Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019045 (hemoglobinopathies)
2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari, from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis, thalassemia-like bone changes, iron overload, high proportion of Hb F in the peripheral blood, reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes, and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents, even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation, thus making the proper diagnosis.
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PMID:Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy. 198 2

The authors report 4 cases of Yersinia enterocolitica (Ye) infection in patients with hemoglobin disorders (3 beta thalassemia major, 1 sickle cell anemia). Patients with hemoglobin disorders are particularly vulnerable to Ye infection. Predisposing factors consist mainly of iron overload and deferoxamine therapy; superinfection with HIV may be an additional factor. The diagnosis is performed by identifying patients at risk and by bacteriologic tests (blood and stool cultures, antibody titers). Therapy includes discontinuation of deferoxamine and initiation of an adequate antibiotic therapy.
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PMID:[Yersinia infection and hemoglobin disorder. Apropos of 4 cases]. 217 Sep 7

The characteristic spectrum of infections in patients with aplastic anemia, chronic neutropenic diseases, sickle cell disease, thalassemia, and other hemoglobinopathies are described. The major risk factor for infection in patients with bone marrow failure is the degree of neutropenia and monocytopenia. In patients with aplastic anemia, invasive fungal infections emerge as the major causes of mortality. Life-threatening infections are rare in patients with chronic neutropenic diseases; however, necrotizing enterocolitis due to Clostridium species may be an exception. Bacterial infections, predominantly with encapsulated bacteria, are the most common cause of death in patients with sickle cell disease, especially those who are younger than 5 years of age. Patients with thalassemia and other hemoglobinopathies are particularly susceptible to life-threatening infections with Yersinia enterocolitica as a result of iron overload or of the chelating therapy with desferrioxamine.
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PMID:Approach to management of fever and infection in patients with primary bone marrow failure and hemoglobinopathies. 835 59

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8+/-2.5% vs. 44.8+/-9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130+/-32 vs. 72+/-19 micromol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2+/-4.5 vs. 16.8+/-3.4 x 10(3) units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in erythroid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.
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PMID:Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. 1008 94

Little is known about treatment of hepatitis C virus (HCV) infection in "other groups" than the general population, namely patients with hematologic or renal disorders and patients with human immune deficiency (HIV) co-infection. The aim was to better define HCV therapies in these groups. We analyzed the medical literature focusing on treatment of HCV infection in other populations to suggest conclusions about indications based on tolerance and efficacy. As in the general population, the decision to treat should be based mainly on liver pathology, and to a lesser extent on virologic profiles (genotype, quantitative viremia). Hemophilia does not modify therapeutic strategies which combine interferon-alpha and ribavirin. Similar combinations should be discussed in patients with inherited hemoglobin disorders but iron overload (secondary hemochromatosis) associated with multiple transfusions may decrease the potential efficacy of interferon-alpha and chronic anemia may limit the use of ribavirin. In hemodialyzed patients, therapy by interferon-alpha is feasible with 3 MU subcutaneously after each hemodialysis three times weekly for 6-12 months. Virologic results are at least similar to those obtained in the general population with frequent pathological improvement. Combinations are not possible because ribavirin is contraindicated for pharmacokinetic reasons. In kidney recipients, interferon-alpha is deleterious and inefficient; ribavirin monotherapy has a potential interest which remains to be evaluated. In HIV co-infected patients, treatment is mandatory given the high rate of cirrhosis and the improved survival related to multiple anti-HIV therapies (which have no clear efficacy for quantitative HCV viremia). Due to the limited efficacy of interferon-alpha monotherapy, the combination of interferon-alpha and ribavirin appears to be the logical treatment. An important point is the in vitro inhibition of phosphorylation by ribavirin of HIV reverse transcriptase inhibitors which has to be analyzed in vivo before the combination can be recommended. On the basis of the results of liver biopsy, antiviral treatments may be proposed for HCV-infected patients with hematologic or renal disorders as well as for HIV co-infected patients. The choice of therapy (monotherapy or combined therapies) should be based on the clinical situation (contraindicated with chronic anemia or renal failure, for example) and its duration on the virologic factors of response as in the general population.
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PMID:Treatment of chronic hepatitis C in special groups. 1062 89

Therapeutic erythrocytapheresis (TEA) has been used in different diseases such as polycythemia vera (PV), secondary erythrocytosis or hemochromatosis as a process of the less cumbersome but more expensive phlebotomy. TEA is preferred in emergency conditions such as thrombocytosis or in conditions such as porphyria cutanea tarda (PCT) or erythropoietic porphyria when plasma exchange (PEX) is often combined with TEA to reduce extracellular levels of uroporphyrin which contribute to plasma hyperviscosity. TEA is often combined with drug therapy that varies from etoposide in PV to EPO and desferoxamine which are used to mobilize and reduce iron stores in hemochromatosis. Benefits from this combination may be more long lasting than expected. Nonetheless for TEA, there is no standard protocol and, clinical experience with this therapy remains highly anecdotal. Therapeutic red cell-exchange (TREX) has been used with much interest over the years, starting with the management of hemolytic disease of the newborn and later used to correct severe anemia in thalassemia patients thereby preventing iron overload. It has also been used for the management of complications of sickle cell disease such as priapism, chest syndrome, stroke, retinal, bone, splenic and hepatic infarction or in preparation for surgery by reducing HbS to less than 30%. Automated apheresis has also favored the use of TREX in conditions such as paroxysmal nocturnal hemoglobinuria and aniline poisoning, arsenic poisoning, Na chlorate intoxications and CO intoxications, hemoglobinopathies, autoimmune hemolytic anemia, reactions due to ABO incompatibility, in preparation for ABO incompatible bone marrow transplantation or for preventing anti-D immunization after the transfusion of D(+) cells to D(-) recipients. Another field of application has been in the emergency management of intraerythrocytic parasite infections such as malaria and babesiosis. Application of TREX may be wide but its real use remains limited. In our personal experience, in 16 years, only 167 TREX procedures have been carried out in a total of 13,747 therapeutic procedures. This represents only 1.21% of the total.
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PMID:Clinical application of therapeutic erythrocytapheresis (TEA). 1083 21

Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.
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PMID:Iron overload and iron-chelating therapy in hemoglobin E-beta thalassemia. 1113 36

Patients affected by beta-thalassemia major require lifelong transfusions because of insufficient or absent production of the beta chain of hemoglobin (Hb). A minority of patients are cured by allogeneic bone marrow transplantation. In the most severe of the hitherto available mouse models of beta-thalassemia, a model for human beta-thalassemia intermedia, we previously demonstrated that globin gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0-8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic potential of gene therapy in the context of a lethal anemia, we now have created an adult model of beta(0)-thalassemia major. In this novel model, mice engrafted with beta-globin-null (Hbb(th3/th3)) fetal liver cells succumb to ineffective erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4 g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin gene transfer were rescued. Long-term chimeras with an average 1.0-2.4 copies of the TNS9 vector in their hematopoietic and blood cells stably produced up to 12 g/dL chimeric Hb consisting of mu alpha(2):hu beta(2) tetramers. Pathologic analyses indicated that erythroid maturation was restored, while EMH and iron overload dramatically decreased. Thus, we have established an adult animal model for the most severe of the hemoglobinopathies, Cooley anemia, which should prove useful to investigate both genetic and pharmacologic treatments. Our findings demonstrate the remarkable efficacy of lentivirus-mediated globin gene transfer in treating a fulminant blood disorder and strongly support the efficacy of gene therapy in the severe hemoglobinopathies.
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PMID:A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. 1248 Jun 89

Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.
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PMID:Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia. 1291 94

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
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PMID:Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. 1463 44


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