Síndrome drepanocítico: Asociación de hemoglobina S Y &ß talasemia / Sickle cell syndrome. Association between hemoglobin S and ß thalassemia

El síndrome drepanocítico HbS/β talasemia responde a la herencia de tipo mendeliana en simultáneo de un alelo βs de la hemoglobina S (HbS) y un alelo de β talasemia. Vinculado fundamentalmente a individuos que comparten ascendencia africana y de países del Mediterráneo. La mutación responsable de la HbS es puntual, mientras que para la β talasemia existen más de 200 mutaciones que causan diferentes grados de deficiencia de síntesis de la cadena de β globina, lo cual justifica la heterogeneidad clínica y genética de este síndrome. Se presenta el caso clínico de un adulto joven de escasos recursos que consulta por dolores óseos de larga data. Registra hemogramas con anemia y marcada microcitosis. Se le realizó electroforesis de Hb detectándose un pico anómalo en posición de HbS y elevada fracción de HbA2. El resultado de la electroforesis de hemoglobina indica dos posibles alteraciones moleculares en simultáneo, por tal motivo se realizó el estudio molecular de las mutaciones más frecuentes en nuestra población de β talasemia y de la mutación puntual responsable de la hemoglobinopatía S. A partir de la clínica y datos del laboratorio bioquímico se diagnosticó el síndrome drepanocítico y se confirmó por biología molecular la portación de las mutaciones IVS-Int 110 G > A (β talasemia) y del codón 6 A > T (GAG→GTG: Glu→Val) responsable de la hemoglobinopatía S. Dado que es una enfermedad de alto impacto sanitario, es importante un adecuado asesoramiento genético a toda la familia.

Sickle cell syndrome HbS/β thalassemia is an inheritable mendelian type disease where two affected alleles are simultaneously present, one from HbS (βS) and the other from β thalassemia. That situation is mainly linked to individuals who share African and Mediterranean ancestors. The mutation responsible for HbS is a point mutation, whereas for β thalassemia, there are more than 200 mutations that cause different degrees of deficiency synthesis of β globin chain, which justifies the clinical and genetic heterogeneity of this syndrome. It is presented a clinical case of a young adult man with limited resources that consulted by longstanding bone pain. The patient presented anemia with a marked microcytosis. Hemoglobin electrophoresis was performed, an abnormal peak in position of HbS and high HbA2 fraction were detected. These last results indicated two possible molecular alterations simultaneously, for this reason the molecular study was performed looking for the most common β thalassemia mutations in our population and, the point mutation responsible for S hemoglobinopathy. Clinical data and biochemical laboratory allowed the diagnosis of sickle cell syndrome. The molecular study confirmed the syndrome carrying mutations IVS-I nt 110 G > A, responsible for β thalassemia and, codon 6 A > T (GAG → GTG: Glu → Val) responsible for S hemoglobinophaty. Since it is a disease of high health impact, it is important to provide genetic counseling to the whole family.

Homozygous sickle cell disease in Uganda and Jamaica a comparison of Bantu and Benin haplotypes / La anemia de células falciformes homocigóticas en Uganda y Jamaica comparación de haplotipos Bantú y Benin

OBJECTIVE: To compare the haematological and clinical features of homozygous sickle cell (SS) disease in Bantu and Benin haplotypes in a cross-sectional study of 115 Ugandan patients attending the Sickle Cell Clinic at Mulago Hospital, Kampala, Uganda, with 311 patients in the Jamaican Cohort Study. METHODS: This involved comparison of clinical features and haematology with special reference to genetic determinants of severity including fetal haemoglobin levels, beta-globin haplotype and alpha thalassaemia status. RESULTS: The Bantu haplotype accounted for 94% of HbS chromosomes in Ugandan patients and the Benin haplotype for 76% of HbS chromosomes in Jamaica. Ugandan patients were marginally more likely to have alpha thalassaemia, had similar total haemoglobin and fetal haemoglobin levels but had higher reticulocyte counts and total bilirubin levels consistent with greater haemolysis. Ugandan patients had less leg ulceration and priapism, but the mode of clinical presentation, prevalence of dactylitis, features of bone pain and degree of delay in sexual development, assessed by menarche, were similar in the groups. In Ugandan patients, a history of anaemic episodes was common but these were poorly documented. CONCLUSION: The haematological and clinical features of the Bantu haplotype in Uganda were broadly similar to the Benin haplotype in Jamaica except for less leg ulceration and priapism and possibly greater haemolysis among Ugandan subjects. Anaemic episodes in Uganda were treated empirically by transfusion often without a clear diagnosis; better documentation including reticulocyte counts and observations on spleen size is necessary to evolve appropriate models of care.

OBJETIVO: Comparar los rasgos clínicos de la anemia de células falciformes homocigóticas (SS) en los haplotipos Bantú y Benin en un estudio transversal de 115 pacientes ugandeses que asisten a la Clínica de la anemia de células falciformes en el Hospital de Mulago, Kampala, Uganda, con 311 pacientes en un estudio de cohorte jamaicano. MÉTODOS: El estudio conllevó la comparación de los rasgos clínicos y hematológicos con referencia especial a los determinantes genéticos de la severidad, incluyendo los niveles de la hemoglobina fetal, haplotipos del gen de la globina beta, y el estado de la alfa talasemia. RESULTADOS: El haplotipo Bantú dio cuenta del 94% de los cromosomas HbS en los pacientes ugandeses, en tanto que los haplotipos Benin dieron cuenta del 76% de los cromosomas de HbS en Jamaica. Los pacientes de Uganda presentaron una probabilidad marginalmente mayor de alfa talasemia, tenían niveles similares de hemoglobina total y hemoglobina fetal, pero en cambio presentaban conteos más altos de reticulocitos así como niveles mayores de bilirrubina total, en correspondencia con una mayor hemólisis. Los pacientes ugandeses presentaban menor ulceración de las piernas y priapismo, pero el modo de presentación clínica, la prevalencia de dactilitis, los rasgos de dolor óseo, y el grado de retraso en el desarrollo sexual, evaluado por la menarquia, fueron similares en todos los grupos. Los pacientes de Uganda se caracterizaron comúnmente por una historia de episodios de anemia, pobremente documentados. CONCLUSIÓN: Los rasgos clínicos y hematológicos del haplotipo Bantú en Uganda fueron considerablemente similares al haplotipo Benin en Jamaica, salvo por una menor presencia de ulceración de las piernas y priapismo, así como posiblemente mayor hemólisis entre los sujetos de Uganda. Los episodios de anemia en Uganda fueron tratados empíricamente mediante transfusión, a menudo sin un diagnóstico claro. Se necesita una mejor documentación - incluyendo conteos de reticulocitos - así como observaciones del tamaño del bazo, a fin de desarrollar modelos de cuidado apropiados.

Haplotipos del gen de la globina beta en portadores de hemoglobina S en Colombia / Beta globin haplotypes in hemoglobin S carriers in Colombia

Introducción. La mutación de la hemoglobina S (HbS) va acompañada por otras mutaciones en la región del cromosoma 11, conocida como conjunto de la globina beta(beta globin cluster). El patrón de combinación de estos polimorfismos da lugar a los haplotipos que se heredan junto con la mutación de la hemoglobina S, se denominan haplotipos de la mutación bs y revisten gran importancia epidemiológica y clínica. Objetivo. Determinar la frecuencia de los principales haplotipos asociados al gen HBB en pacientes colombianos heterocigotos para hemoglobina S. Materiales y métodos. En la Clínica Colsanitas se han estudiado a la fecha 1.200 muestras de sangre periférica de niños en busca de hemoglobinopatías, y se ha encontrado el rasgo falciforme como la hemoglobinopatía más frecuente. Se determinaron los haplotipos del gen HBB que presentaron la mutación beta-S en 33 niños con patrón electroforético de hemoglobina AS, mediante reacción en cadena de la polimerasa (PCR) y enzimas de restricción. Se determinaron el patrón electroforético de la hemoglobina, el nivel de hemoglobina fetal y los parámetros hematológicos de cada individuo. Resultados. Los haplotipos de la hemoglobina S encontrados con mayor frecuencia en la muestra analizada son de origen africano y su orden de aparición fue mayor para el haplotipo Bantú (36,4 %), seguido por Senegal (30,3 %), Benín (21,2 %) y Camerún (12,1 %). La electroforesis de hemoglobina confirmó el fenotipo AS; la dosificación de hemoglobina fetal mostró niveles por debajo de 1 % y los parámetros hematológicos analizados mostraron valores normales en el 100 % de los individuos. Conclusión. Los haplotipos de la HbS encontrados con mayor frecuencia en la muestra estudiada eran de origen africano y su distribución variaba de acuerdo con el lugar de prodedencia del individuo. La mayor frecuencia correspodió al haplotipo Bantú.

Introduction. The hemoglobin S (HbS) mutation is accompanied by other mutations in the region of chromosome 11 known as "beta globin cluster". The pattern of combination of these polymorphisms giving rise to the haplotypes that co-inherit the HbS mutation, are called haplotypes bs, and are of great epidemiological and clinical significance. Objective. The frequencies of major haplotypes associated with S beta-globin gene was determined in Colombian patients heterozygous for hemoglobin S. Materials and methods. As part of the national neonatal screening program at Clínica Colsanitas, located in major cities of Colombia, nearly 1,200 children from different areas of the country were examined for hemoglobinopathies. The sickle cell trait was identified as the most common. S beta-globin gene haplotypes were determined by PCR and restriction enzymes in 33 children with AS hemoglobin electrophoretic patterns (carrier state). In addition, electrophoretic patterns of hemoglobin, fetal hemoglobin levels and hematologic parameters of each individual were identified. Results. The most frequent haplotypes in Colombia were the Bantú haplotype (36.4 %), followed by Senegal (30.3 %), Benin (21.2 %) and Cameroon (12.1 %) haplotypes. Hemoglobin electrophoresis confirmed the AS phenotype in all patients, and fetal hemoglobin levels below 1%. Other hematological parameters were normal in all cases. Conclusion. The HbS haplotypes found more frequently in the sample were of African origin, and their distribution varied according to the place of origin of the individual. The most frequent corresponded to the Bantu haplotype.

Sickle cell disease in Middle East Arab countries.

The sickle cell (HbS) gene occurs at a variable frequency in the Middle Eastern Arab countries, with characteristic distribution patterns and representing an overall picture of blood genetic disorders in the region. The origin of the gene has been debated, but studies using β-globin gene haplotypes have ascertained that there were multiple origins for HbS. In some regions the HbS gene is common and exhibits polymorphism, while the reverse is true in others. A common causative factor for the high prevalence and maintenance of HbS and thalassaemia genes is malaria endemicity. The HbS gene also co-exists with other haemoglobin variants and thalassaemia genes and the resulting clinical state is referred to as sickle cell disease (SCD). In the Middle Eastern Arab countries, the clinical picture of SCD expresses two distinct forms, the benign and the severe forms, which are related to two distinct β-globin gene haplotypes. These are referred to as the Saudi-Indian and the Benin haplotypes, respectively. In a majority of the Middle Eastern Arab countries the HbS is linked to the Saudi-Indian haplotype, while in others it is linked to the Benin haplotype. This review outlines the frequency, distribution, clinical feature, management and prevention as well as gene interactions of the HbS genes with other haemoglobin disorders in the Middle Eastern Arab countries.

Pathophysiological insights in sickle cell disease.

The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile. This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs. This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism. These data altogether have shed a new light on the pathophysiology of the first molecular disease i.e. sickle cell disease.

Hemoglobin S/hemoglobin city of hope compound heterozygote with a subsaharan genetic background and severe bone marrow hypoplasia

Hemoglobin City of Hope (HbCH) (HBB: c.208G>A, beta 69 (E13)Gly>Ser) is a rare, anomalous change. Seven independent carriers reported so far, had not displayed any hematological manifestations. The ethnic origin of the known instances is presumably heterogeneous, although they are mainly Mediterraneans or equatorial West Africans. We describe the case of a compound heterozygote in trans for Hb S (Glu6Val) and Hb City of Hope (Gly69Ser) in an anemic two year-old boy with a severe immune-deficient phenotype and fatal chronic parvovirus B19 infection. Haplotype with the Hb S was Bantu; while it was a mixed atypical Benin/Cameroon for Hb CH. Remote ancestral origin of the City of Hope mutation in this family seems to be SubSaharan African. The compound heterozygosis in trans for hemoglobins S and City of Hope, jointly with an unfavorable HBB control region background and a viral chronic infection, seemed the cause of the fatal outcome in the patient. When accompanied by other Hb deleterious mutations in trans, Hb CH should not be considered any longer as an innocuous or functionally silent variant.

La hemoglobina City of Hope (HbCH) (HBB: c.208G>A, beta 69 (E13)Gly>Ser) es una variante infrecuente, considerada como anómala. Ninguno de los siete heterocigotos simples, genéticamente no relacionados, reportados hasta ahora, ha mostrado hemopatología. El origen étnico de esos casos es presuntamente heterogéneo, pero la mayoría parece mediterráneo o africano-ecuatorial occidental. Se describe el caso de un niño de dos años de edad con fenotipo hipoplásico mieloeritroideo severo e infección crónica por parvovirus B19, heterocigoto compuesto en trans para las hemoglobinas S (Glu6Val) y City of Hope (Gly69Ser ). El haplotipo en fase con la Hb S fue Bantú, mientras que el de la Hb CH fue un combinado atípico Benin/Camerún. El origen ancestral remoto de la mutación City of Hope (y de la Hb S) en esta familia es africano subsahariano. La heterocigosis compuesta en trans para las hemoglobinas S y City of Hope y una secuencia génica predisponente en la región de control de HBB, conjuntamente con la infección por parvovirus B19 pueden ser la causa del curso fatal del paciente. En presencia de otras mutaciones de hemoglobina deletéreas, la Hb City of Hope no debiera ser considerada una variante inocua o funcionalmente silenciosa.

A family study of HbS in a Malay family by molecular analysis

Sickle cell disease (SCD) is an inherited red cell disorder, characterized by the tendency of haemoglobin S or sickle haemoglobin to polymerize and assume a characteristic sickle shape. Molecular analysis has been the mainstay of detection method when confirmation is required. Previously a polymerase chain reaction (PCR)-based restriction enzyme analysis was used for this purpose. A simple bidirectional allele-specific amplification, recently described by Waterfall in 2001 was used to detect the GAG --> GTG mutation on codon 6 of the beta globin gene. Two sets of primers for the mutant and the wild type alleles were used in a single PCR reaction to amplify the regions of interest. The resultant PCR products will produce two fragments at 517 and 267 base pair (bp) respectively. This report highlights the investigations for SCD in the family of a 16-year old girl with recurrent painful crisis affecting the lower limbs whereby the family members are asymptomatic for the disease. Her haemoglobin electrophoresis at an alkaline pH showed dense bands at the HbS and HbF regions, while her father and two sisters had bands at HbS, HbF and HbA. The PCR analysis showed that she was homozygous for the mutation by the presence of only one band at 267 bp fragment, while the father and her sisters were heterozygotes, with the presence of two bands at 267 as well as 517 bp fragments. DNA sequencing of the sample confirmed the mutation. In conclusion, this case report highlighted the simple and cheap yet practical method for molecular confirmation of the presence of HbS gene in subjects with homozygous or heterozygous state of the condition.

Ocorrência de hemoglobina S no estado de Mato Grosso do Sul, Brasil / Occurrence of hemoglobin S in Mato Grosso do Sul state, Brazil

INTRODUÇÃO: As hemoglobinopatias são as alterações genéticas mais comuns no homem, sendo a hemoglobina (Hb) S a mais freqüente entre todas. Sua ocorrência no estado de Mato Grosso do Sul ainda não foi sistematicamente avaliada. OBJETIVOS: Caracterizar a ocorrência de Hb S por genótipos, sexo, idade no momento do diagnóstico, índice de cobertura e prevalência em Mato Grosso do Sul. MATERIAL E MÉTODO: Estudo retrospectivo, transversal e descritivo, desenvolvido com os resultados de triagem neonatal para hemoglobinopatias, utilizando a técnica de cromatografia líquida de alta pressão, no Instituto de Pesquisas, Ensino e Diagnósticos da Associação de Pais e Amigos dos Excepcionais (IPED/APAE) de Mato Grosso do Sul em 2000-2005. RESULTADOS: De 190.809 indivíduos triados, 2.624 (1,38 por cento) encontraram-se alterados, correspondendo a 2.385 neonatos e 239 crianças maiores de 28 dias. Não houve diferença entre os sexos, sendo 1.335 do sexo feminino e 1.289 do masculino. Os genótipos alterados encontrados foram traço falciforme (FAS [99,16 por cento]) e doenças falciformes (FS [0,61 por cento] e FSC [0,23 por cento]). CONCLUSÃO: Esse primeiro estudo de triagem realizado no estado de Mato Grosso do Sul mostra que o programa desenvolvido pelo IPED/APAE está se solidificando no estado e avançando em relação ao índice de cobertura da população e ao diagnóstico precoce. Esses indicadores podem embasar ações preventivas (aconselhamento genético e estudos familiares) e assistenciais (tratamento ambulatorial contínuo), que visam à redução da morbimortalidade de indivíduos acometidos por essas afecções no estado.

BACKGROUND: Hemoglobinopathies are the most common genetic disorders in humans and Hb S is the most frequent among them. Its occurrence in the state of Mato Grosso do Sul has not been systematically analyzed yet. OBJECTIVES: To describe the occurrence of hemoglobin S according to genotypes, gender, age at the moment of diagnosis, cover index and prevalence in the state of Mato Grosso do Sul. MATERIAL AND METHOD: Retrospective, transversal and descriptive study of the results of neonatal screening for hemoglobinopathies performed with high pressure liquid chromatography technique at Instituto de Pesquisa, Ensino e Diagnósticos da Associação dos Pais e Amigos dos Excepcionais (IPED/APAE) in the state of Mato Grosso do Sul (2000-2005). RESULTS: Among 190,809 screened individuals, 2,624 (1.38 percent) showed alterations, 2,385 were neonates and 239 were children aged 28 days or more. There was no difference in gender (1,335 females and 1,289 males). The altered genotypes were FAS (99.16 percent), FS (0.61 percent) and FSC (0.23 percent). CONCLUSION: This first study of neonatal screening in the state of Mato Grosso do Sul revealed that the state program developed by IPED/APAE has been consolidating and advancing as to cover index and early diagnosis. These indicators may be the basis for preventive (genetic counseling and family studies) and assistance measures (continuous ambulatory treatment), which aim at the reduction of morbimortality in individuals with these hemoglobinopathies in the state.

Frecuencia de la hemoglobina S en cinco poblaciones mexicanas y su importancia en la salud pública / Hemoglobin S frequency in five Mexican populations and its importance in public health

OBJETIVO: Informar la frecuencia de heterocigotos para la hemoglobina S (HbS) en cinco poblaciones mexicanas y el haplotipo en cinco muestras con HbS y subrayar su relevancia en la salud pública. MATERIAL Y MÉTODOS: Se tomó una muestra de sangre periférica en 162 individuos no relacionados provenientes de tres poblaciones nahuas (Atocpan y Tlacotenco, DF, e Ixhuatlancillo, Veracruz), y en 131 mestizos (Coyolillo y Poza Rica, Veracruz), previo consentimiento informado. Se determinó el tipo de hemoglobina por electroforesis y se extrajo el DNA de leucocitos de cinco muestras en las que se determinó el haplotipo por PCR y corte con restrictasas. RESULTADOS: Entre los nahuas se reconoció un heterocigoto HbAS (0.6 por ciento) y 18 en mestizos (13.7 por ciento). Se identificaron cuatro haplotipos Bantu y uno Benin. CONCLUSIONES: Estos hallazgos son importantes en términos de la salud pública en poblaciones con alta frecuencia de HbS, para dar información y consejo genético a los portadores y la atención médica oportuna y adecuada a los pacientes.

OBJECTIVE: To provide information regarding the heterozygote frequency for hemoglobin S (HbS) in five Mexican populations, the Haplotype in five S chromosomes, and underscore its importance for public health. MATERIAL AND METHODS: A total of 162 samples from three Nahua populations (Atocpan and Tlacotenco, DF, and Ixhuatlancillo, Veracruz) and 131 from mestizo populations (Coyolillo and Poza Rica, Veracruz) were studied after obtaining informed consent. The hemoglobin type was determined by electrophoresis, and DNA in leucocytes was obtained from five HbS samples. The haplotype was determined by PCR and cut with restrictases, according to literature. RESULTS:We found one heterozygote for hemoglobin S (0.6 percent) among Nahua and 18 among Mestizo groups (13.7 percent). Four haplotypes were Bantu and one was Benin. CONCLUSIONS: These findings are important to public health for populations with a high frequency of HbS, to inform and provide genetic counseling for carriers and medical attention to patients.

Estudo genético-epidemiológico da hemoglobina S em uma população do Sudeste do Brasil / Genetic-epidemiological study of hemoglobin S in a population from Southeastern Brazil

A anemia falciforme, expressão clínica dos homozigotos do gene da hemoglobina S, é a doença hereditária mais freqüente no Brasil. Apesar disso, a metodologia genético-epidemiológica raramente é usada nos estudos brasileiros sobre essa alteração. No presente estudo foram analisados, por meio de um software específico, os dados de 817 heterozigotos do gene da HbS (513 homens e 304 mulheres), não consangüíneos, com idades entre 18 e 65 anos, detectados voluntariamente na cidade de Campinas, SP, Sudeste do Brasil. A constituição genômica caucasóide, negróide e indígena foi avaliada na amostra de portadores da hemoglobina S através do estudo das freqüências alélicas do sistema sangüíneo ABO e comparada com a observada na população geral da mesma cidade. A análise dos dados demonstrou que 52 por cento dos portadores da HbS tiveram sua ancestralidade africana evidenciada pelo seu fenótipo e que 36 por cento dos indivíduos eram procedentes do Nordeste do Brasil, sobretudo da Bahia (15 por cento). Essa imigração interna tende a diminuir a proporção do haplótipo Bantu da hemoglobina S (mais grave) na região de Campinas, aumentando a proporção do haplótipo Benin (mais benigno). A amostra possui um componente gênico negróide de 45 por cento, caucasóide de 41 por cento, e indígena de 14 por cento. Essa composição genômica é significativamente diferente da observada na população geral da mesma cidade, apresentando uma participação gênica maior de negróides e de indígenas (influência da imigração nordestina) e menor de caucasóides. A imigração nordestina e a miscigenação alteraram significativamente o perfil genético-epidemiológico dos portadores da hemoglobina S na região de Campinas, SP.

Sickle cell anemia, the clinical expression of individuals homozygous for the hemoglobin S gene, is the most frequent hereditary disease in Brazil. Nevertheless, a genetic-epidemiological approach is rarely used in Brazilian studies related to this alteration. In the present study, using a specific computer program, data from 817 (513 males and 304 females) non-consanguineous individuals heterozygous for the hemoglobin S gene were studied. The participants, with ages varying from 18 to 65 years old, live from the region of Campinas, Southeastern Brazil. The Caucasoid, Negroid and native Indian genomic backgrounds of this sample were evaluated by a study of allelic frequencies for the ABO blood group system and compared with those observed in the general population from the same city. Data analysis showed that: 52 percent of the hemoglobin S carriers had African ancestry as shown by their phenotypes and that 36 percent of the subjects came from North-eastern Brazil, most from the state of Bahia (15 percent). This internal migration tends to decrease the proportion of the hemoglobin S Bantu (wild) haplotype in the region of Campinas, by increasing the proportion of the Benin haplotype (milder). The frequencies of this sample were Negroes 45 percent, Caucasians 41 percent, and native Indians 14 percent. This genomic constitution is significantly different from that observed in the general population from the same city with greater frequencies of Negroes and native Indians and a lower frequency of Caucasians. Migration from the northeastern and miscegenation have significantly altered the genetic-epidemiological profile of hemoglobin S carriers in the region of Campinas.

Anemia falciforme: polimorfismos gênios em moléculas de adesão (VCAM-1 e ICAM-1), TNF-ALFA-, IL-8 e alterações fonotípicas / Sickle cell anemia: polymorphisms geniuses in molecules of accession (VCAM-1 and ICAM-1), TNF-ALPHA-, IL-8 and amendments fonotípicas

A hemoglobina S é resultado da mutação pontual A>T no sexto códon do gene beta da globina, conduzindo à substituição do ácido glutâmico pela valina na cadeia da globina beta. A anemia falciforme apresenta heterogeneidade clinica, com a gravidade variável atribuída ao pleiotropismo gênico dos pacientes. Logo, alguns pacientes apresentam alterações gênicas variadas que podem refletir na melhora ou não do fenótipo apresentado. O estudo investigou polimorfismos gênicos em moléculas de adesão (VCAM-1 e ICAM-1) e citocinas (TNF-alfa e IL-8) correlacionando-os aos níveis séricos das citocinas, parâmetros hematológicos e manifestações clinicas apresentadas em um grupo de pacientes pediátricos com anemia falciforme em Salvador-Bahia. No estudo foram investigados 125 pacientes pediátricos com anemia falciforme e 212 indivíduos sadios da população de Salvador. Os polimorfismos gênicos foram investigados por PCR-RFLP. Os níveis séricos das citocinas foram avaliados por ELlSA. As análises estatísticas foram realizadas pelo programa EPI-INFO versão 6.04 e a significância foi estabelecida para p < 0,05. Do total de 125 pacientes analisados, 27 (22 por cento) foram heterozigotos para o polimorfismo -833 na região promotora do gene da VCAM-1; 15 (12 por cento) foram heterozigotos para o polimorfismo 1238 no gene da VCAM-1; 50 (40 por cento) foram heterozigotos e oito (2 por cento) homozigotos para o polimorfismo 469 no gene da ICAM-1; 30 (24 por cento) foram heterozigotos e dois (2 por cento) homozigotos para o polimorfismo -308 na região promotora do gene do TNF-alfa; 66(53 por cento) foram heterozigotos e 43 (34 por cento) homozigotos para o polimorfismo -251 na região promotora do gene da IL-8. Nossos resultados demonstraram que não houve associação estatística entre os polimorfismos -308 na região promotora do gene do TNF-alfa e -251 na região promotora do gene da IL-8 e os níveis séricos das citocinas...

Haemoglobin s Oman trait: a sickling variant

A nine-year old boy with Haemoglobin S Oman trait, a sickling variant, is presented. The laboratory haematological findings are elaborated, diagnostic markers high lighted, family studies documented and increased pathogenicity of this variant depending upon the percentage of Haemoglobin S Oman is stressed

Molecular studies on Yemeni sickle-cell-disease patients: Xmn I polymorphism

Our studies of the Saudi population have shown that in patients with mild presentation of sickle-cell disease [SCD] from Saudi Arabia's eastern region, the prevalence of polymorphic sites is high. However, the prevalence is very low in patients with severe SCD from the south-west of the country. We expanded these studies to a group of Yemeni patients with severe SCD, resident in Riyadh. We investigated a total of 60 chromosomes carrying the sickle-cell [Hb S] gene and 14 chromosomes carrying the Hb A gene. Amongst the Hb AA group, the prevalence was 42.9% and 57.1% for the presence [+] and absence [-] of Xmn I polymorphic sites. In the Hb SS individuals, the prevalence of Xmn I polymorphic sites was similar to the prevalence reported in the south-western region of Saudi Arabia

Trimodal distribution of HbS levels in sickle heterozygotes--an useful predictor of the alpha-genotype for population screening.

The trimodal distribution of HbS levels in sickle heterozygotes has been used as an indirect approach to determine the prevalence of alpha-thalassaemia in different population groups. We used this approach to predict the alpha-genotypes of 124 sickle cell heterozygotes where the HbS concentration varied from 20 to 46 per cent with antimodes at 28.0 and 33.0. The alpha-genotypes in these individuals were also determined by Southern blot hybridization. We predicted homozygous (-alpha/-alpha) or heterozygous (-alpha/alpha alpha) alpha-thalassaemia-2 in 78 subjects by the trimodal distribution of HbS. However, actual genotyping showed that 75 patients had alpha-thalassaemia. Forty six of the 47 subjects with a normal alpha-globin genotype (alpha alpha/alpha alpha) could be predicted indirectly. The overall sensitivity was 100 per cent and specificity was 94.2 per cent with a positive predictive value of 96.2 per cent and negative predictive value of 100 per cent. As alpha-genotyping is very expensive and not feasible in most laboratories in India, we conclude that the trimodal distribution of HbS levels is a suitable method for screening for alpha-thalassaemia in population studies.

Haplotipos de la hemoglobina S: importancia epidemiológica, antropológica y clínica / S hemoglobin haplotypes: their epidemiologic, anthropologic, and clinical significance

La relación entre la drepanocitosis y los diferentes haplotipos del gen que codifica la subunidad Bs. de la globina ha permitido llegar a entender mejor las manifestaciones clínicas de aquella enfermedad. El uso de mejores técnicas de laboratorio permite descartar la presencia de otros factores hereditarios capaces de ocultar el verdadero genotipo hemoglobínico. La heterogeneidad clínica de la drepanocitosis, afección caracterizada por la presencia de una hemoglobina anormal denominada HbS, depende de las concentraciones de hemoglobina fetal (HbF), la razón de cadenas Gy a cadenas Ay en la molécula de globina, las concentraciones de 2,3-difosfoglicerato, la presencia de mutaciones ligadas, los haplotipos del gen Bs., la presencia simultánea de a-talasemia, y factores ambientales. En particular, los polimorfismos Senegal y árabe-saudí o indio del conglomerado de genes que codifican la subunidad Bs. se asocian con una evolución clínica menos grave, mientras que los haplotipos de la República Centroafricana (CAR) o Bantú, Camerún y Benín se asocian con drepanocitosis grave. De todos, el haplotipo CAR es el de peor pronóstico (concentraciones de HbF de menos de 12 por cien y razón de Gy:Ay propia de la edad adulta). Estos polimorfismos del ácido desoxirribonucleico, una vez caracterizados, adquieren enorme importancia como marcadores antropológicos y genéticos. En las Américas, los haplotipos Bs. permiten entender mejor las raíces ancestrales africanas de las poblaciones de raza negra. Se ha comprobado la presencia de variedad genética no solo entre las diferentes poblaciones negras de las Américas, sino también dentro de un mismo país, como se observa en Costa Rica

The link between Bs-gene haplotypes and sickle cell anemia has permitted a better understanding of the biological manifestations of this disease. The use of better laboratory methods can help rule out other hereditary factors that can camouflage the real hemoglobin genotype. The clinical heterogeneity of sickle cell disease, which is characterized by the presence of S hemoglobin, can be explained in terms of fetal hemoglobin (HbF) levels, ratio of G chains to A chains, 2,3-diphosphoglycerate levels, linked mutations, Bs haplotypes, coexistence of CX-thalassemia, and environmental factors. The inheritance of Sen and Arab/Indian B-gene cluster polymorphisms is associated with a milder clinical course, whereas the Central African Republic (CAR) or Bantu, Cameroon, and Benin haplotypes are linked with severe sickle cell disease. The CAR haplotype carries the worst prognosis of all (less than 12% HbF levels and adulttype Gy:Ay ratio). Once characterized, these DNA polymorphisms also assume great importance as anthropologic and genetic markers. In America, B haplotypes are contributing to a better understanding of Black American roots and their African ancestry. There is ample evidence of genetic variability not only between different Black populations in America, but also within the same country, as is the case in Costa Rica.

Genetic epidemiology of the three predominant abnormal hemoglobins in India.

Hemoglobinopathies in India are Important public health problems. Of the several abnormal of hemoglobin molecules, there are three variants, viz. Sickle cell, hemoglobin E and hemoglobin D which are predominantly prevalent in India. The cumulative gene frequencies of these hemoglobins have been found to be 5.35% in India. The average gene frequency of sickle cell and hemoglobin D in India has been observed to be 4.3% and 0.86%, respectively. In the North Eastern region of India, the gene frequency of hemoglobin E is 10.9%. Gene frequencies and spatial distribution of the predominant abnormal hemoglobins in India have been discussed in variance with the previous generalisations.

Analysis of sickle cell gene using polymerase chain reaction & restriction enzyme Bsu 361.

A 772bp DNA fragment from human beta-globin gene has been amplified by polymerase chain reaction (PCR) and subjected to restriction enzyme analysis using Bsu 361, an isoschizomer of restriction enzyme Mst II. This protocol has been designed basically to enhance the analytical facility for the detection of sickle cell mutation. A 430bp DNA fragment was found to be associated with the mutant locus, whereas 228bp and 202bp DNA fragments were generated from the normal locus. This difference of about 202bp in the resulting fragments from the mutant and normal loci has improved discriminatory power in the genotype analysis of the sickle cell mutation.

frequency of glucose-6-phosphate dehydrogenase phenotypes and sickle cell gene in Al-Qassim

This study was conducted in the Al-Qassim area located in the central province of Saudi Arabia in order to estimate the frequency of glucose-6-phosphate dehydrogenase [G-6-PD] deficiency and sickle cell genes [Hb S]. Blood samples from 1,015 Saudi males and females were analyzed for hemoglobin types, G-6-PD phenotypes and G-6-PD levels. Only two cases heterozygous to Hb S [ie Hb AS] were identified and the frequency of Hb S gene was 0.000985. The normal G-6-PD was G-6-PD-B+ occurring at a frequency of 0.944 and 0.966 in the male and female population, respectively. Variants identified included G-6-PD-A+, G-6-PD-Mediterranean, G-6-PD- A-, and G-6-PD-Mediterranean-like at frequencies of 0.0164, 0.0282, 0.0023, 0.0094 in the males and 0.0068, 0.0085, 0, 0.0102 in the female population, respectively. The severe G-6-PD deficiency was due mainly to G-6-PD Mediterranean and only one male with G-6-PD-A- [0.0023] was identified. These results showed that Al-Qassim had the lowest frequency of Hb S and G-6-PD deficiency genes compared to all other regions of Saudi Arabia that have been screened thus far

A case of homozygous sickle cell disease in Sri Lanka.

An 11 year old Muslim boy with a 2 month history of fever, loss of appetite, pallor and abdominal distension, had hepato-splenomegaly. Haemoglobin electrophoresis showed the presence of haemoglobins S and F, with complete absence of haemoglobin A. The sickling test was positive. Marital consanguinity was present. In both parents, the sickling test was positive and haemoglobin electrophoresis showed the presence of haemoglobins A and S. This is the first report of homozygous sickle cell disease in Sri Lanka.

Variaciones fenotípicas de las heterocigotos para las hemoglobinas S y C / Phenotypic variations of heterozygotes for hemoglobins S an C

Se estudiaron algunas características cuantitativas sanguíneas en un grupo de heterocigotos AS y AC. Se encontró que cuando la concentración de HbS es menor que el 30%hay cambios cuantitativos en las constantes corpusculares, hemoglobina A2 y hemoglobina fetal con relación al grupo control, lo cual puede estar asociado al número de genes alfa ausentes en el individuo