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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Compound heterozygosity Hb S/Hb Hope (beta 136 Gly-->Asp): a pitfall in the newborn screening for sickle cell disease. 957 56

Sickle cell anemia is a monogenic hereditary disease characterized by a mutation in the beta globin gene. Five major haplotypes associated with the beta S mutation have been defined: Benin, Bantu, Senegalian, Camerounian, and Arabo-Indian. Previous studies in northern Tunisia showed that sickle cell anemia was of Benin origin in this region. Patients from the south of Tunisia, mainly from the Kebili region, were not previously concerned. In this study, we have determined the beta S haplotype and evaluated phenotypical expression of the disease in 14 patients from this latter region. The use of four restriction endonucleases having polymorphic sites in the beta globin gene showed that all patients had the Benin haplotype, confirming the Benin origin of sickle cell anemia in Tunisia. This haplotype is associated with an heterogeneous expression of fetal hemoglobin (HbF) with extremes varying from 2.4 to 16.3% and a mean expression rate of 8.16%, which is in accordance with literature data. In spite of the haplotype homogeneity in our patients, clinical heterogeneity was noted. A unique case of alpha-thalassemia could not explain this heterogeneity. In contrast, we found a certain correlation between fetal hemoglobin expression and clinical severity.
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PMID:[Hemoglobin beta S haplotype in the Kebili region (southern Tunisia)]. 961 41

Molecular analysis of human alpha and beta globin genes reveals extensive polymorphism at these loci. Worldwide distribution of the sickle cell trait has been well known for some time. However, the molecular basis and distribution of thalassemia have been more recently studied. These are the commonest monogenic disorders. For most of them, beta-thalassemia is due to single nucleotide substitutions, small deletions or insertions. They are very heterogeneous and widely dispersed in the Old World. alpha-thalassemia is mainly due to the deletion of one to four alpha genes. On the whole, their distribution is quite similar to beta-thalassemia. With some exceptions, both distributions coincide with present and past regions of malarious endemicity. On the other hand, when looking at individual mutations, no two regions are identical. The question of whether selection by malaria plays a role on observed allele frequencies is still a challenge. The only well clear instance is the beta S mutations, which causes sickle cell anaemia. The role of malaria is but one among other hypothesis for explaining thalassemia distribution and frequencies. A possible scenario could be the following: one (or a few) mutation happened in a population and spread because of its selective advantage, along with the founder effect and/or genetic drift. Migration, founder effect and genetic drift must be invoked to account for some observations. It is still difficult to say why a mutation is highly frequent in one population and not in another., even at equivalent malarial endemicity. On the other hand, many genes should contribute simultaneously, or in synergy, in the process of fighting against malaria. Fitness of each mutation could depend on its genetic background when the mutation arose. Selection must work on a set of genes. Populations who are living now, and genetically very different, could very well be the result of selection on many genes by many infectious agents.
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PMID:[Human globin genes: what can we learn from their polymorphism?]. 1057 59

Sickle cell disease is caused by a mutation in the beta globin gene leading to hemoglobin S (Hb S) production. Several approaches have been explored to prevent Hb S polymerization in red blood cells and the symptoms associated with this disorder. To this end we tested a mammalian expression vector carrying a human beta globin antisense cDNA (pZeobetaAS) fragment in a mouse erythroleukemia cell line expressing the human gamma and beta globin genes. We observed a relative reduction in beta globin mRNA levels compared with gamma mRNA levels in the presence of pZeobetaAS. Moreover, analysis at the protein level showed an average 76% decrease in beta chains and a 517% increase in gamma chain biosynthesis. The inhibitory effect of the antisense vector on globin expression was maintained long term in culture. The expression vector pZeobetaAS was also transfected into primary erythroid progenitors to test its effects on globin genes undergoing normal developmental switching during differentiation. We observed a relative reduction of beta globin mRNA levels compared with gamma mRNA levels. These results support a novel role for antisense cDNA expression vectors as an alternative gene therapy strategy to inhibit betas gene expression in sickle cell disease. Gene Therapy (2000) 7, 438-444.
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PMID:Beta globin gene inhibition by antisense RNA transcripts. 1069 26

A baby girl presented with symptomatic sickle cell disease exacerbated by mild hypoxemia, despite a newborn-screening diagnosis of sickle cell trait. DNA sequencing of the beta globin gene revealed that her maternal beta globin allele was normal. Her paternal allele had not only the expected sickle-trait mutation, betaGlu6Val, but also a second, charge-neutral mutation, betaLeu68Phe. Analysis of the patient's hemoglobin revealed that the double-mutant protein, which we called "hemoglobin Jamaica Plain," had severely reduced oxygen affinity. Structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at an ambient partial pressure of oxygen.
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PMID:Hemoglobin Jamaica plain--a sickling hemoglobin with reduced oxygen affinity. 1547 Feb 11

This report describes a case in which the diagnosis of sickle cell disease (SCD) was established after death. The diagnosis of sickle cell syndrome was made in a 68 year old black patient who was found to have sickled red blood cells in many organs at necropsy although the disease had not been diagnosed during her lifetime. DNA was isolated from a peripheral blood smear obtained on the day of the patient's death. The beta globin gene was polymerase chain reaction amplified and sequenced, revealing that the patient had S-beta(+) thalassaemia. This study shows that blood smears are a suitable source for retrospective DNA analysis studies. This case illustrates that relatively "mild" forms of SCD can be overlooked, despite symptomatology suggestive of a sickle syndrome, and demonstrates the feasibility of the postmortem molecular diagnosis of haemoglobinopathies in such cases.
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PMID:Postmortem molecular diagnosis of sickle beta thalassaemia. 1585 31

Sickle cell disease is a systemic disorder that is caused by a mutation (Glu6Val) in the gene that encodes beta globin. The sickle hemoglobin molecule (HbS) is a tetramer of two alpha-globin chains and two sickle beta-globin chains, and has the tendency to polymerize when deoxygenated. HbS facilitates abnormal interactions between the sickle erythrocyte and leukocytes and endothelial cells, which trigger a complex pathobiology. This multifaceted pathophysiology provides the opportunity to interrupt the disease at multiple sites, including polymerization of HbS, erythrocyte density and cell-cell interactions. For example, it is possible to induce higher concentrations of fetal hemoglobin, which disrupts the pathology-initiating step of HbS polymerization. Furthermore, it is possible to improve the hydration of sickle erythrocytes and it might be feasible to counteract the endothelial, inflammatory and oxidative abnormalities of sickle cell disease. A therapeutic approach that targets several sites of pathobiology might be most promising.
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PMID:Pathophysiologically based drug treatment of sickle cell disease. 1653 Aug 54

Sickle cell disease results from the presence of abnormal beta globin chains within hemoglobin and may be manifested in anemia, vaso-occlusion, and superimposed infection. The gene that causes sickle cell disease is particularly prevalent in populations of African origin; approximately 8% of African Americans and 40% of the members of some African tribes carry the gene for hemoglobin S. Over time, the disease produces various musculoskeletal abnormalities as a result of chronic anemia; these include marrow hyperplasia, reversion of yellow marrow to red marrow, and, occasionally, extramedullary hematopoiesis. Familiarity with the imaging features of sickle cell disease is important for the diagnosis and management of complications. Ischemia and infarction are common complications that may have long-term effects on the growth of bone; these conditions have characteristic radiographic appearances. Infection may be more difficult to identify. Both infection and infarction may occur in muscle and soft tissue alone, without involving bone. However, osteomyelitis must be diagnosed early and treated immediately to prevent bone destruction and deformity; therefore, care must be taken to achieve an accurate diagnosis by identifying or excluding bone involvement. The clinical and radiographic features of acute osteomyelitis may be particularly difficult to distinguish from those of bone infarction. In that context, magnetic resonance (MR) imaging may be useful. At MR imaging, findings of cortical defects, adjacent fluid collections in soft tissue, and bone marrow enhancement are suggestive of infection.
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PMID:Musculoskeletal manifestations of sickle cell disease. 1762 Apr 64

An accurate diagnosis of beta -thalassemia carriers, homozygous patients and identification of different structural hemoglobin variants is important for epidemiological studies as well as for management and prevention of the major hemoglobin disorders. There are many electrophoretic and chromatographic approaches for estimation of HbA2 and Hb F but cation exchange HPLC (CE-HPLC)using automated dedicated machines like the Variant Hb testing system have become the method of choice for these investigations. CE-HPLC also helps in the presumptive identification of many abnormal hemoglobin variants and has been useful for both neonatal screening of sickle cell disease as well as second trimester prenatal diagnosis of thalassemia by fetal blood analysis. Other applications of HPLC in hemoglobinopathies include separation of globin chains, measuring the ratio of gamma globin chains (Ggamma/Agamma) and the recently described denaturing HPLC for detecting mutations in both alpha and beta globin genes.
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PMID:HPLC studies in hemoglobinopathies. 1769 75

Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.
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PMID:Genetic modifiers in hemoglobinopathies. 1899 46


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