Rare causes of hereditary iron overload.

摘要: Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as biologic catalyst. However, when not appropriately shielded or present excess, iron plays key role the formation extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for acquisition, export, transport, and storage well sophisticated mechanisms that maintain intracellular labile pool at an appropriate level. These systems normally tightly control homeostasis but their failure can lead deficiency overload clinical consequences. This review describes several rare loading conditions caused by genetic defects some involved metabolism. A dramatic decrease synthesis plasma transport protein, transferrin, leads massive accumulation nonhematopoietic tissues virtually no available erythropoiesis. Humans mice hypotransferrinemia have remarkably similar phenotype. Homozygous recently identified gene encoding transferrin receptor 2 (hemochromatosis type 3) symptoms those seen patients HFE-associated hereditary hemochromatosis 1). Transferrin primarily expressed liver it unclear how mutant forms overload. Mutations exporter, ferroportin 1, characterized macrophages yet normal levels. Plasma iron, together dominant inheritance, discriminates due mutations 4) from 1. Heme oxygenase 1 essential catabolism heme recycling hemoglobin macrophages. deletion paradoxical nonheme macrophages, hepatocytes, many other cells associated low levels, anemia, endothelial damage, decreased resistance oxidative stress. phenotype occurred child severe deficiency. Recently, mutation L-subunit ferritin has been described causes aberrant L-ferritin altered C-terminus. Individuals this one allele abnormal aggregates brain, globus pallidus. Patients dominantly inherited late-onset disease extrapyramidal dysfunction. Mice targeted disruption regulatory protein (IRP2), translational repressor ferritin, misregulate intestinal mucosa central nervous system. Significant amounts accumulate white matter tracts nuclei, adult IRP2-deficient develop movement disorder consisting ataxia, bradykinesia, tremor. frataxin responsible Friedreich most common ataxias. Frataxin appears regulate mitochondrial (or iron-sulfur cluster) export neurologic cardiac manifestations ataxia iron-mediated toxicity. Finally, Hallervorden-Spatz syndrome, autosomal recessive, progressive neurodegenerative disorder, novel pantothenate kinase (PANK2). The cardinal feature pathologic defect PANK2 predicted cysteine, binds stress iron-rich