescente , Adulto , Peso Corporal/fisiologia , Criança , Pré-Escolar , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esplenectomia , Taiwan/epidemiologia , Adulto Jovem , Talassemia alfa/complicações , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Talassemia alfa/terapia
11.
PLoS One ; 13(11): e0206928, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30388173

RESUMO

INTRODUCTION: Anaemia in women during pregnancy and child bearing age is one of the most common global health problems. Reasons are numerous, but in many cases only minimal attempts are made to elucidate the underlying causes. In this study we aim to identify aetiology of anaemia in women of child bearing age and to determine the relative contributions, effects and interactions of α- and ß-thalassaemia in a region of the world where thalassaemia is endemic. METHODS: A cross sectional study was conducted at the Colombo North Teaching Hospital of Sri Lanka. The patient database of deliveries between January 2015 and September 2016 at University Obstetrics Unit was screened to identify women with anaemia during pregnancy and 253 anaemic females were randomly re-called for the study. Data were collected using an interviewer-administered questionnaire and haematological investigations were done to identify aetiologies. RESULTS: Out of the 253 females who were anaemic during pregnancy and were re-called, 8 were excluded due to being currently pregnant. Of the remaining 245 females, 117(47.8%) remained anaemic and another 22(9.0%) had non-anaemic microcytosis. Of anaemic females, 28(24.8%) were iron deficient, 40(35.4%) had low-normal serum ferritin without fulfilling the criteria for iron deficiency,18(15.3%) had ß-haemoglobinopathy trait and 20(17.0%) had α-thalassaemia trait. Of females who had non-anaemic microcytosis, 14(66.0%) had α-thalassaemia trait. In 4 females, both α- and ß-thalassaemia trait coexist. These females had higher levels of haemoglobin (p = 0.06), MCV (p<0.05) and MCH (p<0.01) compared to individuals with only ß-thalassaemia trait. A significantly higher proportion of premature births (p<0.01) and lower mean birth weights (p<0.05) were observed in patients with α-thalassaemia trait. CONCLUSIONS: Nearly one third of anaemic females in child bearing age had thalassaemia trait of which α-thalassemia contributes to a majority. Both α- and ß-thalassaemia trait can co-exist and have ameliorating effects on red cell indices in heterozygous states. α-Thalassaemia trait was significantly associated with premature births and low birth weight. It is of paramount importance to investigate the causes of anaemia in women of child bearing age and during pregnancy in addition to providing universal iron supplementation.


Assuntos
Anemia/genética , Ferro/deficiência , Talassemia alfa/genética , Talassemia beta/genética , Adulto , Anemia/sangue , Anemia/complicações , Anemia/dietoterapia , Anemia Ferropriva/sangue , Anemia Ferropriva/complicações , Anemia Ferropriva/genética , Anemia Ferropriva/patologia , Suplementos Nutricionais , Feminino , Ferritinas/sangue , Humanos , Recém-Nascido de Baixo Peso , Ferro/sangue , Ferro/uso terapêutico , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/genética , Complicações Hematológicas na Gravidez/prevenção & controle , Nascimento Prematuro/sangue , Nascimento Prematuro/patologia , Sri Lanka/epidemiologia , Inquéritos e Questionários , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/complicações , Talassemia alfa/dietoterapia , Talassemia beta/sangue , Talassemia beta/complicações , Talassemia beta/dietoterapia
12.
Blood Adv ; 2(21): 3035-3044, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425067

RESUMO

In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, α-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. α-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] α-globin genes) and associated with higher prevalence of anemia (P < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection (P = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children.


Assuntos
Anemia/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Malária/diagnóstico , Anemia/complicações , Anemia/epidemiologia , Anemia/patologia , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/complicações , Transtornos Herdados da Coagulação Sanguínea/epidemiologia , Pré-Escolar , Análise Discriminante , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Malária/complicações , Malária/epidemiologia , Malaui/epidemiologia , Masculino , Prevalência , Índice de Gravidade de Doença , Talassemia alfa/complicações , Talassemia alfa/diagnóstico , Talassemia alfa/genética
13.
Int J Mol Sci ; 19(9)2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30231518

RESUMO

α-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX. An ATR-X model mouse lacking Atrx exon 2 displays phenotypes that resemble symptoms in the human intellectual disability: cognitive defects and abnormal dendritic spine formation. We herein target activation of sigma-1 receptor (Sig-1R) that can induce potent neuroprotective and neuroregenerative effects by promoting the activity of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). We demonstrated that treatment with SA4503, a potent activator of Sig-1R, reverses axonal development and dendritic spine abnormalities in cultured cortical neurons from ATR-X model mice. Moreover, the SA4503 treatment rescued cognitive deficits exhibited by the ATR-X model mice. We further found that significant decreases in the BDNF-protein level in the medial prefrontal cortex of ATR-X model mice were recovered with treatment of SA4503. These results indicate that the rescue of dendritic spine abnormalities through the activation of Sig-1R has a potential for post-diagnostic therapy in ATR-X syndrome.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Piperazinas/uso terapêutico , Receptores sigma/metabolismo , Talassemia alfa/tratamento farmacológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ligantes , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Camundongos Endogâmicos C57BL , Talassemia alfa/complicações , Talassemia alfa/fisiopatologia
14.
PLoS One ; 13(9): e0203229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30222732

RESUMO

BACKGROUND: Evidence for association between sickle cell and alpha thalassemia trait and severe malaria is compelling. However, for these polymorphisms associations with uncomplicated malaria, and for G6PD deficiency associations with uncomplicated and severe malaria, findings have been inconsistent. We studied samples from a three-arm case-control study with the objective of determining associations between common host erythrocyte polymorphisms and both uncomplicated and severe malaria, including different severe malaria phenotypes. METHOD: We assessed hemoglobin abnormalities, α-thalassemia, and G6PD deficiency by molecular methods in 325 children with severe malaria age-matched to 325 children with uncomplicated malaria and 325 healthy community controls. Conditional logistic regression was used to measure associations between specified genotypes and malaria outcomes. RESULTS: No tested polymorphisms offered significant protection against uncomplicated malaria. α-thalassemia homozygotes (_α/_α) had increased risk of uncomplicated malaria (OR 2.40; 95%CI 1.15, 5.03, p = 0.020). HbAS and α-thalassemia heterozygous (_α/αα) genotypes protected against severe malaria compared to uncomplicated malaria (HbAS OR 0.46; 0.23, 0.95, p = 0.036; _α/αα OR 0.51; 0.24, 0.77; p = 0.001) or community (HbAS OR 0.23; 0.11, 0.50; p<0.001; _α/αα; OR 0.49; 0.32, 0.76; p = 0.002) controls. The α-thalassemia homozygous (_α/_α) genotype protected against severe malaria when compared to uncomplicated malaria controls (OR 0.34; 95%CI 0.156, 0.73, p = 0.005), but not community controls (OR 1.03; 0.46, 2.27, p = 0.935). Stratifying by the severe malaria phenotype, compared to community controls, the protective effect of HbAS was limited to children with severe anemia (OR 0.17; 95%CI 0.04, 0.65; p = 0.009) and that of _α/αα to those with altered consciousness (OR 0.24; 0.09, 0.59; p = 0.002). A negative epistatic effect was seen between HbAS and _α/αα; protection compared to uncomplicated malaria controls was not seen in individuals with both polymorphisms (OR 0.45; 0.11, 1.84; p = 0.269). G6PD deficiency was not protective against severe malaria. CONCLUSION: Associations were complex, with HbAS principally protective against severe anemia, _α/αα against altered consciousness, and negative epistasis between the two polymorphisms.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/patologia , Malária/sangue , Malária/complicações , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/genética , Hemoglobinas Anormais/genética , Humanos , Lactente , Malária/genética , Masculino , Fenótipo , Polimorfismo Genético , Fatores de Risco , Traço Falciforme/sangue , Traço Falciforme/complicações , Traço Falciforme/genética , Uganda , Talassemia alfa/sangue , Talassemia alfa/complicações , Talassemia alfa/genética
15.
Eur J Haematol ; 101(6): 798-803, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30204261

RESUMO

OBJECTIVE: Determine the effect of fetal hemoglobin (HbF) and α-thalassemia on red blood cell (RBC) deformability of patients with sickle-cell anemia (SCA) with and without hydroxyurea (HU). METHODS: Adult patients were enrolled in the Sickle Cell Program of the Cardeza Foundation (Thomas Jefferson University) and were followed up prospectively during the period in which the Multicenter Study of Hydroxyurea (MSH) in patients with SCA was conducted. Ninety-one patients did not receive HU, 20 patients were enrolled in MSH, and 10 patients were enrolled in an open-label study of HU in SCA. Of the 20 patients enrolled in MSH, 11 took HU and nine took placebo. Control group included 113 normal individuals. Red blood cell deformability index (DI) was measured by ektacytometry. RESULTS: Patients with SCA taking HU (n = 21) had higher DI than those taking placebo (n = 9) or who were not taking this therapy (n = 91). In patients without therapy, those with α-thalassemia (n = 31) had higher DI than those without. We showed a significant positive correlation between the level of HbF and DI. SCA patients without α-thalassemia and HbF <10% (n = 48) had lower DI than patients with α-thalassemia and HbF <10% (n = 23) and patients with (n = 8) or without α-thalassemia but with HbF >10% (n = 12). DI measured in patients without α-thalassemia and HbF >10% was higher than in the three other subgroups. CONCLUSION: Elevated levels of HbF with or without HU and α-thalassemia improve sickle RBC rheology, which, in turn, improve the clinical picture of SCA.


Assuntos
Anemia Falciforme/sangue , Eritrócitos Anormais/metabolismo , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Biomarcadores , Índices de Eritrócitos , Eritrócitos Anormais/efeitos dos fármacos , Hemoglobina Fetal/metabolismo , Genótipo , Hemorreologia/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Resultado do Tratamento , alfa-Globinas/genética , Talassemia alfa/sangue , Talassemia alfa/complicações
16.
Eur J Hum Genet ; 26(8): 1217-1221, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29706636

RESUMO

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , Mutação em Linhagem Germinativa , Retardo Mental Ligado ao Cromossomo X/genética , Osteossarcoma/genética , Talassemia alfa/genética , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/patologia , Criança , Feminino , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/patologia , Osteossarcoma/epidemiologia , Osteossarcoma/patologia , Linhagem , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/complicações , Talassemia alfa/patologia
17.
Clin Hemorheol Microcirc ; 68(2-3): 147-164, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614629

RESUMO

Sickle cell disease (SCD) is one of the most common single disease disorders world-wide. It is remarkable for its clinical heterogeneity, even among individuals with identical genotypes. Some individuals experience morbidity and mortality in early childhood, while others have a relatively mild course, and normal or near normal life expectancy. Many clinical complications are associated with SCD; most notably frequent pain episodes, stroke, acute chest syndrome, avascular necrosis, nephropathy, retinopathy and pulmonary hypertension. While the effects of higher fetal hemoglobin (HbF) levels, UGTA1A polymorphisms, alpha-thalassemia and G6PD deficiency on SCD has been extensively studied, these variables do not explain all of the clinical heterogeneity of SCD. It is not known why some patients develop certain complications, and it is difficult to predict which complications a particular patient will experience. Much work has been done to identify genetic variants associated with these disease complications; many associations remain unvalidated. As the field continues to move beyond small sample collections and candidate gene approaches into whole genome sequencing and merging of samples from all over the world, we will identify more genetic variants associated with development of specific SCD related complications, and hopefully leverage this knowledge into targeted therapies.


Assuntos
Anemia Falciforme/genética , Talassemia alfa/complicações , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Feminino , Humanos , Masculino , Talassemia alfa/patologia
19.
BMJ Case Rep ; 20182018 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-29301806

RESUMO

A Caucasian 24-year-old female patient suffers from two hereditary disorders: alpha-thalassaemia, which is prevalent in Asia and rare in Europe, and haemochromatosis, which is prevalent among northern Europe and rare in Asia. The clinical presentation and management of one of these diseases is controversial for the other. She presented 5 years ago with a clinical picture of refractory iron-deficiency anaemia secondary to menorrhagia. On treating her with the standard iron therapy, her anaemia persists although with adquate iron stores. This prompted further investigations that revealed in addition to hereditary haemochromatosis, alpha-thalassaemia because of abnormal blood indices. The treatment of thalassaemia with either iron or blood transfusion is not advisable in haemochromatosis, while standard treatment of haemochromatosis with venesection will worsen the anaemia. As iron chelating agents were not approved in Australia for haemochromatosis, haematinics support was commenced with a satisfactory improvement of anaemia thus allowing for further venesection.


Assuntos
Hematínicos/uso terapêutico , Proteína da Hemocromatose/genética , Hemocromatose/tratamento farmacológico , Mutação , Talassemia alfa/tratamento farmacológico , Feminino , Hemocromatose/complicações , Hemocromatose/genética , Humanos , Adulto Jovem , Talassemia alfa/complicações , Talassemia alfa/genética
20.
Am J Hematol ; 93(5): 623-629, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29359464

RESUMO

Recently, complications in patients with nontransfusion-dependent thalassemia (NTDT), in particular those with ß-thalassemia intermedia (ß-TI), were found to be significantly different from those in patients with transfusion dependent thalassemia (TDT), mainly ß-thalassemia major (ß-TM). However, this information is rather limited in other forms of NTDT. In this prospective study, adult Thai NTDT patients were interviewed and clinically evaluated for thalassemia related complications. Fifty-seven NTDT patients (age 18-74 years), 59.6% Hb E/ß-thalassemia and 40.4% Hb H disease, were recruited; 26.4% were splenectomized. The most common complications were gallstones (68.4%), osteoporosis (26.3%), and pulmonary hypertension (15.8%). Splenectomy was associated with higher rate of gallstones and serious infection (P = .001 and .052, respectively), consistent with a multivariate analysis (RR = 9.5, P = .044, and RR = 15.1, P = .043, respectively). In addition, a higher hemoglobin level was inversely associated with gallstones in both univariate and multivariate analyses (P = .01 and .022, respectively). Serum ferritin was associated with abnormal liver function (P = .002). In contrast to the previous study, the prevalence of thrombosis was less common in our population (1.7%), probably due to differences in transfusion therapy, ethnicity, and underlying genotypes. For the first time, this prospective study provided the current prevalence of NTDT related complications in a Southeast Asian population with a different underlying genetic basis compared with previous studies. Although individual prevalence of each complication might differ from other studies, several important clinical factors such as splenectomy, degree of anemia, and iron overload seem to be determining risks of developing these complications consistently across different ethnicities.


Assuntos
Talassemia alfa/complicações , Talassemia beta/complicações , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Transfusão de Sangue , Cálculos Biliares/etiologia , Hemoglobina E , Hemoglobina H , Humanos , Hipertensão Pulmonar/etiologia , Pessoa de Meia-Idade , Osteoporose/etiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Esplenectomia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...