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1.
J Clin Pathol ; 62(1): 31-3, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19103855

RESUMEN

BACKGROUND: As a result of population growth in African-Caribbean regions of overseas France, and now immigration essentially from North and sub-Saharan Africa to mainland France, neonatal screening for sickle cell disease (SCD) has been performed in France since 1985 in Guadalupe and dependencies, as a universal test. After several pilot studies, screening was gradually extended to mainland France in 1996. Since 2000, the test has been performed at national level for all newborns defined as being "at risk" for SCD based on ethnic origin. METHODS: A dry blood sample is obtained by heel stick and analysed by isoelectric focusing as a first-line method, followed by either high-performance liquid chromatography or acid agar electrophoresis for confirmation, whenever a variant haemoglobin is observed on isoelectric focusing. RESULTS: In 2007, 28.45% of all newborns in mainland France were screened for SCD. Since 1996, a total of 3,890 newborns have been found to have SCD, and they have been followed up by reference paediatricians. CONCLUSION: Although screening for SCD at birth in France is not universal, it appears that missed babies are relatively infrequent. Despite obvious sociological problems inherent to the at-risk population, the follow-up of SCD babies is rather successful. Due to the birth prevalence of SCD in France, especially in comparison with other common genetic diseases, screening all newborns regardless of ethnic origin is an issue that is being addressed.


Asunto(s)
Anemia de Células Falciformes/diagnóstico , Tamizaje Neonatal/métodos , Anemia de Células Falciformes/epidemiología , Recolección de Muestras de Sangre/métodos , Cromatografía Líquida de Alta Presión , Electroforesis en Gel de Agar , Francia/epidemiología , Hemoglobinopatías/diagnóstico , Hemoglobinopatías/epidemiología , Humanos , Recién Nacido , Focalización Isoeléctrica
3.
Ann Biol Clin (Paris) ; 61(4): 401-9, 2003.
Artículo en Francés | MEDLINE | ID: mdl-12915349

RESUMEN

Hemoglobinopathies have become a significant national health problem in France. The biologists have a pivotal role in the genetic diagnoses. Although sickle cell disease (SCD) is the most frequent abnormality found: not less than 200 new cases are observed each year at birth, many other globin gene variations are found in the various ethnic groups. Since 1995 a neonatal sickle cell screening program has been established for at risk newborns. This programme is supported by the "Association française de dépistage et prévention des handicaps de l'enfant" (AFDPHE). The characterization of hemoglobin genetic variations requires a comprehensive set of laboratory techniques for which we specify here main clinical and technical recommendations.


Asunto(s)
Hemoglobinas/análisis , Análisis Químico de la Sangre/métodos , Análisis Químico de la Sangre/normas , Recolección de Muestras de Sangre , Hemoglobinopatías/sangre , Humanos
4.
J Gynecol Obstet Biol Reprod (Paris) ; 32(1 Suppl): 1S61-4, 2003 Feb.
Artículo en Francés | MEDLINE | ID: mdl-12592166

RESUMEN

An experimental program for neonatal detection of sickle cell disease (SCD) was performed in France in 1990. Our data indicated a high prevalence of SCD, one patient in 1,250 newborns tested. The French national program for neonatal screening for SCD was set up in 1995 by the Association Française pour le Dépistage et la Prévention des Handicaps de l'Enfant (AFDPHE). This is not a systematic program, but only targeted at newborns at risk for SCD.


Asunto(s)
Anemia de Células Falciformes/diagnóstico , Tamizaje Neonatal , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/genética , Francia , Programas de Gobierno , Humanos , Recién Nacido
5.
Hemoglobin ; 25(2): 169-81, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11480779

RESUMEN

Laboratory methods allowing the detection and characterization of hemoglobin variants are reviewed. Protein chemistry techniques such as isoelectrofocusing, electrophoreses under various experimental conditions, cation exchange and reversed phase high performance liquid chromatography, are the most frequently used for the detection of variants. When associated with a few additional data they may lead to a presumptive diagnosis. DNA studies are also developed in many laboratories. Final identification of a variant may be achieved either by molecular biology techniques or by protein sequence analysis in which mass spectrometry now occupies a key position.


Asunto(s)
Técnicas de Laboratorio Clínico , Hemoglobinas Anormales/análisis , Técnicas de Química Analítica/métodos , Técnicas de Laboratorio Clínico/instrumentación , Variación Genética , Hemoglobinas Anormales/genética , Humanos , Análisis de Secuencia de ADN , Análisis de Secuencia de Proteína/métodos
8.
Hemoglobin ; 22(5-6): 469-81, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9859930

RESUMEN

The Ggamma:Agamma ratio is around 70:30 at the time of birth and usually 40:60 in the trace amounts of Hb F found in the adult. Changes in this ratio are observed in several hemoglobin disorders providing insights on the genetics and molecular pathophysiology of these diseases. Several techniques have been proposed to measure the Ggamma:Agamma ratio. We here describe perfusion chromatography which is now in routine use in one of our laboratories. The method involves a high velocity flow of the mobile phase through a porous reversed phase chromatographic stationary bed and allows us to determine this parameter one order of magnitude faster than with conventional high performance liquid chromatography.


Asunto(s)
Cromatografía/métodos , Hemoglobina Fetal/química , Cromatografía Líquida de Alta Presión , Hemoglobina Fetal/análisis , Hemoglobina Fetal/inmunología , Globinas/análisis , Humanos , Recién Nacido , Perfusión
9.
Am J Hematol ; 59(3): 208-13, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9798658

RESUMEN

The gene frequency of the most important hemoglobin (Hb) abnormalities is reported in a population of 171 Togolese newborns. Hb phenotypes, hematological parameters, and the more frequently described alpha-gene deletions were analyzed. Structural abnormalities of beta-globin were observed in 35.7% of the children with a gene frequency of 0.105 for beta(S) and 0.091 for beta(C). The frequency of the different alpha-globin genotypes was alpha alpha/ = 0.71, -alpha/ = 0.28, and alpha alpha alpha/ = 0.01. All of the individuals homozygous for the -alpha genotypes, and most of the heterozygous individuals, carried Hb Bart's. Within the alpha alpha/alpha alpha and the -alpha/alpha alpha groups, several individuals with or without Hb Bart's were found; they did not differ from the others by their red blood cell (RBC) parameters but by their levels of fetal hemoglobin (Hb F). The African alpha2 polymorphism marker, characterized by the replacement of G by TCGGCCC at position 7238 (EMBL HSHBA4, 1993) and of T 7174 by G, was found in 21 newborns. The mean value of Hb F was calculated for each genotype, the mean (G)gamma percentage was 69.4 +/- 4.0%, and the gene frequency of the AgammaT marker was 0.10; this marker was linked to the normal beta-globin cluster.


Asunto(s)
Globinas/genética , Hemoglobina C/genética , Hemoglobina Falciforme/genética , Hemoglobinas Anormales/genética , Recuento de Células Sanguíneas , Femenino , Sangre Fetal/química , Hemoglobina Fetal/análisis , Hemoglobina Fetal/genética , Eliminación de Gen , Dosificación de Gen , Frecuencia de los Genes , Marcadores Genéticos/genética , Hemoglobina C/análisis , Hemoglobina Falciforme/análisis , Hemoglobinas Anormales/análisis , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Masculino , Fenotipo , Polimorfismo Genético , Togo
10.
J Med Screen ; 5(1): 27-30, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9575456

RESUMEN

The presence of Hb Hope associated with Hb S may represent a pitfall (false positive) in the neonatal detection of sickle cell disease by two of the most widely used analytical methods in screening programmes-isoelectric focusing (IEF) and high performance liquid chromatography (HPLC). This example illustrates the need to improve analytical strategies to avoid unnecessary anxiety and summoning of families often from a cultural background in which testing of the father is difficult to obtain. It is suggested that using two independent HPLC procedures might improve the specificity of the screening strategies. Additionally, simple procedures for detection of the most common mutations of the beta globin gene of DNA extracted from dried blood specimens could be easily developed for the control of abnormal samples. These procedures could be introduced into the analytical strategy.


Asunto(s)
Anemia de Células Falciformes/diagnóstico , Tamización de Portadores Genéticos , Hemoglobina Falciforme/genética , Hemoglobinas Anormales/genética , Tamizaje Neonatal , Anemia de Células Falciformes/genética , Ácido Aspártico/genética , Cromatografía Líquida de Alta Presión , Glicina/genética , Humanos , Recién Nacido , Focalización Isoeléctrica , Mutación Puntual
11.
Br J Haematol ; 100(2): 401-6, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9488635

RESUMEN

Single point mutation, which accounts for 92% of the 700 known variants, is the most frequent genetic defect responsible for abnormal haemoglobins. Small deletions (or insertions) involving from one to five residues are also observed, but in only approximately 5% of cases. The remaining variants produce fusion or extended haemoglobins. A deletion of eight residues, which included the distal histidine and its neighbours (alpha50-57, alpha51-58 or alpha52-59), was found in Hb J-Biskra. This new alpha-chain variant was mildly unstable in vitro only and there was no haematological or biochemical evidence of haemolysis in the affected family members. 24 nucleotides were missing in a region of the alpha1 gene showing an identical sequence of eight nucleotides at both ends. Several starting points could therefore lead to the same nucleotide and aminoacid remaining sequence. This deletion is the largest up to now reported in a haemoglobin molecule which is expressed at an almost normal level in the red blood cell. Comparison of the DNA sequences near to the deleted (or inserted) regions in the various haemoglobins carrying this type of abnormality almost always revealed the presence of a sequence that was hypothesized to slow down progression of the replication fork, and of repeats that may lead to possible secondary structures favouring slipped mispairing.


Asunto(s)
Hemoglobinas Anormales/genética , Eliminación de Secuencia , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , ADN/análisis , Electroforesis en Gel de Poliacrilamida , Hemoglobinas Anormales/química , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa
12.
Br J Haematol ; 103(4): 950-6, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9886305

RESUMEN

A Guinean woman, heterozygous for haemoglobin (Hb) S, was studied because of episodes of marked anaemia, repeated typical metaphyseal painful crises and haemosiderosis. Her sickling syndrome resulted from the association of Hb S trait with a severe pyruvate kinase deficiency leading to a 2,3-DPG concentration of twice normal levels. Sequence of the PK-R gene revealed an undescribed mutation in the homozygous or hemizygous state within exon 5 (nucleotide 2670 C-->A), leading to the interchange of Ser 130 into Tyr (PK Conakry). In addition, the patient carried a new haemoglobin variant, Hb Conakry [alpha80(F1) Leu-->Val], which seemed to have a mild effect. The high intraerythrocytic 2,3-DPG concentration induced by the PK deficiency resulted in a decreased oxygen affinity which favoured sickling to a level almost similar to that of Hb S/C compound heterozygous patients. This was confirmed by oxygen binding measurements of Hb A/Hb S erythrocytes in which 2,3-DPG content was modified in vitro. Hysteresis between deoxy- and reoxygenation curves, as well as increase in the n(max) value, demonstrated that the extent of HbS polymerization in the propositus was almost the same as that of RBCs from a homozygous sickle cell patient or those of an A/S heterozygous patient with an artificial in vitro increase of 2,3-DPG concentration.


Asunto(s)
Anemia de Células Falciformes/genética , Globinas/genética , Piruvato Quinasa/deficiencia , Adulto , Anemia de Células Falciformes/enzimología , Femenino , Hemoglobina Falciforme/genética , Heterocigoto , Humanos , Oxígeno/metabolismo , Fenotipo , Piruvato Quinasa/genética
13.
Clin Chem ; 43(1): 34-9, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8990219

RESUMEN

A battery of relatively simple tests allows the presumptive identification of hemoglobin (Hb) variants, making unnecessary structural analysis by protein chemistry methods or DNA sequencing. The primary step in this strategy involves the use of a matrix of electrophoretic mobilities obtained under various experimental conditions. This leads to an unambiguous result in approximately 90% of the cases. Additional tests are required to characterize with more confidence the remaining 10%. We describe here the use of cation-exchange HPLC on the Bio-Rad Variant automated analyzer with the "beta Thalassemia Short" program. By comparing the elution time of 125 human Hb mutants, we found that some variants with almost identical pI values or produced by the same type of amino acid substitution displayed different elution times. We present several examples in which use of the HPLC profile helped establish the diagnosis.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cromatografía por Intercambio Iónico , Hemoglobinas Anormales/análisis , Cationes , Hemoglobina Fetal/análisis , Globinas/química , Globinas/genética , Hemoglobina A2/análisis , Hemoglobina C/análisis , Hemoglobina E/análisis , Hemoglobina Falciforme/análisis , Hemoglobinas Anormales/química , Hemoglobinas Anormales/genética , Humanos , Focalización Isoeléctrica , Mutación , Talasemia beta/sangre
14.
Ann Genet ; 38(4): 206-16, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-8629808

RESUMEN

The French population is the result of mixing of different peoples including the Celts, Saxons, Germans, Italians and Hispanics. Between 1981 and 1993 patients were selected during investigations in France for haematological disorders associated or otherwise with the presence of a haemoglobin (Hb) variant. Further carriers of abnormal Hb were identified by HPLC measurement of glycated Hb in diabetics and by neonatal screening. Four-hundred and thirty-two subjects were found to be heterozygous for one of the 119 different alpha and the beta gene alleles encountered. These variants were characterised by a combination of 6 electrophoretic methods and in some cases by protein structure determinations. Some mutants reflected the population movements in and into France. A few mutants are frequently described in the French Caucasian population: Hb Lepore Boston, Hb D Punjab, whereas others appear to be anthropological markers. Hb Winnipeg has only been found in the West of France (Normandy); Hb J Baltimore is mainly found in French subjects of Spanish origin. Several cases of sporadic and previously undescribed mutations of Hb were identified. The last immigration waves from Africa and Asia appear to have contributed to the evolution of the pattern of haemoglobinopathies in the French population (Hb S, Hb O Arab or Hb C).


Asunto(s)
Globinas/genética , Hemoglobinas Anormales/genética , Alelos , Francia , Frecuencia de los Genes , Humanos , Mutación Puntual , Población Blanca
15.
Hemoglobin ; 18(1): 39-51, 1994 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8195007

RESUMEN

The populations of Morocco, Algeria, and Tunisia are composed of different ethnic groups including Arabs, Berbers, Sub-Saharan Africans, Europeans, and Turks. Between 1981 and 1991, we studied more than 3,000 individuals from these North African countries. One-hundred and eighty-one carried one (or more) unusual hemoglobin variant(s) other than Hb S and Hb C which are the most frequent variants in these countries. Each of these 181 individuals was heterozygous for at least one of the 49 abnormal alpha or beta alleles identified by electrophoretic and/or structural studies, and some homozygotes were detected. A few mutants are common in North Africa: Hb O-Arab, Hb D-Punjab and Hb G-Philadelphia. Other mutants encountered in European or African populations are found in relatively few North African families. The observed polymorphisms in the populations of North Africa probably result largely from their complex ethnic origins.


Asunto(s)
Etnicidad/genética , Frecuencia de los Genes , Globinas/genética , Hemoglobinas Anormales/genética , Argelia/epidemiología , Argelia/etnología , Electroforesis de las Proteínas Sanguíneas , Etnicidad/historia , Europa (Continente)/etnología , Francia/epidemiología , Hemoglobinopatías/epidemiología , Hemoglobinopatías/etnología , Hemoglobinopatías/genética , Hemoglobinas Anormales/clasificación , Historia del Siglo XIX , Historia Antigua , Historia Medieval , Humanos , Tamizaje Masivo , Marruecos/epidemiología , Marruecos/etnología , Mutación , Polimorfismo Genético , Túnez/epidemiología , Túnez/etnología
16.
EMBO J ; 10(11): 3157-65, 1991 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1915288

RESUMEN

In order to obtain a transgenic mouse model of sickle cell disease, we have synthesized a novel human beta-globin gene, beta SAD, designed to increase the polymerization of the transgenic human hemoglobin S (Hb S) in vivo. beta SAD (beta S-Antilles-D Punjab) includes the beta 6Val substitution of the beta S chain, as well as two other mutations, Antilles (beta 23Ile) and D Punjab (beta 121Gln) each of which promotes the polymerization of Hb S in human. The beta SAD gene and the human alpha 2-globin gene, each linked to the beta-globin locus control region (LCR) were co-introduced into the mouse germ line. In one of the five transgenic lines obtained, SAD-1, red blood cells contained 19% human Hb SAD (alpha 2 human 1 beta 2SAD) and mouse-human hybrids in addition to mouse hemoglobin. Adult SAD-1 transgenic mice were not anemic but had some abnormal features of erythrocytes and slightly enlarged spleens. Their erythrocytes displayed sickling upon deoxygenation in vitro. SAD-1 neonates were anemic and many did not survive. In order to generate adult mice with a more severe sickle cell syndrome, crosses between the SAD progeny and homozygous for beta-thalassemic mice were performed. Hemoglobin SAD was increased to 26% in beta-thal/SAD-1 mice which exhibited: (i) abnormal erythrocytes with regard to shape and density; (ii) an enlarged spleen and a high reticulocyte count indicating an increased erythropoiesis; (iii) mortality upon hypoxia; (iv) polymerization of hemolysate similar to that obtained in human homozygous sickle cell disease; and (v) anemia and mortality during development.


Asunto(s)
Anemia de Células Falciformes/fisiopatología , Modelos Animales de Enfermedad , Hemoglobina Falciforme/metabolismo , Anemia de Células Falciformes/mortalidad , Animales , Cromatografía Líquida de Alta Presión , ADN/genética , Electroforesis en Gel de Poliacrilamida , Índices de Eritrocitos , Globinas/genética , Hemoglobina Falciforme/genética , Focalización Isoeléctrica , Ratones , Ratones Transgénicos , Oxígeno/metabolismo , Mapeo Peptídico , Fenotipo , Reacción en Cadena de la Polimerasa , Tripsina
18.
Biochim Biophys Acta ; 1041(3): 250-3, 1990 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-2268670

RESUMEN

The oxygen affinity of hemoglobin Sassari (Asp-126 alpha----His), a variant substituted in the alpha 1 beta 1 interface, was found to be 8-times greater relative to normal adult human hemoglobin. Study of the exchangeable hydrogen-bonded protons by NMR spectroscopy shows only minor changes at the alpha 1 beta 1 interface. In particular, the resonance previously assigned to the proton of the hydrogen bond Asp-126 alpha 1. . . Tyr-35 beta 1 in normal hemoglobin is still present in the variant spectrum, suggesting that His-126 alpha can also form a hydrogen bond with the Tyr-35 beta. The possible explanation of the increased affinity of hemoglobin Sassari and other variants substituted in the same structural region is discussed in terms of perturbations of the equilibrium between the two quaternary states.


Asunto(s)
Hemoglobinas Anormales/química , Carboxihemoglobina/química , Hemoglobina A/química , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Humanos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Sustancias Macromoleculares , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Mutación , Oxígeno/metabolismo , Oxihemoglobinas/química
19.
Am J Hematol ; 35(2): 96-9, 1990 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-2399911

RESUMEN

While investigating the mechanism of a beta-thalassemia intermedia phenotype in a 34 year old Thai male, a new Hb variant beta 126 Val----Gly named Hb Dhonburi was discovered. Genetic and structural studies revealed the existence of a beta zero-thalassemia genotype in association with the beta variant. The new variant is unstable but exhibits normal oxygen binding properties. Hb Dhonburi was also discovered in the mother of the propositus in association with Hb E.


Asunto(s)
Hemoglobinas Anormales/genética , Talasemia/sangre , 1-Propanol , Preescolar , Cromatografía Líquida de Alta Presión , Hemoglobinas Anormales/análisis , Humanos , Masculino , Linaje , Fenotipo , Talasemia/genética
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