Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia is the most common hereditary ataxia. The signs and symptoms of the disorder derive from decreased expression of the protein frataxin, which is involved in iron metabolism. Frataxin chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Decreased expression of frataxin is associated with impairments of iron-sulfur cluster biogenesis and heme synthesis, as well as with mitochondrial dysfunction and oxidative stress. Compounds currently in clinical trials are directed toward improving mitochondrial function and lessening oxidative stress. Iron chelators and compounds that increase frataxin expression are under evaluation. Further elucidation of frataxin's function should lead to additional therapeutic approaches.
Semin Pediatr Neurol 2006 Sep
PMID:Iron dysregulation in Friedreich ataxia. 1710 55

Iron (Fe) is an essential element that is imperative for the redox-driven processes of oxygen transport, electron transport, and DNA synthesis. However, in the absence of appropriate storage or chelation, excess-free Fe readily participates in the formation of toxic-free radicals, inducing oxidative stress and apoptosis. A growing body of evidence suggests that Fe may play some role in neurodegenerative diseases such as Huntington disease, Alzheimer's disease, Parkinson's disease, and particularly Friedreich's ataxia. This review examines the role of Fe in the pathology of these conditions and the potential use of Fe chelators as therapeutic agents for the treatment of neurodegenerative disorders. Consideration is given to the features that comprise a clinically successful Fe chelator, with focus on the development of ligands such as desferrioxamine, clioquinol, pyridoxal isonicotinoyl hydrazone, and other novel aroylhydrazones.
Semin Pediatr Neurol 2006 Sep
PMID:Iron: a new target for pharmacological intervention in neurodegenerative diseases. 1710 58

Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.
J Neurol Sci 2007 Sep 15
PMID:A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization. 1757 44

The aim of this study was to examine the impact of Friedreich ataxia (FRDA) on quality of life (QOL) using a generic tool to explore factors potentially associated with health status. Sixty-three individuals with genetically confirmed FRDA, self completed the Medical Outcomes Study 36 item Short Form Health Survey Version 2 (SF-36V2) and were assessed using the FRDA Rating Scale. Disease-specific, demographic, and social characteristics were also recorded. SF-36V2 results were compared with Australian population norms. Sample subgroups of disease severity and age at disease onset were reviewed. Physical and mental component summaries were examined in relation to clinical and social characteristics using multiple linear regression. QOL is significantly worse in individuals with FRDA compared with population norms. Those with severe disease did not perceive a lower QOL than those with mild or moderate disease except in their physical functioning. A later age of onset and increased disease severity were negatively associated with physical QOL, whilst, increased disease duration was positively associated with mental QOL. There were limitations associated with the use of SF-36V2 in the FRDA population. Further exploration of health-related QOL and FRDA may benefit from the use of a more appropriate generic tool.
Eur J Neurol 2007 Sep
PMID:Quality of life in Friedreich ataxia: what clinical, social and demographic factors are important? 1771 98

Friedreich's ataxia is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulphur cluster defects and high sensitivity to oxidative stress. Glutathione is a major protective agent against oxidative damage and glutathione-related systems participate in maintaining the cellular thiol/disulfide status and the reduced environment of the cell. Here, we present the first detailed biochemical study of the glutathione-dependent redox status of wild-type and frataxin-deficient cells in a yeast model of the disease. There were five times less total glutathione (GSH+GSSG) in frataxin-deficient cells, imbalanced GSH/GSSG pools and higher glutathione peroxidase activity. The pentose phosphate pathway was stimulated in frataxin-deficient cells, glucose-6-phosphate dehydrogenase activity was three times higher than in wild-type cells and this was coupled to a defect in the NADPH/NADP(+) pool. Moreover, analysis of gene expression confirms the adaptative response of mutant cells to stress conditions and we bring evidence for a strong relation between the glutathione-dependent redox status of the cells and iron homeostasis. Dynamic studies show that intracellular glutathione levels reflect an adaptation of cells to iron stress conditions, and allow to distinguish constitutive stress observed in frataxin-deficient cells from the acute response of wild-type cells. In conclusion, our findings provide evidence for an impairment of glutathione homeostasis in a yeast model of Friedreich's ataxia and identify glutathione as a valuable indicator of the redox status of frataxin-deficient cells.
Hum Mol Genet 2008 Sep 15
PMID:Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich's ataxia. 1856 74

Evaluation of therapeutic agents for Friedreich Ataxia (FA) has been limited by a lack of adequate markers of disease progression. We assessed the capacity of health related quality of life (HRQOL) questionnaires to reflect disease status in FA. The SF-36 and several symptom-specific scales were administered to an FA cohort. Scores were compared with norms for the United States population, and to a disease-free control group of similar age and gender. FA patients had significantly lower SF-36 Physical Component Summary scores (PCS) and Physical Functioning Subscale (PFS) scores, and both PCS and PFS scores correlated significantly with disease duration and disability status. Mental Component Summary scores (MCS) did not differ between FA patients and controls. Among symptom-specific scales, scores for the Pain Effects, Bladder Control, and Modified Fatigue Impact scales were significantly worse among FA patients than controls, and generally correlated with markers of disease progression. Findings of this study are consistent with the phenotypic characteristics of FA, and suggest that HRQOL measures are potentially useful as clinical markers of disease status in FA.
J Neurol Sci 2008 Sep 15
PMID:Health related quality of life measures in Friedreich Ataxia. 1857 73

Trypanosoma brucei, the agent of human sleeping sickness and ruminant nagana, is the most genetically tractable representative of the domain Excavata. It is evolutionarily very distant from humans, with a last common ancestor over 1 billion years ago. Frataxin, a highly conserved small protein involved in iron-sulfur cluster synthesis, is present in both organisms, and its deficiency is responsible for Friedreich's ataxia in humans. We have found that T. brucei growth-inhibition phenotype caused by down-regulated frataxin is rescued by means of human frataxin. The rescue is fully dependent on the human frataxin being imported into the trypanosome mitochondrion. Processing of the imported protein by mitochondrial processing peptidase can be blocked by mutations in the signal peptide, as in human cells. Although in human cells frataxin must be processed to execute its function, the same protein in the T. brucei mitochondrion is functional even in the absence of processing. Our results illuminate remarkable conservation of the mechanisms of mitochondrial protein import and processing.
Proc Natl Acad Sci U S A 2008 Sep 09
PMID:Mitochondrial localization of human frataxin is necessary but processing is not for rescuing frataxin deficiency in Trypanosoma brucei. 1876 99

A 55-year-old woman presented with a 10-yeai history of a progressive gait disorder. Her examination showed a spastic paraparesis with brisk deep tendon reflexes, but only minimal limb ataxia and no evidence for a sensory neuropathy The patient was found to be homozygous for the GAA trinucleotide repeal diagnostic of Friedreich's ataxia The presentation of Friedreich's ataxia as a spastic paraparesis reinforces the appreciation of the variable phenotype of this disease.
J Clin Neuromuscul Dis 2000 Sep
PMID:Late-Onset Friedreich's Ataxia Presenting as a Spastic Paraparesis. 1907

Friedreich's ataxia (FRDA) is a neurodegenerative disease due to a pathological expansion of a GAA triplet repeat in the first intron of the FXN gene encoding for the mitochondrial protein frataxin. The expansion is responsible for most cases of FRDA through the formation of a nonusual B-DNA structure and heterochromatin conformation that determine a direct transcriptional silencing and the subsequent reduction in frataxin expression. Among other functions, frataxin is an iron chaperone central for the assembly of iron-sulfur clusters in mitochondria; its reduction is associated with iron accumulation in mitochondria, increased cellular sensitivity to oxidative stress and cell damage. There is, nowadays, no effective therapy for FRDA and current therapeutic strategies mainly act to slow down the consequences of frataxin deficiency. Therefore, drugs that are able to increase the amount of frataxin are excellent candidates for a rational approach to FRDA therapy. Recently, several drugs have been assessed for their ability to increase the amount of cellular frataxin, including human recombinant erythropoietin, histone deacetylase inhibitors, and the PPAR-gamma agonists.
Cerebellum 2009 Sep
PMID:Friedreich's Ataxia: from the (GAA)n repeat mediated silencing to new promising molecules for therapy. 1916 52

Left ventricular hypertrophy (LVH) is a frequent finding in Friedreich's ataxia (FRDA). In previous studies treatment with idebenone, a synthetic analogue of coenzyme Q10, has been associated with a substantial decrease in myocardial hypertrophy, despite great variability in cardiac responsiveness among patients. Here we present the results of a retrospective analysis of a cohort of 35 patients (20 with LVH, 15 without LVH) with confirmed molecular diagnosis of FRDA, treated with idebenone 5 mg/kg/day for up to five years. At the end of the study, we found an increase of interventricular septum and posterior wall thickness in the group without LVH before treatment and no change in the group with LVH before treatment. The neurological picture of the disease significantly deteriorated with time in both groups.
J Neurol 2009 Sep
PMID:Low-dose idebenone treatment in Friedreich's ataxia with and without cardiac hypertrophy. 1936 28


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