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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 (FA) is one of the genetic syndromes sometimes associated with diabetes and the most common hereditary ataxia. It is a autosomal recessive neurodegenerative disease, caused by a mutation in the FRDA gene, which originates decreased expression of frataxin, a mitochondrial protein involved in iron metabolism. The disorder is usually manifest in childhood and is characterised by ataxia, dysarthria, scoliosis and feet deformity. About two thirds of patients have hypertrophic cardiomyopathy, 10% have diabetes and 20% have another glucose homeostasis disorder. Both insulin resistance and beta-cell dysfunction are implicated in this patients' diabetes pathophysiology. The mean half-life is 35 years. Cause of death is usually related to cardiomyopathy or diabetes' complications. We report the case study of two twin sisters with 28 years old, in whom FA was diagnosed in the first decade, both of them with diabetes since their early twenties. A third sister with FA is reported, with no glucose homeostasis disorder. They also have two healthy male brothers. Based in this cases, the FA associated diabetes pathophysiology is discussed, concerning the therapeutic approach to these patients and to their diabetic relatives without neurologic symptoms. The role of molecular genetic testing and genetic counselling are also debated.
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PMID:[Friedreich ataxia and diabetes mellitus--family study]. 1668 89

Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMT1), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7+/-19.3 mg/100 g dry weight) was not significantly higher than normal (31.3+/-24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230+/-172 microg/g wet weight) were not significantly elevated above normal (148+/-86 microg/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis.
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PMID:Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. 1713 88

Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Mouse models have been important tools in dissecting the steps of pathogenesis in FRDA. Furthermore, animal models that reproduce some of the key events in a pathology are essential for the development of effective therapies, both pharmacological and gene therapy approaches. This chapter presents an overview of the current mouse models that have been developed for FRDA.
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PMID:Conditional mouse models for Friedreich ataxia, a neurodegenerative disorder associating cardiomyopathy. 1720 63

Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membrane-permeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with age-matched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s(-1) (+/- 1.6 s(-1)) to 15.7 s(-1) (+/- 0.7 s(-1); P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r = 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neuropathy and ataxic gait in the youngest patients. To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and hematologic disorders.
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PMID:Selective iron chelation in Friedreich ataxia: biologic and clinical implications. 1737 41

Cardiomyopathy is an important and frequently life limiting manifestation of Friedreich's ataxia (FA), the most prevalent form of autosomal recessive ataxia. Left ventricular mass is used as primary outcome measure in recent intervention studies but systematic analyses of FA cardiomyopathy are sparse. To assess cardiac hypertrophy by cardiac magnetic resonance imaging (MRI) in vivo, we assessed 41 adult patients with genetically confirmed FA and 33 age- and sex-matched healthy controls by cardiac MRI and echocardiogarphy. Septal hypertrophy and left ventricular mass index were determined by two independent raters. MRI revealed hypertrophy of the interventricular septum in 40% and increased left ventricular mass index in 29% of patients. Interobserver variability was less than 5% for both measures. GAA repeat length had only minor influence on interventricular septum thickness. Left ventricular mass index decreased with age. Severity of ataxia did not correlate with cardiac disease. In echocardiography wall diameter was assessable only in 31 of 41 FA patients with 32% of patients presenting septal hypertrophy and 6% increased left ventricular mass index. We conclude that cardiac hypertrophy is present only in a minority of adult FA patients. If despite this limitation intervention studies use left ventricular mass as outcome measure, MRI is recommended as the most accurate assessment of cardiac anatomy in vivo.
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PMID:Cardiomyopathy in Friedreich's ataxia-assessment by cardiac MRI. 1754 70

Friedreich's ataxia is the most common hereditary neurodegenerative disorder, and more than half of all patients show echocardiographic evidence of cardiomyopathy. Although angina has been reported in these patients, the role of coronary artery disease has previously been dismissed and is therefore underestimated. Premature obstructive coronary disease has rarely been angiographically demonstrated in patients with Friedreich's ataxia. We present an unusual case of a 35-year-old woman with Friedreich's ataxia who presented with intermittent chest pressure associated with dyspnea and diaphoresis. Cardiac catheterization revealed a chronically occluded left circumflex coronary artery and a high-grade stenosis of the left anterior descending coronary artery. A Cypher stent, placed within the left anterior descending artery, left no residual stenosis. This case illustrates the importance of fully investigating anginal symptoms in patients with Friedreich's ataxia, because coronary artery disease is likely underdiagnosed in this population. Early diagnosis may permit aggressive management and may delay the progression to end-stage cardiomyopathy.
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PMID:Friedreich's ataxia as a cause of premature coronary artery disease. 1817 44

Expansion of an unstable GAA.TTC repeat in the first intron of the FXN gene causes Friedreich ataxia by reducing frataxin expression. Deficiency of frataxin, an essential mitochondrial protein, leads to progressive neurodegeneration and cardiomyopathy. The degree of frataxin reduction correlates with GAA.TTC tract length, but the mechanism of reduction remains controversial. Here we show that transcription causes extensive RNA.DNA hybrid formation on GAA.TTC templates in bacteria as well as in defined transcription reactions using T7 RNA polymerase in vitro. RNA.DNA hybrids can also form to a lesser extent on smaller, so-called 'pre-mutation' size GAA.TTC repeats, that do not cause disease, but are prone to expansion. During in vitro transcription of longer repeats, T7 RNA polymerase arrests in the promoter distal end of the GAA.TTC tract and an extensive RNA.DNA hybrid is tightly linked to this arrest. RNA.DNA hybrid formation appears to be an intrinsic property of transcription through long GAA.TTC tracts. RNA.DNA hybrids have a potential role in GAA.TTC tract instability and in the mechanism underlying reduced frataxin mRNA levels in Friedreich Ataxia.
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PMID:A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. 1769 31

This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While antioxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA.TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts, as well as the molecular basis for gene silencing in FRDA.
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PMID:Small molecules affecting transcription in Friedreich ataxia. 1782 40

Many antioxidants have been suggested as potential treatments for Friedreich ataxia, but have not been tested in clinical trials. We found that a majority of patients in our cohort already use such antioxidants, including idebenone, which is not available at a pharmaceutical grade in the United States. Younger age, cardiomyopathy and shorter GAA repeat length were independent predictors of idebenone use, but no factors predicted use of other antioxidants. This confirms that non-prescription antioxidant use represents a major confounder to formal trials of existing and novel agents for Friedreich ataxia.
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PMID:Antioxidant use in Friedreich ataxia. 1798 88

A frequent cause of death in Friedreich's ataxia patients is cardiomyopathy, but the molecular alterations underlying this condition are unknown. We performed 2-DE to characterize the changes in protein expression of hearts using the muscle creatine kinase frataxin conditional knockout (KO) mouse. Pronounced changes in protein expression profile were observed in 9 week-old KO mice with severe cardiomyopathy. In contrast, only several proteins showed altered expression in asymptomatic 4 week-old KO mice. In hearts from frataxin KO mice, components of the iron-dependent complex-I and -II of the mitochondrial electron transport chain and enzymes involved in ATP homeostasis (creatine kinase, adenylate kinase) displayed decreased expression. Interestingly, the KO hearts exhibited increased expression of enzymes involved in the citric acid cycle, catabolism of branched-chain amino acids, ketone body utilization and pyruvate decarboxylation. This constitutes evidence of metabolic compensation due to decreased expression of electron transport proteins. There was also pronounced up-regulation of proteins involved in stress protection, such as a variety of chaperones, as well as altered expression of proteins involved in cellular structure, motility and general metabolism. This is the first report of the molecular changes at the protein level which could be involved in the cardiomyopathy of the frataxin KO mouse.
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PMID:Proteomic analysis of hearts from frataxin knockout mice: marked rearrangement of energy metabolism, a response to cellular stress and altered expression of proteins involved in cell structure, motility and metabolism. 1834 Jun 35


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