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)

A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.
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PMID:Mitochondria, NO and neurodegeneration. 1098 56

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I-III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.
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PMID:Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone. 1128 79

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

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.
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PMID:Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives. 1206 11

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

Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.
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PMID:Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy. 1469 32

Friedreich's ataxia is one of the most frequent ataxias of childhood. The disease is inherited in autosomal recessive mode. It is caused by deficiency of mitochondrial protein frataxin, which is responsible for the degenerative impairment of the spinocerebellar and corticospinal tracts and posterior columns of the spinal cord and for the heart damage. We present a case report of a patient with a complete clinical syndrome. Patient experienced slowly progressive neurological symptomatology from the age of 6 years, which consisted of instability, gait abnormalities, tremor and ataxia. Adult patient became immobile with severe quadruparesis and dysarthria. Cardiac involvement presented in adulthood with multifocal atrial tachycardia became the chief symptom. Hypertrophic cardiomyopathy was diagnosed. Diagnosis of Friedreich's ataxia was confirmed by genetic analysis. Pharmacotherapy with coenzyme Q10 and carnitine was introduced with effort to slow down progression of cardiac impairment. Causal treatment is still impossible.
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PMID:[Cardiac manifestations of Friedreich's ataxia]. 1506 Nov 20

Friedreich's ataxia is caused by a pronounced lack of frataxin, a mitochondrial protein of not fully understood function. Lack of frataxin homologues in yeast and mice leads to increased sensitivity to oxidative stress, depletion of proteins with iron-sulfur clusters like respiratory chain complexes I-III and aconitase, and to iron accumulation in mitochondria. Similar effects have been demonstrated in human disease with increased markers of oxidative DNA damage in urine and impaired oxidative phosphorylation in in vivo exercise studies using 31 Phosphorus magnetic resonance spectroscopy (31P-MRS). Therapeutical trials mainly focus on antioxidative treatment with coenzyme Q10 or its short-chain variant idebenone. Promising effects on cardiac hypertrophy in uncontrolled preliminary studies contrast with minor effects in controlled trials and no effect of antioxidants on neurological deficits has been established. Preliminary encouraging 31P-MRS data exist for the treatment with L-carnitine but not with creatine. However, all these interventions may take effect too late in the pathogenic process. Alternative strategies aiming at an enhancement of frataxin by stem cell transplantation, gene transfer or frataxin supplementation are desirable. Additionally, more efficient biomarkers are needed to monitor treatment effects.
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PMID:Therapeutic strategies in Friedreich's ataxia. 1535 99

Heart involvement in patients with Friedreich ataxia (FRDA) is a condition marked by inevitable progressive deterioration, with premature death. There is currently no specific treatment for FRDA. Recently, a therapy with idebenone, a short-chain coenzyme Q10 analogue, was reported to reduce left ventricular mass by 20% in about half of FRDA patients, but a double-blind placebo-controlled study did not fully confirm these results. In this case report, we present a 5-year follow-up of symmetrical concentric hypertrophic cardiomyopathy (HCM) in an FRDA patient treated with high-dose propranolol. The therapy resulted in a reduction in the thickness of the septal and posterior left ventricular walls and complete normalization of diffuse electrocardiographic repolarization abnormalities. To the best of our knowledge, this is the first such case to be reported in the literature, demonstrating the positive effects of high-dose beta-blocker treatment on heart involvement in patients with FRDA.
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PMID:High-dose beta-blocker hypertrophic cardiomyopathy therapy in a patient with Friedreich ataxia. 1623 5

Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.
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PMID:Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. 1636 37


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