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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Friedreich's ataxia (FA) is a severe inherited spinocerebellar ataxia that primarily affects the nervous system and heart leading to early confinement in a wheelchair and death. The gene defective in FA, FRDA, encodes a mitochondrial protein known as frataxin. A triplet repeat expansion within intron 1 of the FRDA gene results in a marked decrease in frataxin expression. Over the last 5 years it has become clear that this results in mitochondrial iron accumulation that generates oxidative stress and results in damage to critical biological molecules. Drugs that reduce oxidative stress have a limited effect on the progression and pathology of the disease, probably because these agents cannot remove the iron accumulation. In this review, the potential of iron chelators, namely the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) analogues, as agents to remove mitochondrial iron deposits is discussed. These ligands have been specifically designed to enter and target mitochondrial iron pools, which is a property lacking in desferrioxamine, the only chelator in widespread clinical use. This latter drug may not have any beneficial effect in FA patients, probably because of its hydrophilicity that prevents mitochondrial access. Indeed, standard chelation regimens will probably not work in FA, as these patients do not exhibit gross iron-loading. Considering that there is no effective treatment for FA, it is essential that the therapeutic potential of iron chelators that target mitochondrial iron pools is assessed experimentally.
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PMID:Friedreich's ataxia: iron chelators that target the mitochondrion as a therapeutic strategy? 1255 17

Friedreich's ataxia is the most common recessive ataxia associated with life-threatening cardiomyopathy. It results from a loss of function of frataxin that ultimately leads to oxidative insult, particularly to neurons and cardiomyocytes. The disease is progressive, the oxidative insult being presumably subsequent to an abnormal iron/sulfur cluster synthesis that causes mitochondrial respiratory chain disease and impaired signalling of one antioxidant pathway. After a detailed in vitro study, idebenone, a short chain homologue of coenzyme Q(10) with potent antioxidant properties, was given to patients. The antioxidant had a dramatic and rapid effect on the cardiomyopathy in most patients. Although a subset of patients also report various improvements, implying that idebenone could have a broader spectrum of action including some neurological improvements, the antioxidant did not have noticeable effects on the ataxia. Several hypotheses on the mechanisms that could account for the contrasting effects of the antioxidant on clinical symptoms of Friedreich's ataxia are discussed in this review. The considerable difficulties still being encountered in ascertaining the effect of antioxidants on the course of the neurological condition are also considered.
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PMID:The use of antioxidants in Friedreich's ataxia treatment. 1266 13

The authors report 1-year prospective data on eight patients with Friedreich ataxia. Idebenone did not halt the progression of ataxia. At the end of therapy, cardiac ultrasound demonstrated significant reduction of cardiac hypertrophy in six of eight patients. Cardiac strain and strain rate imaging showed that the reduction of hypertrophy is preceded by an early and linear improvement in cardiac function. Idebenone reduced erythrocyte protoporphyrin IX levels in five of six patients with elevated baseline levels; however, changes did not consistently relate to cardiac improvement.
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PMID:Idebenone treatment in Friedreich's ataxia: neurological, cardiac, and biochemical monitoring. 1487 56

Increasing evidence suggests that iron-mediated oxidative stress might underlie the development of neurodegeneration in Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by decreased expression of frataxin, a protein implicated in iron metabolism. In this study, we demonstrate that, in fibroblasts of patients with FRDA, the cellular redox equilibrium is shifted toward more protein-bound glutathione. Furthermore, we found that actin is glutathionylated, probably as a result of the accumulation of reactive oxygen species, generated by iron overload in the disease. Indeed, high-pressure liquid chromatography analysis of control fibroblasts in vivo treated with FeSO4 showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation. Actin glutathionylation contributes to impaired microfilament organization in FRDA fibroblasts. Rhodamine phalloidin staining revealed a disarray of actin filaments and a reduced signal of F-actin fluorescence. The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. When we treated FRDA fibroblasts with reduced glutathione, we obtained a complete rescue of cytoskeletal abnormalities and cell viability. Thus, we conclude that oxidative stress may induce actin glutathionylation and impairment of cytoskeletal functions in FRDA fibroblasts.
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PMID:Actin glutathionylation increases in fibroblasts of patients with Friedreich's ataxia: a potential role in the pathogenesis of the disease. 1291 1

Friedreich Ataxia (FRDA), the most common inherited ataxia, arises from defective expression of the mitochondrial protein frataxin, which leads to increased mitochondrial oxidative damage. Therefore, antioxidants targeted to mitochondria should be particularly effective at slowing disease progression. To test this hypothesis, we compared the efficacy of mitochondria-targeted and untargeted antioxidants derived from coenzyme Q10 and from vitamin E at preventing cell death due to endogenous oxidative stress in cultured fibroblasts from FRDA patients in which glutathione synthesis was blocked. The mitochondria-targeted antioxidant MitoQ was several hundredfold more potent than the untargeted analog idebenone. The mitochondria-targeted antioxidant MitoVit E was 350-fold more potent than the water soluble analog Trolox. This is the first demonstration that mitochondria-targeted antioxidants prevent cell death that arises in response to endogenous oxidative damage. Targeted antioxidants may have therapeutic potential in FRDA and in other disorders involving mitochondrial oxidative damage.
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PMID:Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. 1292 74

Iron-sulfur proteins participate in a wide range of biochemical processes, including many that are central to mitochondrial electron transfer and energy metabolism. Mutations in two such proteins, frataxin and ABCB7, cause Friedreich ataxia and X-linked sideroblastic anemia with ataxia, respectively, rendering other participants in this pathway functional candidates for hereditary ataxia syndromes. Recently frataxin was shown to have an identical phylogenetic distribution with two genes and was most likely specifically involved in the same sub-process in iron-sulfur cluster assembly as one gene, designated hscB, in bacteria. To set the stage for an analysis of the potential role of this candidate gene in human disease, we defined the human HscB cDNA, its genomic locus, and its pattern of expression in normal human tissues. The isolated human HscB cDNA spans 785 bp and encodes a conserved 235-amino-acid protein, including a putative mitochondrial import leader. The HscB gene is found at chromosome 22q11-12 and is composed of six exons and five introns. Northern blot analyses of RNA from adult and fetal tissues defined a pattern of expression in mitochondria-rich tissues similar to that of frataxin, an expression pattern compatible with its implied role in mitochondrial energetics and related disease phenotypes.
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PMID:Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding HscB, a J-type co-chaperone. 1293 16

Friedreich ataxia (FRDA) is the most common recessive ataxia caused by reduced expression of frataxin, a nuclear encoded mitochondrial protein. In this study we examined the effects of 3-nitropropionic acid (3-NP) on frataxin expression in FRDA patient and control lymphoblasts and in rat pheochromocytoma cell line (PC12) overexpressing human frataxin. Our studies showed an up-regulation of frataxin expression in both FRDA and control lymphoblasts following exposure to 3-NP. In addition, in transgenic frataxin overexpressing cells 3-NP caused an increase of frataxin protein.
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PMID:3-Nitropropionic acid increases frataxin expression in human lymphoblasts and in transgenic rat PC12 cells. 1455 Sep 25

Several lines of evidence suggest that the cerebellum may play a role in higher-order olfactory processing. In this study, we administered the University of Pennsylvania Smell Identification Test (UPSIT), a standardised test of olfactory function, to patients with ataxias primarily due to cerebellar pathology (spinocerebellar ataxias and related disorders) and to patients with Friedreich ataxia, an ataxia associated mainly with loss of afferent cerebellar pathways. UPSIT scores were slightly lower in both patient groups than in the control subjects, but no differences were noted between the scores of the Friedreich and the other ataxia patients. Within the Friedreich ataxia group, the smell test scores did not correlate with the number of pathologic GAA repeats (a marker of genetic severity), disease duration, or categorical ambulatory ability. UPSIT scores did not correlate with disease duration, although they correlated marginally with ambulatory status in the patients with cerebellar pathology. This study suggests that olfactory dysfunction may be a subtle clinical component of degenerative ataxias, in concordance with the hypothesis that the cerebellum or its afferents plays some role in central olfactory processing.
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PMID:Olfactory dysfunction in degenerative ataxias. 1457 Aug 42

There has been rapid progress in the understanding of several aspects of Friedreich's ataxia (FA) since the gene mutation was identified in 1996. At the clinical level, now it is possible to confirm that the majority of patients fullfilling clinical criteria for classic FA have the FA gene mutation but some do not, indicating genetic heterogeneity. Also, the phenotype associated with the FA mutation is much wider than that defined by clinical criteria and includes ataxia with retained or brisk reflexes as well as late onset ataxia with or without retained reflexes. It is now clear that the unstable GAA expansion that underlies FA causes a deficiency of the mitochondrial protein frataxin, leading to potentially harmful oxidative injury associated with excessive iron deposits in mitochondria. In addition, pathogenesis may involve a primary defect in synthesis of iron-sulfur cluster containing enzymes. Therapeutic attempts are already using anti-oxidant strategies and such efforts are likely to be enhanced by the rapid availability of animal models of the disease.
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PMID:Friedreich ataxia. 1465 4


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