Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme-regulated eIF2alpha kinase (HRI) is essential for regulating globin translation in iron deficiency and in beta-thalassemia. We investigated the role of heme-regulated eIF2alpha kinase in hemoglobin and red blood cell production as well as in iron homeostasis in a mouse model of iron overload. We show that HRI deficiency does not significantly affect red cell parameters of hemochromatosis (HFE(-)(/)(-)) mice. Importantly, heme-regulated eIF2alpha kinase deficiency exacerbates decreases in hepcidin expression and splenic macrophage iron in HFE(-)(/)(-) mice. Furthermore, the serum level of bone morphogenic protein 2, which positively regulates hepcidin, is reduced in heme-regulated eIF2alpha kinase deficiency, but not in HFE deficiency.
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PMID:Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE-/- mice. 1836 82

ABSTRACT Genetically modified rice that incorporates twofold to threefold increased amounts of iron is being developed. The product could provide improved nutrition to iron-deficient persons but may be a health hazard to large numbers of humans who are prone to iron overload. Clinical disorders such as African siderosis, beta-thalassemia, hemochromatosis, and alcoholic siderosis are of special concern. Conditions associated with iron loading include fatigue and depression; arthritis; endocrine disorders such as stunted growth, impotence, and diabetes; gastrointestinal maladies; infections and malignancies; several neurological diseases; and, not least, cardiovascular system decay. Therefore, it would be prudent to label sacks of iron-enriched rice to indicate that "this product may be dangerous to persons with iron loading conditions".
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PMID:Iron-enriched rice: the case for labeling. 1923 76

Osteoporosis is a remarkably frequent complication of iron loading conditions such as thalassemia, sicklemia, African siderosis, hemochromatosis, smoking, alcoholism, HIV infection, and cessation of menstruation. The metal suppresses osteoblast formation of bone and may also stimulate osteoclast resorption of bone. Iron also inhibits anterior pituitary synthesis of gonadotrophs. This, in turn, results in depressed formation of gonadal hormones. The tendency of iron-loaded persons to become osteoporotic may be enhanced by gonadal hormone deficiency. Iron binding agents that could specifically withhold excess skeletal iron (and be excreted as the iron chelate) might have therapeutic utility.
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PMID:Role of iron in osteoporosis. 1933 60

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.
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PMID:Iron overload in the Asian community. 1957 77

Homozygous beta-thalassemia is a common genetic disorder in the Arabian Peninsula and an important cause of morbidity in Kuwait. The anemia is so severe that chronic blood transfusions, and the resulting iron overload, cause a shift in immunoregulatory balances and a deficiency in zinc. It was reported that individual immunological profile of CD8+ T-lymphocytes may have a modifying effect on the severity of iron overload in HFE homozygous hemochromatosis patients, with low numbers being negatively correlated with the total amount of body iron stores. This has not been tested in thalassemia major patients. This study was designed to utilize flow cytometric immunophenotyping to characterize effects of regular blood transfusion, and high serum ferritin levels because of irregular use of iron chelation therapy on T lymphocytes (CD2, CD3, CD4 and CD8), B lymphocytes (CD19) and natural killer cells (CD56) and zinc levels in the blood of patients with thalassemia major (n = 49) and healthy normal controls (n = 60) in Kuwait. None of the patients had active infections. T-cell markers' percentage levels were comparable between patients and controls (P > 0.05), while B cell marker (CD19) was significantly higher in patients (P = 0.007). Patients had lower percentage levels of CD56 cells (P = 0.007) and normal serum zinc. All patients had high serum ferritin levels with no significant correlation to CD8+ T lymphocytes (P > 0.05). High iron stores did not have an effect on T lymphocytes' profile, with normal zinc levels perhaps related to non compliance with chelation therapy. The high B cell marker may be indicative of stimulation of antibody producing cells as a result of regular blood transfusions.
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PMID:Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused beta-thalassemia major patients. 1945 75

Excess iron is found in brain nuclei from neurodegenerative patients (with Parkinson's, Alzheimer's and Huntington's diseases) and also in the liver and spleen of cirrhosis, hemochromatosis and thalassaemia patients. Ferritin, the iron-storing protein of mammals, is known to darken T(2)-weighted MR images. Understanding NMR tissue behavior may make it possible to detect those diseases, to follow their evolution and finally to establish a protocol for non-invasive measurement of an organ's iron content using MRI methods. In this preliminary work, the MR relaxation properties of embalmed iron-containing tissues were studied as well as their potential correlation with the iron content of these tissues. Relaxometric measurements (T(1) and T(2)) of embalmed samples of brain nuclei (caudate nucleus, dentate nucleus, globus pallidus, putamen, red nucleus and substantia nigra), liver and spleen from six donors were made at different magnetic fields (0.00023-14 T). The influence of the inter-echo time on transverse relaxation was also studied. Moreover, iron content of tissues was determined by inductively coupled plasma atomic emission spectroscopy. In brain nuclei, 1/T(2) increases quadratically with the field and depends on the inter-echo time in CPMG sequences at high fields, both features compatible with an outer sphere relaxation theory. In liver and spleen, 1/T(2) increases linearly with the field and depends on the inter-echo time at all fields. In our study, a correlation between 1/T(2) and iron concentration is observed. Explaining the relaxation mechanism for these tissues is likely to require a combination of several models. The value of 1/T(2) at high field could be used to evaluate iron accumulation in vivo. In the future, confirmation of those features is expected to be achieved from measurements of fresh (not embalmed) human tissues.
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PMID:Variable-field relaxometry of iron-containing human tissues: a preliminary study. 1957 79

There have been major developments in the field of iron metabolism in the past decade following the identification of the HFE gene and the mutation responsible for the C282Y substitution in the HFE protein. While HFE-associated hemochromatosis occurs predominantly in people of northern European extraction, other less-common mutations can lead to the same clinical syndrome and these may occur in other populations in the Asian-Pacific region. The most common of these is the mutation that leads to changes in the ferroportin molecule, the protein responsible for the transport of iron across the basolateral membrane of the enterocyte and from macrophages. Recent research has unraveled the molecular processes of iron transport and regulation of how these are disturbed in hemochromatosis and other iron-loading disorders. At the same time, at least one new oral iron chelating agent has been developed that shows promise in the therapy of hemochromatosis as well as thalassemia and other secondary causes of iron overload. It is pertinent therefore to examine the developments in the global field of iron overload that have provided insights into the pathogenesis, disease penetrance, comorbid factors, and management.
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PMID:The global burden of iron overload. 1966 41

The beta-thalassemias are genetic disorders that are caused by the absent or insufficient production of the beta-chain of hemoglobin. This deficiency causes ineffective erythropoiesis and hemolytic anemia. Without treatment, the severe form of the disease is lethal within the first decade of life. The only curative therapeutic option to date is allogeneic bone marrow transplantation from a matched, related donor, which carries a low risk of morbidity and mortality. Most patients, however, lack a matched donor and are thus managed with palliative therapy, consisting of lifelong transfusion therapy combined with pharmacological chelation to curb iron accumulation. Despite a major improvement in the chelation therapy and supportive care, the major cause of death in these patients is cardiac failure due to secondary hemochromatosis. The goal of globin gene therapy is to offer a potentially curative treatment to patients lacking a matched, related donor, based on the transfer of a regulated beta-globin gene in autologous CD34+ hematopoietic cells collected following G-CSF mobilization. Our clinical trial at Memorial Sloan-Kettering Cancer Center builds on a 20-year long investigation to develop an erythroid-specific vector to regulate beta-globin transgene expression in the progeny of transduced hematopoietic stem cells. To minimize the risks to the patient, the genetically modified cells will be infused after extensive biosafety testing of the transduced cells and following the administration of a reduced intensity (non-myeloablative) conditioning regimen. The protocol will be offered to patients with transfusion-dependent ss-thalassemia who are 15 years or older and lack a matched, related donor.
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PMID:Gene therapy for homozygous beta-thalassemia. Is it a reality? 2000 25

This study highlights the iron profile of myelodysplastic patients in the era of hepcidin and its pro-hormone, pro-hepcidin. Previous studies have focused on the anemia of chronic renal failure, thalassemia, and hemochromatosis. We determined if pro-hepcidin played a role in iron overload in patients with myelodysplasia (MDS). Thirty adult patients with MDS and 20 healthy adults (controls) were selected. Our results revealed a statistically significant difference in pro-hepcidin levels between the two tested groups (Z = 2.9, p = 0.003). There was a weak positive correlation between pro-hepcidin and hematocrit (HCT; r = 0.49, p = 0.02) in the healthy group only. Neither age, subtypes of MDS, gender, soluble transferrin receptor (sTFR) or ferritin affected the pro-hepcidin level in patients with MDS. The role of ineffective erythropoiesis in the regulation of pro-hepcidin is superior to the role of chronic blood transfusion therapy.
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PMID:Serum prohepcidin level in myelodysplasia. 2050 58

An accurate assessment of body iron accumulation is essential for the diagnosis and therapy of iron overload in diseases, such as hemochromatosis, thalassemia and other forms of severe anemias. The magnetic iron detector (MID) is a room-temperature susceptometer, which measures the total iron overload in the liver. Since February 2005, about 600 patients have been assessed using this device. The iron overload is obtained by calculating the difference between the measured magnetization signal of the patient and the patient's background signal. The latter is the magnetization signal that the patient would generate with normal iron content. This study presents the method for calculating the background signal of healthy volunteers and the application of the same method to patients with iron burden in order to evaluate their overload. The present MID sensitivity is 0.8 g and the reproducibility of the iron overload measurement of the same patients is lower than 0.5 g. The MID does not require calibration with liver biopsies. We correlated the MID measurements with the results of 26 biopsies (R = 0.62), 64 superconducting quantum interference device susceptometer measurements (R = 0.79), 666 serum ferritin concentration measurements (R = 0.72), and 41 MRI- R2* measurements (R = 0.71).
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PMID:Total iron-overload measurement in the human liver region by the magnetic iron detector. 2056 30


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