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)

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and progressive storage resulting in organ damage. HFE gene mutations C282Y and H63D are responsible for the majority of HH cases. A third HFE mutation, S65C, has been associated with the development of a mild form of hemochromatosis. The beta-thalassemia trait is characterized by mild, ineffective erythropoiesis that can induce excess iron absorption and ultimately lead to iron overload. The aim of this study was to evaluate the effect of genetic markers (HFE mutations C282Y, H63D, and S65C) on the iron status of beta-thalassemia carriers. A total of 101 individuals heterozygous for beta-thalassemia and 101 normal control individuals were studied. The allelic frequencies of C282Y (1.5 versus 3.5%), H63D (15.3 versus 18.3%), and S65C (1.0 versus 1.5%) did not differ significantly between beta-thalassemia carriers and normal controls. Serum iron (P=0.029) and transferrin saturation (P=0.009) were increased in beta-thalassemia carriers heterozygous for H63D mutation. The number of subjects carrying C282Y or S65C mutations was too low to conclude their effect on the iron status. These results suggest that the beta-thalassemia trait tends to be aggravated with the coinheritance of H63D mutation, even when present in heterozygosity.
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PMID:The role of HFE mutations on iron metabolism in beta-thalassemia carriers. 1553 48

Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin-ferroportin interaction in iron homeostasis.
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PMID:Hepcidin in iron overload disorders. 1567 38

Liver iron measurements using biosusceptometers have been validated on two low-TC SQUID (Superconducting Quantum Interference Device) systems (New York and Hamburg) built in the 1980's. Recently, two new instruments have been installed in Torino, Italy (2001), and Oakland, California (2003). The design of the Oakland system is similar to those in Hamburg and Torino. Improvements were made to adjust for significant environmental noise, moreover, an active electronic noise cancellation, a computer controlled water coupling reference system using a pressure feedback and a faster data acquisition system using software lockin amplifiers have been implemented. All 3 systems (Hamburg, Torino, Oakland) are using the same standardized operational protocol. Presented herein are the data collected from 276 patients measured with the SQUID biosusceptometer at Oakland since installation. The results from 149 patients with beta-thalassemia (beta-Thal, age: 2-66 y), 76 patients with sickle-cell disease (SCD, age: 5-55 y), 35 patients with various rare diseases (RD, age: 2-80 y), and 16 patients with hereditary hemochromatosis (HHC, age: 6-74 y) are reported. The liver iron concentration in the different groups are 222 - 7570 (beta-Thal), 518 - 7918 (SCD), 511 - 6234 (RD), 258 - 2041 (HHC) microg/g-liver (in vivo wet weight). The long-term reproducibility (12 months) in a patient on constant treatment regimen demonstrated a mean liver iron of 1141 +/- 133 microg/g-liver. The new SQUID Ferritometer located on the US West coast will give more patients access to this non-invasive liver iron assessment.
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PMID:The new SQUID biosusceptometer at Oakland: first year of experience. 1601

Iron imbalance/accumulation has been implicated in oxidative injury associated with many degenerative diseases such as hereditary hemochromatosis, beta-thalassemia, and Friedreich's ataxia. Mitochondria are particularly sensitive to iron-induced oxidative stress - high loads of iron cause extensive lipid peroxidation and membrane permeabilization in isolated mitochondria. Here we detected and characterized mitochondrial DNA damage in isolated rat liver mitochondria exposed to a Fe2+-citrate complex, a small molecular weight complex. Intense DNA fragmentation was induced after the incubation of mitochondria with the iron complex. The detection of 3' phosphoglycolate ends at the mtDNA strand breaks by a 32P-postlabeling assay, suggested the involvement of hydroxyl radical in the DNA fragmentation induced by Fe2+-citrate. Increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine also suggested that Fe2+-citrate-induced oxidative stress causes mitochondrial DNA damage. In conclusion, our results show that iron-mediated lipid peroxidation was associated with intense mtDNA damage derived from the direct attack of reactive oxygen species.
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PMID:Mitochondrial DNA damage associated with lipid peroxidation of the mitochondrial membrane induced by Fe2+-citrate. 1693 39

Hereditary hemochromatosis is a disorder of iron metabolism characterized by increased iron intake and progressive storage and is related to mutations in the HFE gene. Interactions between thalassemia and hemochromatosis may further increase iron overload. The ethnic background of the Brazilian population is heterogeneous and studies analyzing the simultaneous presence of HFE and thalassemia-related mutations have not been carried out. The aim of this study was to evaluate the prevalence of the H63D, S65C and C282Y mutations in the HFE gene among 102 individuals with alpha-thalassemia and 168 beta-thalassemia heterozygotes and to compare them with 173 control individuals without hemoglobinopathies. The allelic frequencies found in these three groups were 0.98, 2.38, and 0.29% for the C282Y mutation, 13.72, 13.70, and 9.54% for the H63D mutation, and 0, 0.60, and 0.87% for the S65C mutation, respectively. The chi-square test for multiple independent individuals indicated a significant difference among groups for the C282Y mutation, which was shown to be significant between the beta-thalassemia heterozygote and the control group by the Fisher exact test (P value = 0.009). The higher frequency of inheritance of the C282Y mutation in the HFE gene among beta-thalassemic patients may contribute to worsen the clinical picture of these individuals. In view of the characteristics of the Brazilian population, the present results emphasize the need to screen for HFE mutations in beta-thalassemia carriers.
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PMID:HFE gene mutations in Brazilian thalassemic patients. 1716 Feb 66

Since the discovery of HFE gene in 1996, considerable progress has been made concerning the iron-metabolism and its major abnormalities. Five types of hereditary hemochromatosis are actually known: type 1 (HFE gene), type 2A (HJV gene), type 2B (HAMP gene), type 3 (TfR2 gene), type 4 (SLC40A1 gene). The HFE C282Y +/+ mutation is responsible for the most frequent type of hemochromatosis in France. Various secondary causes can lead to iron-overload: associated genetic diseases, exogenous iron intake, thalassaemia and refractory anaemia, hepatic siderosis, alcoholic hepatitis, cutaneous porphyria and cirrhosis. The deleterious consequences of iron-overload are due to the interactions of the environmental factors. The role of HFE heterozygote mutations is still discussed. In clinical practice, the interpretation of a serum ferritin increase is a frequent problem that needs a careful evaluation based on the tranferrin saturation measurement. Significant increase of both these factors is in favour of an HFE C282Y +/+ hemochromatosis, after exclusion of a hepatocellular insufficiency or a refractory anaemia. Nevertheless, high ferritin is not always a marker of iron-overload. Thus, there are many disorders increasing the serum ferritin levels without iron overload : cytolysis (hepatic...), inflammatory or infectious syndromes, high alcohol intake, neoplasia... Looking for HFE mutations help to separate type 1 hemochromatosis from other conditions mainly hepatic siderosis (metabolic disorders). The identification of rare types of hemochromatosis (types 2-4) is only required in particular cases. The evaluation of the iron overload is now based on hepatic MRI determination rather than liver biopsy. Repeated phlebotomies remain the essential way to decrease the iron overload in HFE hemochromatosis and to prevent the occurrence of severe and irreversible complications (cirrhosis, arthropathies, cardiac failure, and diabetes). Because of the link established between the amount of iron-overload and the occurrence of complications and the mortality over-risk in HFE C282Y +/+ hemochromatosis, venesections must be started when serum ferritin is higher than 300 microg/l in man and 200 microg/l in woman, whatever the clinical manifestations are and obviously before the symptomatic phase of the disease.
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PMID:[Hereditary and acquired iron overload]. 1737 75

Hereditary hemochromatosis is an autosomal recessive and most commonly inherited single gene disorder among Caucasians, with a prevalence of 5 per 1,000 and a carrier frequency of 1 in 10. Two point mutations were described and are referred as C282Y and H63D. In the present study, we have analyzed 729 north Indian samples for C282Y and H63D mutations. Of these, no allele of the C282Y mutation was seen, while 3 homozygous and 43 heterozygous for the H63D mutation were seen in the patients of thalassemia group. However, 47 cases were found heterozygous for the H63D mutation among the normal groups (11.16%).
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PMID:Status of HFE mutation in thalassemia syndromes in north India. 1740 64

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25-amino-acid peptide hepcidin is up-regulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it was considered the most common disease among Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and only its genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype. Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias. While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.
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PMID:Iron storage disease: facts, fiction and progress. 1754 May 89

This communication explores the temporal link between the age-associated increase in body iron stores and the age-related incidence of Alzheimer's disease (AD), the most prevalent cause of senile dementia. Body iron stores that increase with age could be pivotal to AD pathogenesis and progression. Increased stored iron is associated with common medical conditions such as diabetes and vascular disease that increase risk for development of AD. Increased stored iron could also promote oxidative stress/free radical damage in vulnerable neurons, a critical early change in AD. A ferrocentric model of AD described here forms the basis of a rational, easily testable experimental therapeutic approach for AD, which if successful, would be both widely applicable and inexpensive. Clinical studies have shown that calibrated phlebotomy is an effective way to reduce stored iron safely and predictably without causing anemia. We hypothesize that reducing stored iron by calibrated phlebotomy to avoid iron deficiency will improve cerebrovascular function, slow neurodegenerative change, and improve cognitive and behavioral functions in AD. The hypothesis is eminently testable as iron reduction therapy is useful for chronic diseases associated with iron excess such as nonalcoholic steatohepatitis (NASH), atherosclerosis, hereditary hemochromatosis and thalassemia. Testing this hypothesis could provide valuable insight into the causation of AD and suggest novel preventive and treatment strategies.
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PMID:Getting the iron out: phlebotomy for Alzheimer's disease? 1919 95

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


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