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's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.
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PMID:Crystal structure of human frataxin. 1090 Jan 92

Expanded GAA.TTC trinucleotide repeats in intron 1 of the frataxin gene cause Friedreich's ataxia (FRDA) by reducing frataxin mRNA levels. Insufficient frataxin, a nuclear encoded mitochondrial protein, leads to the progressive neurodegeneration and cardiomyopathy characteristic of FRDA. Previously we demonstrated that long GAA.TTC tracts impede transcription elongation in vitro and provided evidence that the impediment results from an intramolecular purine.purine.pyrimidine DNA triplex formed behind an advancing RNA polymerase. Our model predicts that inhibiting formation of this triplex during transcription will increase successful elongation through GAA.TTC tracts. Here we show that this is the case. Oligodeoxyribonucleotides designed to block particular types of triplex formation provide specific and concentration-dependent increases in full-length transcript. In principle, therapeutic agents that selectively interfere with triplex formation could alleviate the frataxin transcript insufficiency caused by pathogenic FRDA alleles.
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PMID:Alleviating transcript insufficiency caused by Friedreich's ataxia triplet repeats. 1112 84

A 4 year old boy underwent cardiac transplantation because of cardiomyopathy with ischaemia. Following transplantation he developed neurological signs of Friedreich's ataxia and the diagnosis was confirmed with genetic testing. Cardiomyopathy is a rare presentation of Friedreich's ataxia and to our knowledge this is the first reported transplant operation for the cardiomyopathy associated with this condition.
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PMID:Friedreich's ataxia presenting after cardiac transplantation. 1115 98

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.
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PMID:Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. 1117 86

Mitochondria are the principal site of generation of energy in form of adenosine triphosphate (ATP). They contain the enzymes of the Krebs and fatty acid cycles and the respiratory pathway. Ocular tissues with high energy consumption and dependence on oxidative energy production like the optic nerve, the retina, and the pigment epithelium are often involved in mitochondrial diseases. This article reviews the genetic mitochondrial diseases involving the visual system. Their most important ocular findings include: acute or slowly progressive bilateral visual loss and visual field loss due to an optic neuropathy or retinal degeneration, bilateral progressive decreased ocular motility, and bilateral upper lid ptosis. The following diseases are discussed: Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrom (KSS); Chronic Progressive External Ophthalmoplegia (CPEO); Autosomal Recessive Cardiomyopathy, Ophthalmoplegia (ARCO); Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Episodes (MELAS); Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Mitochondrial Neuropathy, Gastro-Intestinal Encephalomyopathy (MNGIE); Myoclonus Epilepsy, Ragged-Red-Fibers (MERRF); Wilson's disease; Friedreich's ataxia. Diagnosis of mitochondrial encephalomyopathies is established by screening for mutations in blood or muscle biopsy samples. No specific therapies which influence the course of mitochondrial encephalomyopathies are known. Drugs interacting with the mitochondria function, alcohol consumption and smoking should be avoided.
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PMID:[Eye diseases in mitochondrial encephalomyopathies]. 1121 87

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 ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.
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PMID:Idebenone in patients with Friedreich ataxia. 1140 22

Currently, echocardiography is the technique of choice in the noninvasive assessment of left ventricular (LV) function. Unlike the assessment of LV systolic function, its role is limited in the quantification of LV diastolic function where only global LV filling can be assessed. Tissue Doppler echocardiography (TDE) is a recently introduced imaging technique which allows for direct assessment of LV myocardial contraction and relaxation. Therefore, parameters derived from TDE showed provide a more accurate assessment of LV systolic and diastolic function. Doppler myocardial velocity gradient (MVG) is a new parameter derived from TDE, which enables the measurement of the spatial distribution of transmyocardial velocities over the cardiac cycle. The most studied application of this technique relates to the earlier and more sensitive diagnosis of different forms of cardiomyopathy. Based on the Doppler MVG measurement, patients with ischaemic cardiomyopathy can be differentiated from those with idiopathic dilated cardiomyopathy. In both diseases MVG is reduced in systole, but as opposed to dilated cardiomyopathy, MVG in patients with ischaemic cardiomyopathy is also markedly reduced in early diastole. MVG derived from TDE also provides new diagnostic insights into genetically determined heart muscle diseases. It has been shown that an early diastolic MVG < or = 7 s-1 is characteristic for patients with hypertrophic cardiomyopathy and differentiates this group of patients from 'athletes' heart, independently of the degree of LV hypertrophy. A recent study has also shown that in Friedreich ataxia related cardiomyopathy there is a close relation between the degree of genotype abnormalities and the degree of reduction in the MVG. Also, the assessment of Doppler MVG enables the differentiation of restrictive cardiomyopathy from constrictive pericarditis. Based on available literature it appears that TDE derived MVG enhances the information available from conventional echocardiography and helps to establish an earlier diagnosis in patients with primary and secondary myocardial diseases.
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PMID:[Doppler myocardial velocity gradient as a new diagnostic index for the assessment of myocardial disease]. 1157 38

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.
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PMID:Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy. 1171 73


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