ubiquinone and Friedreich-Ataxia

Friedreich's Ataxia is an autosomal recessive genetic disease causing the defective gene product, frataxin. A body of literature has been focused on the attempts to counteract frataxin deficiency and the consequent iron imbalance, in order to mitigate the disease-associated pro-oxidant state and clinical course. The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane. A body of evidence points to the strong antioxidant properties of these cofactors, and to their potential contribution in mitoprotective strategies in Friedreich's Ataxia clinical evolution. Thus, we suggest the rationale for planning combination strategies based on the 3 mitochondrial cofactors and of some antioxidants and iron binders as mitoprotective cocktails in Friedreich Ataxia patients, calling attention to clinical practitioners of the importance to implement clinical trials.

Topics: Animals; Antioxidants; Carnitine; Deferiprone; Friedreich Ataxia; Humans; Iron Chelating Agents; Linoleic Acids; Mitochondria; Ubiquinone

Topics: Antioxidants; Clinical Trials as Topic; Friedreich Ataxia; Humans; Optic Atrophy, Hereditary, Leber; Ubiquinone

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012.. To assess the effects of pharmacological treatments for Friedreich ataxia.. On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies.. We considered randomised controlled trials (RCTs) or quasi-RCTs of pharmacological treatments (including vitamins) in people with genetically-confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months.. Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane.. We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high-dose versus low-dose coenzyme Q10 and vitamin E (the trialists considered the low-dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion.In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co-operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant-treated and the placebo groups (mean difference 0.79 points, 95% confidence interval -1.97 to 3.55 points; low-quality evidence).The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End-diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low.There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year-long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis.. Low-quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low-quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low-quality evidence, serious and non-serious adverse events were rare in both antioxidant and placebo groups. No non-antioxidant agents have been investigated in RCTs of 12 months' duration.

Topics: Antioxidants; Friedreich Ataxia; Heart; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography; Vitamin E

Friedreich's ataxia (FA) is associated with progressive cardiac hypertrophy resulting from a genetic abnormality in the frataxin gene. Cardiac involvement is the most common cause of death (59%) in FA patients. Cardiac related death occurs at a significantly younger age than non-cardiac related death. Idebenone is a short-chain quinone analogue with a potent free-radical scavenger action. This drug has the potential to preserve and even improve mitochondrial function.Studies on Idebenone treatment showed rather conflicting results on FA cardiomyopathy. The present article reviews the clinical features of FA cardiomyopathy, imaging techniques used to diagnose, follow and monitor therapy which aimed to revert FA cardiomyopathy.

Topics: Friedreich Ataxia; Heart; Heart Function Tests; Humans; Ubiquinone

Friedreich's ataxia is a debilitating progressive neurodegenerative disease associated with cardiomyopathy and other features. The underlying cause is a deficiency of the mitochondrial protein frataxin which causes mitochondrial iron deposition, increased oxidative stress and impaired adenosine triphosphate production. Over the last 15 years, multiple clinical trials have assessed the efficacy of antioxidant agents in this disease. This article reviews trials of the two most important agents, namely co-enzyme Q10 and idebenone.

Topics: Antioxidants; Friedreich Ataxia; Humans; Ubiquinone

Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

Topics: Adrenal Cortex Hormones; Ataxia; Cerebellar Ataxia; Chronic Disease; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondrial Diseases; Muscle Weakness; Ubiquinone; Vitamin E; Vitamin E Deficiency

Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis and pes cavus. Heart abnormalities cause premature death in 60% to 80% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the first update of a review published in 2009.. To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia.. We searched The Cochrane Neuromuscular Disease Group Specialized Register (11 July 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), AMED (January 1985 to July 2011), CINAHL Plus (January 1937 to July 2011), LILACS (January 1982 to July 2011), ORPHANET (1990 to July 2011), TRIP (1998 to July 2011) and PEDRO (October 1999 to July 2011).. Randomised controlled trials (RCTs) or quasi-RCTs of drug treatment in people with genetically confirmed Friedreich ataxia. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. We excluded trials of shorter duration than 12 months.. Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. We planned to collect adverse event data from included studies.. More than 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants, using the synthetic antioxidant idebenone 5 mg/kg, fulfilled the selection criteria for this review. Other RCTs were of insufficient duration. We identified no additional RCT when the searches were updated in 2011. In the included study, the primary outcome specified for this review, change in ICARS scale, did not reveal any significant differences with idebenone treatment compared to placebo. The secondary outcome of change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not assessed. The second secondary outcome, change in left ventricular mass as measured by echocardiography, did improve significantly; there was a 10.7% worsening after 12 months of treatment in the placebo group and a 5.6% improvement in the idebenone group. The mean difference was 16.37% (95% CI 95% 2% to 31%). There were no adverse events. We considered the included study at low risk of bias in five of the seven domains assessed. A larger trial using idebenone published an interm report in May 2010 stating that the study had failed to reach its primary endpoint, which was change in the ICARS scale.. No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but the clinical relevance of this change was not assessed in the included study.

Topics: Antioxidants; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Rare Diseases; Ubiquinone; Ultrasonography

Idebenone is a synthetic short chain benzoquinone that acts as an electron carrier in the mitochondrial electron transport chain, thereby, facilitating the production of ATP. In addition, idebenone is an antioxidant and can inhibit lipid peroxidation and may protect cell membranes and mitochondria from oxidative damage. High dose idebenone (Catena(®)) is approved in Canada for the symptomatic treatment of Friedreich's ataxia and is currently under clinical investigation for use in a number of mitochondrial and neuromuscular diseases.. This review summarizes the pharmacology, pharmacokinetic and clinical efficacy/safety data of idebenone and its metabolites and provides an update of the clinical trials completed and in progress.. Following oral administration, idebenone is rapidly metabolized via oxidative shortening by a number CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) to yield QS10, QS8, QS6 and QS4. Idebenone and these metabolites concomitantly undergo conjugation via glucuronidation and sulfatation to yield conjugated moieties represented as idebenone-C, QS10-C, QS8-C, QS6-C and QS4-C. Previous reports in the literature were only able to quantify plasma concentrations of idebenone measured together with its conjugates. More recently, highly sensitive and specific liquid chromatography method with tandem mass spectrometric methods have been developed, allowing the quantification of the parent molecule idebenone and its main metabolite QS10, separately.. After absorption, idebenone is rapidly metabolized by first pass metabolism and shows dose-proportional pharmacokinetics in healthy subjects in daily doses up to 2250 mg. The recent development of advanced analytical techniques allows the detection of idebenone and unconjugated metabolites in plasma and consequently opens the possibility for evaluation of pharmacokinetic/pharmacodynamic relationships which will be helpful to further understand the metabolism and therapeutic potential of idebenone. In clinical studies, idebenone was safe and well tolerated at doses up to 2250 mg/day.

Topics: Administration, Oral; Animals; Antioxidants; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Friedreich Ataxia; Humans; Tandem Mass Spectrometry; Ubiquinone

This paper reviews the history and pre-clinical development of idebenone and summarises the results of clinical studies, published from 1999 to 2008, on the use of idebenone in the treatment of patients with Friedreich ataxia (FRDA). As a benzoquinone that can undergo reversible redox reactions, idebenone influences the electron balance in mitochondria. In vitro studies have shown that it acts both as an anti-oxidant, preventing damage to the mitochondrial membrane, and, more importantly, as an electron carrier, supporting mitochondrial function and adenosine triphosphate (ATP) production. In clinical studies, idebenone has been well tolerated by patients with various pathological conditions. The most common adverse events have been gastrointestinal effects of mild to moderate severity. No neurotoxic or adverse cardiac reactions have been reported in pre-clinical or clinical studies. The good safety profile of idebenone is supported by large clinical trials in Alzheimer's disease and by post-marketing surveillance. Phase 1 studies demonstrated the safety and tolerability of idebenone at relatively high doses (up to 60 mg/kg/day). Results from 11 clinical studies (randomised, controlled, and open-label trials), involving a total of about 200 patients, provide evidence of improvement in both cardiac hypertrophy and neurological symptoms among patients with FRDA treated with idebenone.

Topics: Animals; Antioxidants; Cardiomyopathy, Hypertrophic; Friedreich Ataxia; Humans; Nervous System Diseases; Ubiquinone

Several reports in the literature describe the effects of low-dose (5 mg/kg/day) idebenone in significantly reducing cardiac hypertrophy in patients with Friedreich ataxia. However, the effects of idebenone on neurological function have not been reliably determined in these studies; when neurological parameters were reported, results were often inconclusive, usually because of subject heterogeneity and lack of adequate statistical power. In two of these studies, some patients showed beneficial effects of idebenone on their cardiomyopathy only when the dose was increased, prompting the systematic investigation of higher doses of idebenone. Following a phase 1 dose escalation study, a phase 2 tolerability and efficacy trial with low, intermediate, and high doses of idebenone was conducted. The results suggested that treatment with intermediate- and high-dose idebenone had beneficial effects on neurological symptoms. On the basis of these results, two phase 3 trials have been initiated, one in the United States with young ambulatory patients and one in Europe without limits on age and disease severity.

Topics: Antioxidants; Cardiomyopathies; Clinical Protocols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Friedreich Ataxia; Humans; Nervous System Diseases; Ubiquinone

Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction.

Topics: Animals; Antioxidants; Deferiprone; Enzyme Inhibitors; Erythropoietin; Friedreich Ataxia; Histone Deacetylase Inhibitors; Humans; Iron Chelating Agents; Organophosphorus Compounds; Pyridones; Recombinant Proteins; Ubiquinone

Friedreich ataxia is a rare inherited, autosomal recessive, neurological disorder characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, pes cavus and heart abnormalities which may cause premature death in 60 to 80% of people. There is no easily defined clinical or biochemical marker and no known treatment.. To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia.. We searched The Cochrane Neuromuscular Disease Group Trials Specialized Register (17 December 2008), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2008) MEDLINE (January 1950 to December 2008), EMBASE (January 1980 to December 2008) and other sources.. All randomised controlled trials (RCTs) or quasi-randomised trials which examined drug treatment in people with genetically confirmed Friedreich ataxia were examined. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography.. Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria.. Over 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants using the synthetic antioxidant, idebenone 5 mg/kg, fulfilled the selection criteria for this review. Another RCT was of insufficient duration and the other studies were open clinical trials. In the included study, the primary outcome, change in ICARS scale, did not reveal any significant differences with idebenone treatment. The secondary outcome, change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not carried out. The second secondary outcome, change in left ventricular mass, as measured by echocardiography, did improve significantly (P = 0.007). There were no adverse events. A larger RCT using idebenone is in progress, of which the primary outcome is change in the ICARS scale. However, the results are not yet available.. No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but no research on clinical relevance of this change has been done.

Topics: Antioxidants; Friedreich Ataxia; Humans; Ubiquinone

Friedreich's ataxia is an autosomal recessive neurodegenerative disease where impaired mitochondrial function and excessive production of free radicals play a central pathogenetic role. Idebenone, a synthetic analogue of coenzyme Q, is a powerful antioxidant that was first administrated to Friedreich's ataxia patients less than 10 years ago.. The aim of this study was to evaluate the efficacy of idebenone administration and define the optimal dosage.. A critical evaluation of all open and double-blinded idebenone trials in Friedreich's ataxia patients was undertaken.. Idebenone is well tolerated in paediatric and adult patients. Most trials demonstrated a positive effect on cardiac hypertrophy. The neurological function is in general not modified in adult patients, but a dose-dependent effect was demonstrated in young Friedreich's ataxia patients. Further double-blinded high-dose trials should evaluate idebenone in Friedreich's ataxia early in the disease course.

Topics: Antioxidants; Clinical Trials as Topic; Dose-Response Relationship, Drug; Friedreich Ataxia; Humans; Magnetic Resonance Angiography; Ubiquinone

Since the identification of the genetic mutation causing Friedreich's ataxia (FRDA) our understanding of the mechanisms underlying disease pathogenesis have improved markedly. The genetic abnormality results in the deficiency of frataxin, a protein targeted to the mitochondrion. There is extensive evidence that mitochondrial respiratory chain dysfunction, oxidative damage and iron accumulation play significant roles in the disease mechanism. There remains considerable debate as to the normal function of frataxin, but it is likely to be involved in mitochondrial iron handling, antioxidant regulation, and/or iron sulphur centre regulation. Therapeutic avenues for patients with FRDA are beginning to be explored in particular targeting antioxidant protection, enhancement of mitochondrial oxidative phosphorylation, iron chelation and more recently increasing FRDA transcription. The use of quinone therapy has been the most extensively studied to date with clear benefits demonstrated using evaluations of both disease biomarkers and clinical symptoms, and this is the topic that will be covered in this review.

Topics: Animals; Ataxia; Benzoquinones; Coenzymes; Disease Models, Animal; Friedreich Ataxia; Humans; Iron; Mutation; Neurodegenerative Diseases; Oxidative Stress; Oxygen; Quinones; Time Factors; Ubiquinone; Vitamin E

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Antiparkinson Agents; Apoptosis; Clinical Trials as Topic; Friedreich Ataxia; Hepatitis C; Humans; Mitochondria; Myocardial Reperfusion Injury; Neuroprotective Agents; Organophosphorus Compounds; Oxidative Stress; Parkinson Disease; Ubiquinone

Coenzyme Q10 is administered for an ever-widening range of disorders, therefore it is timely to illustrate the latest findings with special emphasis on areas in which this therapeutic approach is completely new. These findings also give further insight into the biochemical mechanisms underlying clinical involvement of coenzyme Q10.. Cardiovascular properties of coenzyme Q10 have been further addressed, namely regarding myocardial protection during cardiac surgery, end-stage heart failure, pediatric cardiomyopathy and in cardiopulmonary resuscitation. The vascular aspects of coenzyme Q10 addressing the important field of endothelial function are briefly examined. The controversial issue of the statin/coenzyme Q10 relationship has been investigated in preliminary studies in which the two substances were administered simultaneously. Work on different neurological diseases, involving mitochondrial dysfunction and oxidative stress, highlights some of the neuroprotective mechanisms of coenzyme Q10. A 4-year follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10 and vitamin E showed a substantial improvement in cardiac and skeletal muscle bioenergetics and heart function. Mitochondrial dysfunction likely plays a role in the pathophysiology of migraine as well as age-related macular degeneration and a therapy including coenzyme Q10 produced significant improvement. Finally, the effect of coenzyme Q10 was evaluated in the treatment of asthenozoospermia.. The latest findings highlight the beneficial role of coenzyme Q10 as coadjuvant in the treatment of syndromes, characterized by impaired mitochondrial bioenergetics and increased oxidative stress, which have a high social impact. Besides their clinical significance, these data give further insight into the biochemical mechanisms of coenzyme Q10 activity.

Topics: Antioxidants; Cardiovascular Diseases; Coenzymes; Friedreich Ataxia; Humans; Macular Degeneration; Migraine Disorders; Mitochondria; Oxidative Stress; Ubiquinone

Topics: Amyotrophic Lateral Sclerosis; Child; Clinical Trials as Topic; Coenzymes; Friedreich Ataxia; Heart Arrest; Humans; Huntington Disease; Mitochondrial Diseases; Nervous System Diseases; Parkinson Disease; Ubiquinone

Coenzyme Q10 (Q10) is available as an over-the-counter dietary supplement in the United States. While its use could be considered a form of alternative therapy, the medical profession has embraced the use of Q10 in specific disease states, including a series of neurologic and muscular diseases. Clinical laboratory monitoring is available for measurement of total Q10 in plasma and tissue and for measurement of redox status, ie, the ratio of reduced and oxidized forms of Q10. Many published studies have been anecdotal, in part owing to the rarity of some diseases involved. Unfortunately, many studies do not report Q10 levels, and, thus, the relationship of clinical response to Q10 concentration in plasma frequently is not discernible. Consistent laboratory monitoring of patients treated with this compound would help ease interpretation of the results of the treatment, especially because so many formulations of Q10 exist in the marketplace, each with its own bioavailability characteristics. Q10 has an enviable safety profile and, thus, is ideal to study as an adjunct to more conventional therapy. Defining patient subpopulations and characteristics that predict benefit from exogenous Q10 and defining therapeutic ranges for those particular applications are major challenges in this field.

Topics: Coenzymes; Epilepsies, Myoclonic; Friedreich Ataxia; Humans; Huntington Disease; Kearns-Sayre Syndrome; Mitochondrial Encephalomyopathies; Muscular Diseases; Nervous System Diseases; Parkinson Disease; Ubiquinone

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.

Topics: Antioxidants; Coenzymes; Electron Transport; Frataxin; Friedreich Ataxia; Humans; Iron; Iron Chelating Agents; Iron-Binding Proteins; Mitochondria; Oxidative Stress; Ubiquinone

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease causing limb and gait ataxia and cardiomyopathy. The disease gene encodes a mitochondrial protein of unknown function, frataxin. The loss of functional frataxin is caused by a large GAA trinucleotide expansion in the first intron of the gene, thus impairing gene transcription. The lack of frataxin appears to result primarily in disabled recruitment of early antioxidant defenses, resulting in oxidative insult to the highly sensitive iron-sulfur proteins aconitase and three mitochondrial respiratory chain complexes (I-III). Accordingly, antioxidant-based therapy appears promising in counteracting the course of the disease.

Topics: Animals; Antioxidants; Benzoquinones; Carrier Proteins; Frataxin; Friedreich Ataxia; Humans; Iron; Iron-Binding Proteins; Mice; Ubiquinone

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.

Topics: Antioxidants; Carrier Proteins; Coenzymes; Cytoprotection; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Stress; Point Mutation; Trinucleotide Repeats; Ubiquinone; Vitamin E

Topics: Alzheimer Disease; Animals; Antioxidants; Benzoquinones; Cerebrovascular Disorders; Friedreich Ataxia; Humans; Liver Diseases; Ubiquinone

Topics: Aconitate Hydratase; Antioxidants; Benzoquinones; Frataxin; Friedreich Ataxia; Humans; Iron; Iron-Binding Proteins; Mitochondria; Phosphotransferases (Alcohol Group Acceptor); Ubiquinone

Friedreich's ataxia is the most common inherited ataxia, and pathogenesis is known to involve mitochondrial oxidative stress. Idebenone is a potent antioxidant which has already been evaluated in several clinical trials in FRDA, with reports of symptomatic benefit but inconclusive objective results. Following patient consultation on design, we have completed a treatment-withdrawal study to establish whether patients could correctly determine their treatment allocation to placebo or idebenone. Our aim was to capture subjective experiences of symptoms such as fatigue, which can be difficult to measure with questionnaires or semi-quantitative scales, particularly in chronic, slowly progressive conditions.. Patients taking idebenone for at least 12 months as part of the open-label MICONOS Extension Study were randomized to receive either placebo or idebenone continuation for 2-month treatment cycles. The primary endpoint was patient assessment of treatment assignment.. A total of 29 patients were randomized, forming the idebenone group (n = 16) and the placebo group (n = 13). No significant differences were detected between the idebenone and placebo groups on assessment of treatment assignment or early study withdrawal. A small but significant difference in ataxia rating scale scores was detected between treatment groups when considering ambulatory patients only.. This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2-month period. We hope that this study design will help inform future trials so that patients' experiences of symptoms are more reliably measured.

Topics: Adult; Antioxidants; Double-Blind Method; Female; Friedreich Ataxia; Humans; Male; Patient Reported Outcome Measures; Ubiquinone

To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism.. We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale.. EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p < 0.001).

Topics: Adult; Central Nervous System Agents; Double-Blind Method; Female; Friedreich Ataxia; Humans; Male; Severity of Illness Index; Ubiquinone; Visual Acuity

Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression. The authors present their experience of 5 Friedreich ataxia patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The patients were monitored for laboratory parameters, cardiac assessment, neurological evaluations, and quality of life. The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.

Topics: Adolescent; Adult; Antioxidants; Deferiprone; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Friedreich Ataxia; Humans; Iron Chelating Agents; Male; Pyridones; Quality of Life; Treatment Outcome; Ubiquinone; Young Adult

The objective of the study was to test the efficacy, safety and tolerability of triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia (FRDA) patients in a clinical pilot study.. Patients included in this study were 10 males and three females, 14-61 years of age (average 30.2 ± 12.1), diagnosed with FRDA with normal ventricular function. Patients were treated with triple therapy with deferiprone at 5-25 mg/kg/day, idebenone at 10-20 mg/kg/day and riboflavin at 10-15 mg/kg/day for 15-45 months. The efficacy of this triple therapy was assessed by change from baseline on the scale for the assessment and rating of ataxia (SARA) and by the change from baseline in echocardiogram parameters.. Four patients discontinued due to adverse events (AEs) related with deferiprone. The annual worsening rate (AWR) was estimated in this series as 0.96 (CI 95%: 0.462-1.608) SARA score, whereas AWR for our FRDA cohort was estimated as 2.05 ± 1.23 SARA score. LVMI only decreased by 6.5 g/m(2) (6.2%) at the end of the first year of therapy. LVEF remained stable, except in case of three patients.. Our results seem to indicate some uncertain benefit on the neurological and heart functions of this triple therapy in FRDA.

Topics: Adolescent; Adult; Deferiprone; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Pilot Projects; Pyridones; Riboflavin; Severity of Illness Index; Treatment Outcome; Ubiquinone; Ultrasonography; Ventricular Dysfunction, Left; Young Adult

Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 μg darbepoetin alfa every 2 or 3 weeks, 10-20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.

Topics: Adolescent; Adult; Antioxidants; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Friedreich Ataxia; Hematinics; Humans; Male; Middle Aged; Pilot Projects; Riboflavin; Ubiquinone; Young Adult

The aim of this study was to investigate the efficacy of idebenone on neurological function as assessed by ICARS and FARS neurological rating scales in pediatric Friedreich's ataxia (FRDA) patients. Sixty-eight pediatric patients were enrolled in an open-label extension study (IONIA-E) where patients received idebenone (Catena(®), 150 mg film-coated tablets) at a weight-adjusted dose of 1,350/2,250 mg/day for 12 months after patients had completed a double-blind, randomized, placebo-controlled study (IONIA) receiving either idebenone at a weight-adjusted dose of 450/900 or 1,350/2,250 mg/day or placebo for 6 months. Changes in ICARS and FARS total scores and subscores were recorded for the 12-month IONIA-E study and for the 18-month combined IONIA and IONIA-E study period. Data analyzed by a mixed-model repeated-measures ANCOVA relative to baseline resulted in least square means for the change in ICARS for the IONIA-E study of +0.98 points (SEM 0.73; p = 0.180), indicating a trend for worsening. However, combined with the IONIA study the change was -1.03 ± 0.68 points (p = 0.132), indicating a trend for improvement in neurological function over the 18-month period. Importantly, patients who received idebenone 1,350/2,250 mg/day over this period significantly improved in neurological function (change in ICARS: -3.02 ± 1.22, p = 0.014). The improvement in neurological function over time was best seen when the posture and stance subscore was excluded from the analysis. Comparable data were obtained with the FARS. The findings of the open-label IONIA-E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurological function and improving fine motor skills and speech.

Topics: Adolescent; Antioxidants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Female; Friedreich Ataxia; Humans; Male; Treatment Outcome; Ubiquinone

Friedreich ataxia is a rare disease caused by GAA-trinucleotide-repeat expansions in the frataxin gene, leading to marked reduction of qualitatively normal frataxin protein. Recently, human recombinant erythropoietin was reported to increase frataxin levels in patients with Friedreich ataxia.. We performed a 6-month, randomized placebo-controlled, double-blind, dose-response pilot trial to assess the safety and efficacy of erythropoietin in increasing frataxin levels. Sixteen adult patient with Friedreich ataxia were randomly assigned to erythropoietin (n = 11) or matching placebo (n = 5). All patients continued Idebenone treatment (5 mg/kg/day). Treatment consisted of a 6-month scaling-up phase, in which erythropoietin was administered intravenously at the following doses: 20,000 IU every 3 weeks, 40,000 IU every 3 weeks, and 40,000 IU every 2 weeks.. Erythropoietin treatment was safe and well tolerated, but did not result in any significant hematological, clinical, or biochemical effects in Friedreich ataxia patients.

Topics: Adult; Antioxidants; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Male; Recombinant Proteins; Statistics, Nonparametric; Time Factors; Treatment Outcome; Ubiquinone; Young Adult

Friedreich ataxia (FRDA) is commonly associated with hypertrophic cardiomyopathy, but little is known about its frequency, severity, or treatment. In this 6-month randomized, double-blind, controlled study, we sought to determine whether idebenone improves cardiac measures in FRDA.. Seventy pediatric subjects were treated either with idebenone (450/900 mg/d or 1,350/2,250 mg/d) or with placebo. Electrocardiograms (ECGs) were assessed at each visit, and echocardiograms, at baseline and week 24.. We found ECG abnormalities in 90% of the subjects. On echocardiogram, 81.4% of the total cohort had left ventricular (LV) hypertrophy, as measured by increased LV mass index-Dubois, and the mean ejection fraction (EF) was 56.9%. In linear regression models, longer PR intervals at baseline were marginally associated with longer GAA repeat length (P = .011). Similarly, GAA repeat length did not clearly predict baseline EF (P = .086) and LV mass by M-mode (P = .045). Left ventricular mass index, posterior wall thickness, EF, and ECG parameters were not significantly improved by treatment with idebenone. Some changes in echocardiographic parameters during the treatment phase correlated with baseline status but not with treatment group.. Idebenone did not decrease LV hypertrophy or improve cardiac function in subjects with FRDA. The present study does not provide evidence of benefit in this cohort over a 6-month treatment period.

Topics: Adolescent; Antioxidants; Cardiomyopathy, Hypertrophic; Child; Clinical Trials, Phase III as Topic; Double-Blind Method; Echocardiography, Doppler; Electrocardiography; Female; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Male; Ubiquinone; Ventricular Function

To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity.. Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress.. Exercise physiology laboratory in a single clinical research center.. Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA.. Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months.. Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment.. Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo.. Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Antioxidants; Child; Deoxyguanosine; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Female; Friedreich Ataxia; Humans; Male; Oxidative Stress; Oxygen Consumption; Ubiquinone

To assess the efficacy of idebenone on neurological function in patients with Friedreich ataxia.. Randomized, double-blind, placebo-controlled intervention trial.. Children's Hospital of Philadelphia and the University of California at Los Angeles.. Seventy ambulatory pediatric patients (age, 8-18 years) with a baseline International Cooperative Ataxia Rating Scale (ICARS) score of 10 to 54.. Participants were randomized into 1 of 3 treatment arms: 450 or 900 mg of idebenone per day (in those with a body weight < or = or >45 kg, respectively; n = 22); 1350 or 2250 mg of idebenone per day (n = 24); or placebo (n = 24).. Mean change from baseline to week 24 in ICARS score was the primary efficacy variable. Mean change in Friedreich Ataxia Rating Scale (FARS) score, performance measures, and activities of daily living were the secondary efficacy variables.. Patients who received idebenone improved by 2.5 points on mean ICARS score compared with baseline, while patients in the placebo group improved by 1.3 points. Patients who took idebenone also improved by 1.6 points on the FARS, while patients taking placebo declined by 0.6 points. For both end points, the difference between the idebenone and placebo groups was not statistically different.. Idebenone did not significantly alter neurological function in Friedreich ataxia during the 6-month study. Larger studies of longer duration may be needed to assess the therapeutic potential of drug candidates on neurological function in Friedreich ataxia. Trial Registration clinicaltrials.gov Identifier: NCT00537680.

Topics: Adolescent; Antioxidants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Female; Friedreich Ataxia; Humans; Male; Neurologic Examination; Severity of Illness Index; Ubiquinone

The purpose of this study was to describe gait parameters in children and adolescents with a diagnosis of Friedreich ataxia (FA) and examine the relationship between disease severity, measured by the Friedreich Ataxia Rating Scale (FARS) and gait parameters. The study examined whether FARS scores can discriminate between those who walk independently and those who require assistance.. Thirty-eight children (aged 5-11 years) and adolescents (aged 12-17 years) with genetically confirmed FA were divided into two groups based on locomotor status: group 1, subjects who were able to walk independently, and group 2, subjects who required assistance for walking. Temporal and spatial gait parameters were collected using the Stride Analyzer computerized foot switch system and compared with age-matched normative data. The FARS was used to measure disease severity. Correlation coefficients and the Mann-Whitney U test of differences were used to evaluate associations and discern differences between groups.. In subjects with FA, gait parameters of velocity and cadence were slower and stride length was shorter compared with age-matched children without disabilities. These parameters were significantly correlated with FARS score (r = 0.696, 0.667, 0.537; respectively, all P values <0.001). Total FARS scores were correlated with locomotor status (ç value r = 0.623; P < 0.01) and could categorize subjects into groups based on independent walking or need for assistance, 73% and 87% of the time, respectively.. Subjects with FA exhibited specific abnormal gait characteristics relative to age-matched individuals. Disease severity, as measured by the FARS, was associated with gait velocity, stride length, and cadence. FARS scores can be used to categorize subjects by locomotor status and may be a useful screening tool to identify those requiring assistance.

Topics: Adolescent; Antioxidants; Child; Child, Preschool; Friedreich Ataxia; Gait; Gait Apraxia; Humans; Motor Activity; Predictive Value of Tests; Severity of Illness Index; Ubiquinone; Walking

A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial.. Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data.. At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels.. A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.

Topics: Adolescent; Adult; Antioxidants; Dose-Response Relationship, Drug; Electron Transport Chain Complex Proteins; Endpoint Determination; Energy Metabolism; Female; Friedreich Ataxia; Humans; Male; Mitochondria; Muscle, Striated; Oxidative Stress; Predictive Value of Tests; Treatment Outcome; Ubiquinone; Up-Regulation; Vitamin E; Vitamin E Deficiency; Young Adult

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.

Topics: Adolescent; Adult; Age Factors; Age of Onset; Antioxidants; Cardiomyopathies; Clinical Trials as Topic; Cohort Studies; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Mitochondria; Nonprescription Drugs; Oxidative Stress; Patient Selection; Placebo Effect; Self Medication; Trinucleotide Repeat Expansion; Ubiquinone

Friedreich ataxia (FA) is the most frequent autosomal recessive cerebellar ataxia. Although the phenotype is well known, disease progression has not been evaluated in a prospective manner.. To perform a long-term prospective follow-up of neurological, cardiological, and oculomotor function in patients with FA (FA patients).. In this open-labeled prospective survey, we examined 104 FA patients every 6 months during a median period of 5 years (range, 6 months to 7 years), with a systematic standardized protocol. Data are reported as mean +/- SD.. Neurological examinations were performed at the Federation of Neurology and the Department of Genetics of the Salpêtrière Hospital, Paris, France. Cardiological follow-up was performed at the Department of Cardiology; oculomotor examinations were performed at the Institut National de la Santé et de la Récherche Médicale Unit 679, at the same hospital. Patients We studied 104 FA patients with a confirmed molecular diagnosis. None were receiving antioxidant therapy at baseline; 88 accepted treatment with the coenzyme Q(10) analogue idebenone (5 mg/kg per day). Sixteen preferred not to be treated.. Neurological status was evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and a quantitative writing test. Cardiological evaluations included echocardiography, electrocardiography, and Holter monitoring. Oculomotor function was evaluated by electro-oculography to determine the frequency of square wave jerks.. The total ICARS score worsened during follow-up, whether or not the patients were treated with idebenone (1.93 +/- 0.25 and 4.43 +/- 1.56 points per year, respectively). The total ICARS score increased faster in patients with onset before age 15 years compared with the others (2.6 +/- 0.4 [n = 51] vs 1.1 +/- 0.3 [n = 37]; P = .05). The posture subscore increased faster in patients able to stand at baseline, who also had shorter disease durations than patients unable to stand (1.25 +/- 0.12 vs 0.47 +/- 0.22 point per year; P<.001). Neurological progression was underestimated, however, by the ICARS scores, which reached a plateau in patients with long disease durations. Oculomotor function slightly deteriorated (0.09 +/- 0.02 Hz per year; P<.001). Left ventricular mass index decreased (-4.1 +/- 1.5 g/m(2) per year; P = .008), as did ejection fraction (-1.32% +/- 0.29% per year; P<.001).. The neurological condition of FA patients deteriorated slowly over time, even with idebenone treatment. Although cardiac hypertrophy decreased under treatment, cardiac function did not improve. The ICARS scale is not appropriate to evaluate the progression of FA in patients with long disease durations. Additional quantitative measures may improve the reliability of this scale.

Topics: Adolescent; Adult; Aged; Antioxidants; Benzoquinones; Disease Progression; Echocardiography; Electrocardiography, Ambulatory; Electrooculography; Follow-Up Studies; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Middle Aged; Neurologic Examination; Paris; Prospective Studies; Time Factors; Treatment Outcome; Trinucleotide Repeat Expansion; Ubiquinone

Friedreich ataxia (FA) is a progressive, multisystem degenerative disorder in which oxidative stress is believed to have a role. Recent clinical studies indicate that the antioxidant idebenone, administered at 5 mg/kg per day, reduces the cardiac hypertrophy that occurs in FA, but improvement in neurologic measures is unclear. Some studies suggest that higher doses of idebenone may be more effective, but pharmacology and toxicology at higher doses have not been investigated in human beings.. To determine the safety, tolerability, and pharmacokinetics of increasing doses of idebenone in subjects with FA.. Open-label, phase 1A dose-escalation trial followed by an open-label, 1-month phase 1B trial.. National Institutes of Health Clinical Center, Bethesda, Md.. Phase 1A included 78 subjects with FA (24 adults, 27 adolescents, and 27 children), and phase 1B included 15 subjects with FA (5 adults, 5 adolescents, and 5 children).. Oral idebenone was administered to groups of 3 subjects in each age cohort during day 1. In phase 1A, the dose was increased in 10-mg/kg increments in each successive dose group to a maximum of 75 mg/kg. In phase 1B, oral idebenone was administered at 60 mg/kg divided in 3 doses per day for 1 month.. We studied the type, number, and frequency of adverse events, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, area under the curve, and half-life.. In the first phase of the study, no dose-limiting toxicity was observed and the maximum allowed dose of 75 mg/kg was achieved in all cohorts. Plasma levels of total idebenone were found to increase proportional to drug dose up to 55 mg/kg. Variability in absorption of the drug was observed, but drug half-life was relatively consistent across dose levels. In the second phase of the study, 14 of 15 subjects with FA tolerated idebenone at a dose of 60 mg/kg per day for 1 month. All adverse events were mild, and pharmacokinetic parameters including maximum drug concentration, time to maximum drug concentration, and half-life did not differ significantly across age cohorts.. These findings indicate that higher doses of idebenone lead to a proportional increase in plasma levels up to 55 mg/kg per day and that high-dose idebenone is well-tolerated in patients with FA. These findings are essential to planning efficacy trials of high-dose idebenone in FA and other degenerative diseases in which oxidative damage has been implicated.

Topics: Absorption; Administration, Oral; Adolescent; Adult; Antioxidants; Benzoquinones; Child; Dose-Response Relationship, Drug; Female; Friedreich Ataxia; Half-Life; Humans; Male; Osmolar Concentration; Time Factors; Ubiquinone

Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown.. 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632.. Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores.. Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Activities of Daily Living; Adolescent; Antioxidants; Benzoquinones; Child; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Female; Friedreich Ataxia; Humans; Male; Nervous System; Neutropenia; Severity of Illness Index; Ubiquinone

Decreased mitochondrial respiratory chain function and increased oxidative stress have been implicated in the pathogenesis of Friedreich ataxia (FRDA), raising the possibility that energy enhancement and antioxidant therapies may be an effective treatment.. To evaluate the long-term efficacy of a combined antioxidant and mitochondrial enhancement therapy on the bioenergetics and clinical course of FRDA.. Open-labeled pilot trial over 47 months.Patients Seventy-seven patients with clinical and genetically defined FRDA. Intervention A combined coenzyme Q(10) (400 mg/d) and vitamin E (2100 IU/d) therapy of 10 patients with FRDA over 47 months.. Clinical assessment using echocardiography and the International Cooperative Ataxia Rating Scale and cardiac and skeletal muscle bioenergetics as assessed using phosphorus P 31 magnetic resonance spectroscopy.. There was a significant improvement in cardiac and skeletal muscle bioenergetics that was maintained throughout the 47 months of therapy. Echocardiographic data revealed significantly increased fractional shortening at the 35- and 47-month time points. Comparison with cross-sectional data from 77 patients with FRDA indicated the changes in total International Cooperative Ataxia Rating Scale and kinetic scores over the trial period were better than predicted for 7 patients, but the posture and gait and hand dexterity scores progressed as predicted.. This therapy resulted in sustained improvement in mitochondrial energy synthesis that was associated with a slowing of the progression of certain clinical features and a significant improvement in cardiac function.

Topics: Adolescent; Adult; Antioxidants; Child; Coenzymes; Drug Therapy, Combination; Energy Metabolism; Follow-Up Studies; Frataxin; Friedreich Ataxia; Heart; Humans; Iron-Binding Proteins; Middle Aged; Mitochondria; Muscle, Skeletal; Myocardium; Oxidative Stress; Pilot Projects; Treatment Outcome; Ubiquinone; Vitamin E

The authors carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients with Friedreich ataxia. They found significant reductions of interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group, with no improvement in other heart ultrasound measures or neurologic condition. The absolute cardiac changes were modest, but the findings suggest that larger trials should assess whether idebenone reduces ventricular hypertrophy in patients with Friedreich ataxia.

Topics: Adolescent; Adult; Benzoquinones; Cardiomyopathy, Hypertrophic; Child; Erythrocytes; Female; Frataxin; Free Radical Scavengers; Free Radicals; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Iron-Binding Proteins; Male; Mitochondria; Oxidative Stress; Prospective Studies; Protoporphyrins; Ubiquinone

The authors report 1-year prospective data on eight patients with Friedreich ataxia. Idebenone did not halt the progression of ataxia. At the end of therapy, cardiac ultrasound demonstrated significant reduction of cardiac hypertrophy in six of eight patients. Cardiac strain and strain rate imaging showed that the reduction of hypertrophy is preceded by an early and linear improvement in cardiac function. Idebenone reduced erythrocyte protoporphyrin IX levels in five of six patients with elevated baseline levels; however, changes did not consistently relate to cardiac improvement.

Topics: Adolescent; Adult; Benzoquinones; Cardiomyopathy, Hypertrophic; Child; Erythrocytes; Female; Frataxin; Free Radical Scavengers; Free Radicals; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Iron-Binding Proteins; Male; Mitochondria; Oxidative Stress; Prospective Studies; Protoporphyrins; Stroke Volume; Ubiquinone

Antioxidant therapy has been applied to Friedreich's ataxia patients. We assessed the effect of idebenone treatment in patients with Friedreich's ataxia.. open-label trial. Nine Friedreich's ataxia patients (age range 11 - 19 years) were treated with idebenone (5 mg/kg/day). Patients were evaluated before the start of the therapy and throughout one year of treatment by International Cooperative Ataxia Rating Scales (ICARS) scores, neurophysiological investigations and echocardiographic measurements. Serum idebenone concentrations were measured by HPLC with electrochemical detection. The number of GAA repeats at the frataxin gene was analyzed by PCR.. Serum idebenone concentrations ranged between 0.04 - 0.37 micro mol/L. Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy (r = 0.883; p = 0.002). Significant reduction was observed comparing the ICARS scores in baseline conditions and after 3 months of treatment (p = 0.017). No differences were observed in echocardiographic measurements after the start of the therapy.. Cerebellar improvement was notable in mild patients after the first 3 months of therapy. Idebenone treatment at early stages of the disease seems to reduce the progression of cerebellar manifestations. Further blind trials with a greater number of patients and higher doses are needed to fully assess the therapeutic potential of idebenone in Friedreich's ataxia.

Topics: Adolescent; Adult; Antioxidants; Benzoquinones; Cerebellum; Child; Echocardiography; Female; Follow-Up Studies; Friedreich Ataxia; Humans; Male; Recovery of Function; Time Factors; Ubiquinone

Friedreich's ataxia encodes a protein of unknown function, frataxin. The loss of frataxin is caused by a large GAA trinucleotide expansion in the first intron of the gene, resulting in deficiency of a Krebs cycle enzyme, aconitase, and of three mitochondrial respiratory chain complexes (I-III). This causes oxidative stress. Idebenone, a short chain quinone acting as an antioxidant, has been shown to protect heart muscle against oxidative stress in some patients.. To assess the efficiency of idebenone on cardiac hypertrophy in Friedreich's ataxia.. Prospective, open trial.. Tertiary care centre.. Idebenone (5 mg/kg/day) was given orally to 38 patients with Friedreich's ataxia aged 4-22 years (20 males, 18 females). Cardiac ultrasound indices were recorded before and after idebenone treatment.. After six months, cardiac ultrasound indicated a reduction in left ventricular mass of more than 20% in about half the patients (p < 0.001). The shortening fraction was initially reduced in six of the 38 patients (by between 11-26%) and it improved in five of these. In one patient, the shortening fraction only responded to 10 mg/kg/day of idebenone. No correlation was found between responsiveness to idebenone and age, sex, initial ultrasound indices, or the number of GAA repeats in the frataxin gene.. Idebenone is effective at controlling cardiac hypertrophy in Friedreich's ataxia. As the drug has no serious side effects, there is a good case for giving it continuously in a dose of 5-10 mg/kg/day in patients with Friedreich's ataxia at the onset of hypertrophic cardiomyopathy.

Topics: Adolescent; Adult; Antioxidants; Benzoquinones; Cardiomegaly; Child; Child, Preschool; Female; Friedreich Ataxia; Humans; Male; Prospective Studies; Stroke Volume; Treatment Outcome; Ubiquinone; Ventricular Dysfunction, Left

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.

Topics: Antioxidants; Benzoquinones; Cardiomyopathies; Cross-Over Studies; Echocardiography; Female; Friedreich Ataxia; Humans; Magnetic Resonance Spectroscopy; Male; Mitochondria; Muscle, Skeletal; Radionuclide Imaging; Ubiquinone

Despite the growing interest and the potential benefits of idebenone as a repurposed drug for different orphan conditions, data regarding its monitoring are scarce. Our main goal was to report plasma idebenone values in a cohort of Friedreich's ataxia (FRDA) patients during a long-term follow-up. Taking advantage of this, we also assessed cardiological and neurological status together with idebenone values and genetic background.. Long-term follow-up retrospective study in 27 FRDA patients with a disease onset at the paediatric age treated with idebenone by compassionate use. Plasma idebenone was measured by HPLC with electrochemical detection.. Median plasma idebenone values increased when doses were increased, but apparently linearity was lost in the highest dose group. Marked intraindividual and interindividual differences were observed among patients. We did not find a consistent positive effect after analysis of paired data at the beginning and the end of the study. We only found a correlation between some cardiological measures and the duration of idebenone therapy at high doses, but with uncertain significance.. The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.

Topics: Adolescent; Antioxidants; Biological Variation, Individual; Biological Variation, Population; Child; Child, Preschool; Chromatography, High Pressure Liquid; Compassionate Use Trials; Drug Monitoring; Electrochemical Techniques; Female; Follow-Up Studies; Friedreich Ataxia; Humans; Male; Predictive Value of Tests; Retrospective Studies; Time Factors; Treatment Outcome; Ubiquinone; Young Adult

Topics: Adolescent; Compassionate Use Trials; Female; Friedreich Ataxia; Humans; Insulin-Like Growth Factor I; Ubiquinone; Vitamin E

Topics: Adolescent; Adult; Aspartic Acid; Cerebellum; Child; Choline; Diffusion Magnetic Resonance Imaging; Female; Friedreich Ataxia; Humans; Linear Models; Male; Middle Aged; Neuroprotective Agents; Proton Magnetic Resonance Spectroscopy; Severity of Illness Index; Ubiquinone; Young Adult

Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is caused by silencing of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis.. Application of our previously established FRDA human induced pluripotent stem cell (hiPSC) derived cardiomyocytes model as a platform to assess the efficacy of treatment with either the antioxidant coenzyme Q10 analog, idebenone (IDE) or the iron chelator, deferiprone (DFP), which are both under clinical trial.. DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 25 μM and 10nM respectively which agreed with the reduced rate of intracellular accumulation of iron by DFP treatment from 25 to 50 μM. With regard to cardiac electrical-contraction (EC) coupling function, decay velocity of calcium handling kinetics in FRDA-hiPSC-cardiomyocytes was significantly improved by DFP treatment but not by IDE. Further mechanistic studies revealed that DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline level of respiratory chain protein, succinate dehydrogenase (CxII) and cytochrome c oxidase (COXIV). In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by resumed level of ferritin (FTH) back to basal level and the attenuated transferrin receptor (TSFR) mRNA level suppression thereby reducing further iron uptake.. DFP modulated iron homeostasis in FRDA-hiPSC-cardiomyocytes and effectively relieved stress-stimulation related to cardiomyopathy. The resuming of redox condition led to the significantly improved cardiac prime events, cardiac electrical-coupling during contraction.

Topics: Antioxidants; Deferiprone; Drug Evaluation, Preclinical; Frataxin; Friedreich Ataxia; Gene Expression Regulation; Homeostasis; Humans; Induced Pluripotent Stem Cells; Iron; Iron Chelating Agents; Iron-Binding Proteins; Myocytes, Cardiac; Oxidative Stress; Pyridones; Reverse Transcriptase Polymerase Chain Reaction; RNA; Ubiquinone

It is generally accepted that Friedreich's ataxia (FRDA) is caused by a deficiency in frataxin expression, a mitochondrial protein involved in iron homeostasis, which mainly affects the brain, dorsal root ganglia of the spinal cord, heart and in certain cases the pancreas. However, there is little knowledge as to other possible genes that may be affected in this disorder, and which can contribute to its complexity. In the current study we compared human periodontal ligament cells gene expression of healthy individuals and FRDA patients. The expression of active-caspase 3, as well as other apoptosis-related genes, was increased in the FRDA cells. Furthermore, iron-sulphur cluster genes, as well as oxidative stress-related genes were overexpressed in FRDA. Moreover, brain-derived neurotrophic factor, neuregulin 1 and miR-132 were all upregulated. These three genes are capable of regulating the expression of each other. Interestingly, when the cells from FRDA patients were co-cultured in the presence of idebenone and deferiprone, caspase expression decreased while antioxidant gene expression, as well as frataxin expression, increased. Regarding epigenetic mechanisms, the frataxin gene was hypermethylated, compared to the healthy counterparts, in the upstream GAA repetitive region. Of the three DNA methyltransferases, DNMT1 but not DNMT3׳s gene expression was higher in FRDA cells. In conclusion, our data show that FRDA cells present altered expression of genes related to cell cycle, oxidative stress and iron homeostasis which may be implicated in the increased apoptotic levels. Also, the altered expression is in a certain degree normalized in the presence of idebenone and deferiprone.

Topics: Antioxidants; Apoptosis; Azacitidine; Brain-Derived Neurotrophic Factor; Caspase 3; Cells, Cultured; Decitabine; Deferiprone; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Frataxin; Friedreich Ataxia; Gene Expression Profiling; Humans; Iron Chelating Agents; Iron-Binding Proteins; MicroRNAs; Neuregulin-1; Oxidative Stress; Periodontal Ligament; Pyridones; Superoxide Dismutase; Ubiquinone

Friedreich's ataxia (FRDA), the most common hereditary ataxia, is characterized by progressive degeneration of the central and peripheral nervous system, hypertrophic cardiomyopathy and a high risk of diabetes. FRDA is caused by abnormally low levels of frataxin, a highly conserved mitochondrial protein. Drosophila has been previously successfully used to model FRDA in various cell types, including neurons and glial cells. Here, we report the development of a Drosophila cardiac model of FRDA. In vivo heart imaging revealed profound impairments in heart function in frataxin-depleted Drosophila, including a strong increase in end-systolic and end-diastolic diameters and a decrease in fractional shortening (FS). These features, reminiscent of pathological phenotypes in humans, are fully rescued by complementation with human frataxin, suggesting conserved cardiac functions of frataxin between the two organisms. Oxidative stress is not a major factor of heart impairment in frataxin-depleted flies, suggesting the involvement of other pathological mechanisms notably mitochondrial respiratory chain (MRC) dysfunction. Accordingly, we report that methylene blue (MB), a compound known to act as an alternative electron carrier that bypasses mitochondrial complexes I-III, was able to prevent heart dysfunction. MB also partially rescued the phenotype when administered post-symptomatically. Analysis of MB derivatives demonstrates that only compounds with electron carrier properties are able to prevent the heart phenotype. Thus MB, a compound already used for several clinical applications, appears promising for the treatment of the heart dysfunctions that are a major cause of death of FRDA patients. This work provides the grounds for further evaluation of MB action in mammals.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Drug Evaluation, Preclinical; Frataxin; Friedreich Ataxia; Gene Knockdown Techniques; Humans; Iron-Binding Proteins; Male; Methylene Blue; RNA Interference; Ubiquinone

Friedreich's ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator deferiprone (DFP) and the antioxidant idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.

Topics: Aconitate Hydratase; Animals; Antioxidants; Deferiprone; Disease Models, Animal; Drosophila; Frataxin; Friedreich Ataxia; Hyperoxia; Iron; Iron-Binding Proteins; Mitochondria; Mutation; Oxidative Stress; Phenotype; Pyridones; Ubiquinone

Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare.. To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel.. Description of a series.. Academic research.. Six patients with FAexdel and 46 patients with typical FA.. FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification.. We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA.. Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis.

Topics: Adult; Antioxidants; Cardiomyopathies; Disease Progression; Electromyography; Exons; Family Health; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Magnetic Resonance Imaging; Male; Middle Aged; Sequence Deletion; Trinucleotide Repeat Expansion; Ubiquinone

An 18-year-old lady had presented to us with insidious onset progressive gait ataxia of 5-year duration. Her sister had similar complaints and type 1 diabetes mellitus. Examination revealed, gait ataxia, impaired tandem gait, babinski sign and severe swaying on testing for Romberg's sign. All deep tendon reflexes were exaggerated. On investigations, there was no evidence for diabetes mellitus or nutritional deficiencies. Electrocardiogram and echocardiogram were normal. Magnetic spine resonance showed marked atrophy of cervical cord with normal cerebellum. The genetic testing disclosed expanded GAA repeat length on both alleles of FXN gene. The GAA repeat length on both alleles was much less than mean length observed in Friedreich's ataxia. This case highlights how strongly the genotype influences the neurological and systemic manifestations as well as severity of disease in Friedreich's ataxia.

Topics: Adolescent; Antioxidants; Atrophy; Exercise Therapy; Female; Frataxin; Friedreich Ataxia; Genotype; Humans; Iron-Binding Proteins; Magnetic Resonance Imaging; Phenotype; Reflex, Babinski; Spinal Cord; Trinucleotide Repeat Expansion; Ubiquinone

Iron chelators are a new therapeutical approach for patients with Friedreich's ataxia, on the basis that oxidative cell damage that occurs in these patients is due to the increasing deposits of mitochondrial iron pools. The objective of the study was to evaluate the effects of the combined therapy of idebenone and low oral doses of deferiprone on the neurological signs and cardiac function parameters. This study was designed as a prospective open-label single-arm study. Twenty Friedreich's ataxia patients were treated with idebenone (20 mg/kg/day) and deferiprone (20 mg/kg/day) for 11 months. Patients were evaluated before the start and throughout the study with the International Cooperative Ataxia Rating Scale (ICARS) scores, echocardiographic measurements and MRI (magnetic resonance imaging) techniques to asses brain iron deposits in the dentate nucleus. No significant differences were observed in total ICARS scores when comparing baseline status and the end of the study in the whole group of patients. Posture and gait scores increased significantly after 11 months of therapy (Wilcoxon's test, p = 0.04) and kinetic function improved significantly (Wilcoxon's test, p = 0.015). Echocardiography data showed a significant reduction of the interventricular septum thickness (Wilcoxon's test, p = 0.04) and in the left ventricular mass index (Wilcoxon's test, p = 0.038) after the start of the therapy. The MRI values in the dentate nucleus showed a statistically significant reduction (Wilcoxon's test p = 0.007) between baseline conditions and after 11 months of the therapy. Combined therapy with idebenone and deferiprone in patients with FDRA indicates a stabilizing effect in neurologic dysfunctions due to an improvement in the kinetic functions, with a worsening of gait and posture scores. Heart hypertrophy parameters and iron deposits in dentate nucleus improved significantly. Combined therapy was well tolerated with mild side effects, apart from the risk of neutropenia and progressive reduction of plasma iron parameters.

Topics: Adolescent; Adult; Antioxidants; Blood Cell Count; Brain Chemistry; Child; Deferiprone; Drug Therapy, Combination; Dysarthria; Female; Friedreich Ataxia; Gait Disorders, Neurologic; Heart Function Tests; Humans; Iron; Iron Chelating Agents; Magnetic Resonance Imaging; Male; Neurologic Examination; Oculomotor Muscles; Prospective Studies; Pyridones; Speech Disorders; Ubiquinone; Ultrasonography; Young Adult

Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others.. Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1α and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells.. The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA.

Topics: Adenosine Triphosphate; Adolescent; Adult; Aging; Alleles; AMP-Activated Protein Kinases; Antioxidants; Catalase; Child; Disease Progression; DNA-Binding Proteins; Energy Metabolism; Female; Fibroblasts; Friedreich Ataxia; Gene Expression Regulation; Glutathione Peroxidase; Heat-Shock Proteins; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Proteins; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Transcription Factors; Trinucleotide Repeats; Ubiquinone

Idebenone has been used as therapy for Friedreich ataxia for more than a decade. Although several studies have assessed the influence of therapy on neurologic or cardiac function, there is a paucity of data surrounding patient-reported outcome measures. In an observational study of the effect of intermediate-dose idebenone (20 mg/kg per day) on quality of life and neurologic function measures, seven patients with Friedreich ataxia were assessed using the Pediatric Quality of Life Inventory, the International Cooperative Ataxia Rating Scale, and an Activities of Daily Living Scale before initiation of idebenone therapy and after 1 year of therapy. Physical scores on the Pediatric Quality of Life Inventory were universally worse after 1 year, and correlated with decreased activities of daily living scores. Despite worsening physical scores, there was a trend toward improved total, emotional, social, and school components of quality of life scores after 1 year of idebenone therapy. There was no statistically significant change in Pediatric Quality of Life Inventory scores between baseline and 1 year of idebenone therapy. Functional ability, as measured by activities of daily living scores, appeared to have the most influence on the perception of physical quality of life, which may be important in planning future therapeutic trials.

Topics: Activities of Daily Living; Adolescent; Female; Follow-Up Studies; Friedreich Ataxia; Humans; Male; Prospective Studies; Quality of Life; Ubiquinone

Topics: Antioxidants; Friedreich Ataxia; Humans; Ubiquinone

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.

Topics: Adult; Analysis of Variance; Antioxidants; Cohort Studies; Echocardiography; Female; Follow-Up Studies; Friedreich Ataxia; Heart; Heart Septum; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Retrospective Studies; Severity of Illness Index; Ubiquinone

In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement.. In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment.. During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores.. In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05).. In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.

Topics: Adolescent; Age Factors; Antioxidants; Child; Evoked Potentials, Somatosensory; Friedreich Ataxia; Humans; Longitudinal Studies; Muscle Strength Dynamometer; Neural Conduction; Treatment Outcome; Ubiquinone

Antioxidant therapy is a new therapeutical approach for patients with Friedreich ataxia.. To assess the effectiveness of long-term idebenone treatment in Friedreich ataxia patients.. An open-labelled prospective study. Ten paediatric patients (age range 8-18 years) and 14 adults (age range 18-46 years) with genetic diagnosis of Friedreich ataxia were treated with idebenone (5-20mg/kg/day) for 3-5 years. Neurological evolution was evaluated using the International Cooperative Ataxia Rating Scale (ICARS), and cardiological outcomes using echocardiography.. In paediatric patients, no significant differences were observed in ICARS scores and echocardiographic measurements when comparing baseline status and after 5 years of follow-up. Concerning adult cases, ICARS scores showed a significant increase in neurological dysfunctions during 3 years of therapy (Wilcoxon test, p=0.005), while echocardiographic measurements remained unchanged.. Our results indicate that longer-term idebenone treatment prevented progression of cardiomyopathy in both paediatric and adult patients, whereas its stabilizing effect on neurological dysfunction was present only in the paediatric population, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may be an important factor in the effectiveness of the therapy.

Topics: Adolescent; Adult; Antioxidants; Child; Echocardiography; Female; Follow-Up Studies; Friedreich Ataxia; Heart Diseases; Heart Function Tests; Humans; Male; Neurologic Examination; Neuropsychological Tests; Treatment Outcome; Ubiquinone; Young Adult

Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy. This life threatening symptom can be ameliorated by the administration of idebenone, a short chain quinone antioxidant, supporting additional evidence that oxidative stress plays a major role in the pathogenesis of this disease. In this study we analyze the combinatorial effect of different antioxidants on cell viability of FRDA fibroblasts and of RAT-1 immortalized fibroblasts exposed to oxidative stress. We find that an equimolar mixture of idebenone and vitamin E is more potent than each of the compound alone. Increased potency was also obtained with a novel synthetic antioxidant (Fe-Aox29) combining the active groups from both idebenone and vitamin E. These results indicate, that idebenone and vitamin E might act synergistically to counteract oxidative stress in fibroblasts from FRDA patients.

Topics: Animals; Antioxidants; Benzoquinones; Cell Line, Transformed; Cell Survival; Chromans; Fibroblasts; Friedreich Ataxia; Humans; Hydrogen Peroxide; Protective Agents; Rats; Reactive Oxygen Species; Ubiquinone; Vitamin E

The results of treatment with noben (idebenon), an improved structural analogue of coenzyme Q10, of 34 patients with Friedrich's disease are presented. In all cases, the clinical diagnosis was confirmed by the presence of a typical mutation, an expansion of trinucleotide GAA-repeats, in the FRDA gene. All patients received noben as a main drug in dosage 5 mg/kg daily during 3 months. An examination of the patients included modern laboratory and instrumental methods, analysis of levels of lactic and pyruvic acids and their ratio in the peripheral blood. Also parameters of lipid peroxidation and mitochondrial dehydrogenase activity in peripheral lymphocytes were studied. Positive changes were found in the majority of patients for muscle strength in extremities, tolerability to physical loadings, general fatigue, movement activity, speech and coordination functions, along with significant improvement of biochemical and cytochemical status. The results obtained suggest a positive effect of noben on cell energy metabolism in this severe disorder from the group of mitochondrial cytopathies.

Topics: Adolescent; Adult; Antioxidants; Child; DNA Mutational Analysis; DNA, Mitochondrial; Dose-Response Relationship, Drug; Energy Metabolism; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Lipid Peroxidation; Lymphocytes; Middle Aged; Mitochondria; Mutation; Oxidoreductases; Treatment Outcome; Ubiquinone

Topics: Antioxidants; Benzoquinones; Cardiotonic Agents; Clinical Trials as Topic; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Mitochondria, Heart; Oxidative Stress; Ubiquinone; Ultrasonography

Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron accumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterization of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo-controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilization for the treatment of FRDA.

Topics: Animals; Benzoquinones; Cardiomyopathy, Dilated; Disease Models, Animal; Electrocardiography; Frataxin; Friedreich Ataxia; Iron-Binding Proteins; Iron-Sulfur Proteins; Mice; Mitochondria; Myocardium; Oxidative Stress; Ubiquinone

We studied plasma and cerebrospinal fluid (CSF) concentrations of idebenone in five Friedreich ataxia patients on treatment with this antioxidant, and plasma and CSF ubiquinone-10 (Q (10)) concentrations in 15 controls. CSF idebenone concentrations were below the detection limit in 3 Friedreich ataxia patients and no association could be demonstrated between plasma and CSF idebenone values. Q (10) CSF concentrations (median: 2.25 nmol/L) were approximately 300 times lower than those of plasma (median: 0.77 micro mol/L). No correlation was observed between plasma and CSF Q (10) concentrations. A significantly positive correlation was observed between CSF total protein values (range 8.1 - 107.5 mg/dL; median: 29.5) and CSF Q (10) concentrations (Spearman test: r = 0.664; p = 0.01). Our findings suggest that less idebenone is distributed to the brain than to other tissues, although CSF does not appear to be an appropriate material for treatment monitoring of idebenone and other quinoid compounds.

Topics: Adolescent; Adult; Antioxidants; Benzoquinones; Blood-Brain Barrier; Case-Control Studies; Child; Coenzymes; Friedreich Ataxia; Humans; Ubiquinone

Topics: Benzoquinones; Double-Blind Method; Free Radical Scavengers; Friedreich Ataxia; Humans; Hypertrophy, Left Ventricular; Randomized Controlled Trials as Topic; Research Design; Ubiquinone

Severe hypertrophic cardiomyopathy in a 15 years old child with Friedreich ataxia was treated with idebenone on the basis of a preliminary study reported in the literature. After 3 months of treatment the muscle thickness and mass and idices of diastolic function on echocardiogram and ischaemic signs on ECG changed significantly.. Our data proves the preliminary results, so idebenobe treatment is very effective in the disease, where a deficiency of frataxin is involved in the regulation of mitochondral iron content which is responsible for myocardial injury. We suggest the widespread use of idebenone to treat patients with Friedreich ataxia and hypertrophic cardiomyopathy to improve the fatal prognosis of this type of cardiomyopathy.

Topics: Adolescent; Antioxidants; Benzoquinones; Cardiomyopathy, Hypertrophic; Child; Echocardiography; Electrocardiography; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondria, Heart; Treatment Outcome; Ubiquinone

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.

Topics: Antioxidants; Benzoquinones; Cell Death; Drug Delivery Systems; Fibroblasts; Friedreich Ataxia; Humans; Mitochondria; Models, Biological; Organophosphorus Compounds; Oxidative Stress; Ubiquinone; Vitamin E

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.

Topics: Benzoquinones; Biological Assay; Biomimetics; Coenzymes; Fibroblasts; Friedreich Ataxia; Glutathione; Glutathione Peroxidase; Humans; In Vitro Techniques; Models, Biological; Ubiquinone

Idebenone is a quinone analog that is applied in the treatment of several neurological disorders including Friedreich ataxia and mitochondrial encephalomyopathies. Our aim was to develop an easy and sensitive analytical HPLC-procedure for the determination of idebenone in the serum of patients treated with this drug. Serum samples from nine paediatric patients diagnosed with Friedreich ataxia and receiving idebenone treatment were analyzed. Idebenone was separated from serum by reverse high-pressure liquid chromatography and analyzed using an electrochemical detection procedure. No interferences were observed during analysis of patient samples obtained prior to idebenone treatment. Calibration of idebenone concentration indicated a linear range between 500 pmol/l and 5 micromol/l and calculation of within-run and between-run coefficients of variation suggested adequate analytical quality for reliable determination. In agreement with previously reported data, during drug therapy, idebenone serum concentrations (basal conditions, range 0.1-0.49 micromol/l) were greatly elevated 90 min after an oral dose (range 0.66-3.63 micromol/l). Thus, we have developed a simple and rapid method that offers adequate analytical quality for accurate idebenone determination.

Topics: Adolescent; Antioxidants; Benzoquinones; Child; Chromatography, High Pressure Liquid; Electrochemistry; Female; Friedreich Ataxia; Humans; Male; Monitoring, Physiologic; Pharmacology, Clinical; Ubiquinone

Friedreich's ataxia (FRDA) is a neuro-degenerative disease causing limb and gait ataxia and hypertrophic cardiomyopathy. It results from a triplet expansion in the first intron of the frataxin gene encoding a mitochondrial protein of yet unknown function. Cells with low frataxin content display generalized deficiency of mitochondrial iron-sulfur cluster-containing proteins, which presumably denotes overproduction of superoxide radicals in these organelles. Idebenone, a short-chain quinone, may act as a potent free radical scavenger protecting mitochondria against oxidative stress. We therefore carried out an open trial of idebenone (oral supplementation; 5mg/kg/day) in a large series of FRDA patients and followed their left ventricular mass and function. Consistent and definitive worsening being observed in the natural course of the disease and cardiac hypertrophy having no chance of spontaneous reversal and to be subject to a placebo effect, the patient's heart status before and after the treatment was used to unambiguously establish the effect of the drug. After six months, heart ultrasound revealed more than 20% reduction of left ventricular mass in about half of the patients (p < 0.001) and no significant change in the other half. Since any measurable reversion of this pathogenic trait is highly significant, this demonstrates the efficiency of idebenone in controlling heart hypertrophy in FRDA. Owing to the absence of side effects of the drug, idebenone (up to 15mg/kg/day) should be prescribed for FRDA patients continuously as early as possible.

Topics: Administration, Oral; Adolescent; Adult; Antioxidants; Benzoquinones; Cardiomyopathy, Hypertrophic; Carrier Proteins; Child; Child, Preschool; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Male; Treatment Outcome; Ubiquinone; Ventricular Function, Left

Topics: Aconitate Hydratase; Benzoquinones; Coenzymes; Deferoxamine; Electron Transport Complex II; Friedreich Ataxia; Humans; Iron; Iron-Sulfur Proteins; Multienzyme Complexes; Oxidoreductases; Quinones; Succinate Dehydrogenase; Ubiquinone

Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia.. Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily).. Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g).. Our in-vitro data suggest that both iron chelators and antioxidant drugs that may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.

Topics: Adult; Antioxidants; Benzoquinones; Cardiac Volume; Cardiomyopathies; Child; Electron Transport Complex II; Female; Friedreich Ataxia; Humans; Iron Chelating Agents; Male; Multienzyme Complexes; Myocardium; Oxidoreductases; Succinate Dehydrogenase; Ubiquinone

Topics: Antioxidants; Benzoquinones; Female; Friedreich Ataxia; Glutathione Peroxidase; Glutathione Reductase; Humans; Selenium; Ubiquinone