Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-field strength magnetic resonance imaging is an accurate clinical technique for detecting the relative distribution of ferritin in the brain. In normal adults, iron is found in highest concentrations in the globus pallidus, red nucleus, pars reticulata of the substantia nigra, and dentate nucleus of the cerebellum; its distribution is clearly mapped as signal hypointensity (darkness) on a T2-weighted image due to local-field heterogeneities produced by ferritin. Iron is absent at birth and increases in concentration in the putamen in the elderly. Poorly drug-responsive Parkinson's disease (multiple-system atrophy) is characterized by premature signal hypointensity in the putamen and caudate, while Hallervorden-Spatz disease exhibits abnormal hypointensity in the globus pallidus in children. Dyskinetic disorders often have abnormal signal hyperintensity (whiteness) in the putamen related to gliosis.
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PMID:Magnetic resonance imaging and extrapyramidal movement disorders. 271 6

Although iron accumulates in the brain in a number of pathological conditions, including Hallervorden-Spatz syndrome, Parkinson's disease, and neurosyphilis, studies of brain iron metabolism have been performed only rarely. Neuronal-enriched cultures were prepared from fetal mouse brain. After 18 days the cells were exposed to radiolabeled iron. Total iron uptake and incorporation into ferritin were rapid and linear over four hours. The addition of either methylamine or ammonium chloride, both known blockers of transferrin-iron release through their lysosomotropic properties, inhibited total iron uptake. Methylamine also inhibited the rate of ferritin-iron incorporation, most likely by interfering with transferrin-iron release. The data suggest that neuronal iron transport, much like that in other mammalian tissues, is transferrin mediated and that blockers of transferrin-iron release may be of value in conditions in which there is brain iron overload.
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PMID:Iron uptake by mammalian cortical neurons. 646 62

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.
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PMID:Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. 894 32

Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation.
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PMID:Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease. 900 53

A 59-year-old patient progressively developed dementia, hallucinations and facial dyskinesia. Brain T and T2-weighted MRI images showed low signal intensity on basal ganglia specially striatum, posterior thalamic and dentate nuclei. He had no evidence of ceruloplasmin and a high level of ferritin in the serum. Liver biopsy confirmed accumulation of iron in the cytoplasm of many hepatocytes. Similar clinical and biological signs were also observed in two brothers. All the three siblings were homozygous for a hereditary ceruloplasmin deficiency. This new clinico-pathological entity, first described in 1987, is different from Wilson's disease, Hallervorden-Spatz's disease and idiopathic hemochromatosis and linked to a mutation of the ceruloplasmin gene located on chromosome 3.
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PMID:[Cerebral hemosiderosis related to hereditary ceruloplasmin deficiency. Clinical familial case study]. 977 37

The dark discoloration of globus pallidus and substantia nigra pars reticularis in the Hallervorden-Spatz syndrome is due to the accumulation of iron. Routine iron stains detect the metal mostly in microglia and macrophages, but scattered neurons are also reactive. Axonal spheroids are characteristic of the disease, and many of these expansions give a positive iron reaction. Globus pallidus and substantia nigra are normally rich in iron, and additional "storage" of the metal has often been considered the essential factor in the pathogenesis of Hallervorden-Spatz syndrome. However, other equally iron-rich structures, such as the red nucleus and the dentate nucleus, remain unaffected. In normal globus pallidus and substantia nigra pars reticularis, double-label immunofluorescence microscopy of ferritin, as an indirect marker of cellular iron localization, and phosphorylated neurofilament protein reveal close proximity of ferritin-reactive microglial and oligodendroglial processes to tightly packed axons. It is proposed that a primary axonal disorder allows the seepage of iron into the axoplasm. Iron may contribute to the axonal disease, but accumulation of the metal probably should be viewed as an epiphenomenon. Pallidal and nigral iron excess is not unique to Hallervorden-Spatz syndrome, and some previously reported postmortem examinations may actually represent pallidonigroluysian atrophy.
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PMID:Iron in the Hallervorden-Spatz syndrome. 1155 45

Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
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PMID:Rare causes of hereditary iron overload. 1238

Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this metal plays a crucial role in the formation of toxic oxygen radicals that can attack all biological molecules. Organisms are equipped with specific proteins designed for iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. This review describes several hereditary iron-overloading conditions that are confined to the brain. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich's ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron-sulfur cluster formation, and the neurologic and cardiac manifestations of Friedreich's ataxia are due to iron-mediated mitochondrial toxicity. Patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus. Finally, aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by loss-of-function mutations in ceruloplasmin gene that leads to misregulation of both systemic and central nervous system iron trafficking. Affected individuals suffer from extrapyramidal signs, cerebellar ataxia, progressive neurodegeneration of retina, and diabetes mellitus. Excessive iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various neurodegenerative disorders.
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PMID:Hereditary causes of disturbed iron homeostasis in the central nervous system. 1510 72

The classification of hereditary abnormalities of iron metabolism was recently expanded and diversified. Genetic hemochromatosis now corresponds to six diseases, namely classical hemochromatosis HFE 1; juvenile hemochromatosis HFE 2 due to mutations in an unidentified gene on chromosome 1; hemochromatosis HFE 3 due to mutations in the transferrin receptor 2 (TfR2); hemochromatosis HFE 4 caused by a mutation in the H subunit of ferritin; and hemochromatosis HFE 6 whose gene is hepcidine (HAMP). Systemic iron overload is also associated with aceruloplasminemia, atransferrinemia and the "Gracile" syndrome caused by mutations in BCS1L. The genes responsible for neonatal and African forms of iron overload are unknown. Other genetic diseases are due to localized iron overload: Friedreich's ataxia results from the expansion of triple nucleotide repeats within the frataxin (FRDA) gene; two forms of X-linked sideroblastic anemia are due to mutations within the delta aminolevulinate synthetase (ALAS 2) or ABC-7 genes; Hallervorden-Spatz syndrome is caused by a pantothenate kinase 2 gene (PANK-2) defect; neuroferritinopathies; and hyperferritinemia--cataract syndrome due to a mutation within the L-ferritin gene. In addition to this wide range of genetic abnormalities, two other features characterize these iron disorders: 1) most are transmitted by an autosomal recessive mechanism, but some, including hemochromatosis type 4, have dominant transmission; and 2) most correspond to cytosolic iron accumulation while some, like Friedreich's ataxia, are disorders of mitochondrial metabolism.
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PMID:[Genetics of hereditary iron overload]. 1550 16

The influence of iron deposits on T2 values and the content of metabolites in the brain of three patients with DNA proved pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome) was studied. An eye-of-the-tiger sign, a typical MR finding for PKAN, was observed in two patients with the same mutation. A hypointensive lesion in a whole globus pallidus was observed in the third patient with the additional mutation. T2 values in the globus pallidus of the patients were about 40% shorter than in controls (71/48 ms in controls vs. patients), which corresponds to the increase of Fe concentration based on the ferritin basis from 17 mg for controls to 48 mg (100 g wet brain weight) in PKAN patients. 1H MR spectroscopy (MRS) has mainly been used to describe neuronal damage represented by decreased NAA (6.4 mmol vs. 9 mmol) and Cr/PCr (7.0 mmol vs. 9.8 mmol) concentrations in the basal ganglia region of the patient group to controls; MRS is much more case-sensitive and describes individual development of the disease as demonstrated in the difference between the spectra of typical PKAN patients (1, 2), and the patient (3) with atypical PKAN development. Any significant changes of metabolite concentration with the exception glutamine, glutamate and GABA were found in the white matter.
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PMID:MR relaxometry and 1H MR spectroscopy for the determination of iron and metabolite concentrations in PKAN patients. 1556 11


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