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)

The hypothesis is that an abnormal oxygen-hemoglobin dissociation curve is a primary or a secondary defect in patients with Friedreich's ataxia was investigated in 12 subjects with this disease. Hemoglobin and P50 were measured and compared with age and sex matched controls. The mean hemoglobin concentration was 14.2 g% and the P50 was 26.25 torr for the patients and 13.8 g% and 26.27 torr in the controls. These results indicate that the oxygen transport system is normal in this disease and likely exclude an abnormal oxygen dissociation curve as a primary or a secondary factor in the pathophysiology of the cardiomyopathy and the neuromyopathy found in this disease.
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PMID:Oxygen transport in patients with Friedreich's ataxia. 64 3

The purpose of this case study was to determine whether a patient with Friedreich ataxia (FA) would experience a clinically significant physiologic adaptation to aerobic endurance training. A 38-year-old man with FA underwent graded exercise testing with collection of expired gases on a bicycle ergometer before and after training, to determine maximum work capacity and oxygen consumption. Training consisted of 27 electrocardiographically monitored exercise sessions on the ergometer, each for 20 to 25 minutes at a workload adjusted to achieve an exercising heart rate equal to 70% to 85% of his pretest maximum, preceded and followed by a stretching routine. Large increases in cardiorespiratory and work measures demonstrated clinically important physiologic adaptations to aerobic conditioning in this patient. Peak VO2 increased 27% and peak ventilation increased 21%. Total exercise time increased five minutes, reflecting a 50-watt increase in maximum workload. In addition, the patient experienced a 4.75-kg weight loss. A medically supervised endurance training program can increase aerobic work capacity and promote weight loss in patients with FA who can pedal a bicycle at training level intensities.
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PMID:Endurance exercise training in Friedreich ataxia. 280 61

Oxidative stress has been implicated in many diseases. The chief source of reactive oxygen species within the cell is the mitochondrion. We have characterized a variety of the biochemical and metabolic effects of inactivation of the mouse gene for the mitochondrial superoxide dismutase (CD1-Sod2(tm1Cje)). The Sod2 mutant mice exhibit a tissue-specific inhibition of the respiratory chain enzymes NADH-dehydrogenase (complex I) and succinate dehydrogenase (complex II), inactivation of the tricarboxylic acid cycle enzyme aconitase, development of a urine organic aciduria in conjunction with a partial defect in 3-hydroxy-3-methylglutaryl-CoA lyase, and accumulation of oxidative DNA damage. These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
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PMID:Mitochondrial disease in superoxide dismutase 2 mutant mice. 992 56

We showed recently that the yeast mitochondrial intermediate peptidase (YMIP polypeptide; gene symbol, OCT1) promotes mitochondrial iron uptake by catalyzing the maturation of iron-utilizing proteins and exacerbates the mitochondrial iron accumulation that results from loss of yeast frataxin, a mitochondrial protein required for mitochondrial iron efflux. This suggests that the human MIP (HMIP polypeptide; gene symbol MIPEP) may be one of the loci predicted to influence the clinical manifestations of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by lack of human frataxin. To begin to test this hypothesis, we have characterized HMIP at the functional and genomic levels. We show that HMIP can complement a yeast knock-out mutant lacking YMIP, demonstrating that HMIP and YMIP are functional homologues. The MIPEP gene spans 57 kb and consists of 19 exons that correlate with the functional domains of HMIP. Primer extension analysis has identified a major transcript of the MIPEP gene expressed differentially and predominantly in tissues with high oxygen consumption, while sequence analysis of approximately 2 kb of 5'-flanking DNA has revealed putative Mt1/3/4, NF-kappaB, and AP-1 elements that may regulate MIPEP expression in these tissues. Using a new polymorphic (CA)(n) repeat in intron 4, MIPEP has been genetically mapped within a 7-cM interval between markers D13S283 and D13S217 on 13q12. This work provides the basis for molecular analysis of MIPEP in FRDA and possibly other neurodegenerative diseases.
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PMID:Functional and genomic analysis of the human mitochondrial intermediate peptidase, a putative protein partner of frataxin. 1078 57

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.
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PMID:Glutathione, oxidative stress and neurodegeneration. 1093 Nov 72

The possible causes of abnormal iron metabolism in patients with Friedreich's ataxia are considered. Reduced expression of a frataxin homologue in yeast is associated with mitochondrial iron accumulation at the expense of cytosolic iron, and the same phenomenon can be demonstrated in these patients. A decrease in cytosolic iron causes the expression of a high-affinity iron-uptake protein, and therefore Friedreich's ataxia can be considered to be a disease of abnormal intracellular iron distribution. Friedreich's ataxia is of autosomal recessive inheritance, and the gene associated with it has been mapped to chromosome 9. This encodes the protein frataxin which regulates mitochondrial iron transport. The commonest mutation causing this disorder is an expanded GAA repeat in the gene for this protein. Different point mutations may account for some of the variations in the phenotypic features that are often found, and these variations are discussed. These findings have raised therapeutic possibilities in a condition for which previously there was no specific treatment. There are intracellular enzymes which are very sensitive to injury by oxygen-free radicals. Treatment has therefore been tried with ibebenone which acts as a free-radical scavenger, with some evidence of improvement. Iron chelating agents, such as deferoxamine, have also been given, but the finding of normal serum iron and ferritin casts doubt on the rationale of this. However the finding that the accumulation of iron in the mitochondria of the cells in patients with this form of ataxia will cause oxidative stress and cell death, gives hope for more effective treatment in the future, possibly with gene therapy.
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PMID:Friedreich's ataxia and iron metabolism. 1111 Oct 58

Increased generation of reactive oxygen species may underlie the pathophysiology of Friedreich ataxia (FRDA). The authors measured concentrations of 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage, in urine and of dihydroxybenzoic acid (DHBA), a marker of hydroxyl radical attack, in plasma of 33 patients with FRDA. They found a 2.6-fold increase in normalized urinary 8OH2'dG but no change in plasma DHBA as compared with controls. Oral treatment with 5 mg/kg/day of the antioxidant idebenone for 8 weeks significantly decreased urinary 8OH2'dG concentrations, indicating that 8OH2'dG may be useful in monitoring therapeutic interventions in patients with FRDA.-1721
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PMID:Oxidative stress in patients with Friedreich ataxia. 1111 10

Increasing lines of evidence suggest a key role for mitochondrial damage in neurodegenerative diseases. Brain aging, Parkinson's disease, Alzheimer's disease, Huntington's disease and Friedreich's ataxia have been associated with several mitochondrial alterations including impaired oxidative phosphorylation. Mitochondrial impairment can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in oxidative damage and programmed cell death. This paper reviews the mechanisms of N-acetylcysteine action at the cellular level, and the possible usefulness of this antioxidant for the treatment of age-associated neurodegenerative diseases. First, this thiol can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. Second, N-acetylcysteine can act by direct reaction between its reducing thiol group and reactive oxygen species. Third, it has been shown that N-acetylcysteine can prevent programmed cell death in cultured neuronal cells. And finally, N-acetylcysteine also increases mitochondrial complex I and IV specific activities both in vitro and in vivo in synaptic mitochondrial preparations from aged mice. In view of the above, and because of the ease of its administration and lack of toxicity in humans, the potential usefulness of N-acetylcysteine in the treatment of age-associated mitochondrial neurodegenerative diseases deserves investigation.
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PMID:Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases. 1133 49

Friedreich's ataxia is an autosomal recessive neuro-degenerative disorder involving both central and peripheral nervous system. Patients also show a systemic clinical picture presenting heart disease and diabetes mellitus or glucose intolerance. The disease is caused by mutations in the FRDA gene mapped on chromosome 9q13. The product of the gene is frataxin, an 18 kDa soluble mitochondrial protein with 210 amino acids. Crystal structure suggests a new, not previously reported, protein fold. The most frequent mutation is the expansion of a GAA trinucleotide repeat located within the first intron of the gene, and represents 98% of the mutations. Point mutations are described in compound heterozygous subjects with one expanded allele. A two-step model of GAA normal alleles towards premutation alleles, which might generate further full expanded mutations in the population with Indo-European ancestry, has been postulated. Clinical phenotype is variable and an inverse correlation with the GAA expansion size has been observed. Analysis of the GAA triplet is a strong molecular tool for clinical diagnosis, genetic counselling and prenatal diagnosis. Friedreich's ataxia patho-genesis is not solved yet. Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. Iron is accumulated in the mitochondrial matrix of both the yeast frataxin deficient mutant and the patient fibroblasts. It has been postulated that iron-induced oxygen radical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology. A second hypothesis postulates a direct role of frataxin in the mitochondrial energy activation and oxidative phosphorylation. Iron chelator drugs and antioxidant drugs have been postulated for Friedreich's treatment. No results from clinical trials are available yet, but idebenone, a short-chain quinone, seems to reduce the size of hypertrophic cardiomyopathy and levels of oxidative stress molecules in patients.
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PMID:Friedreich's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review). 1135 Dec 69

Friedreich's ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P-MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease-modifying strategy in this neurodegenerative disorder.
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PMID:Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia. 1135 49


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