Friedreich's Ataxia: Idebenone Treatment in Early Stage Patients

Artuch, Rafael; Aracil, A.; Mas, Ana; Colomé, Catrina; Rissech, Miquel; Monrós, Eugènia; Pineda, Mercédes

doi:10.1055/s-2002-34494

Cited by 114 publications

(82 citation statements)

References 15 publications

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“…6 To achieve optimal therapeutic gain, medication strategies for ataxia should be introduced at an early stage. 7 Treatment effects are mostly assessed by surrogate ataxia markers, such as the International Cooperative Ataxia Rating Scale (ICARS). However, ICARS scores in children have not been validated, and it is unclear whether ICARS scores are confounded by other factors such as muscle weakness.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, previous studies in children with FRDA have described improved ICARS scores after experimental treatment with (antioxidative) idebenone medication. 7 However, the 'improved' ICARS scores were interpreted against adult rather than paediatric comparison values. 8 Since ICARS scores in healthy comparison children are likely to 'improve' with age (by maturation), longitudinally improved ICARS scores do not necessarily reflect a positive therapeutic effect.…”

Section: Resultsmentioning

confidence: 99%

“…In young children with FRDA (with moderate muscle weakness), such a relationship seems less obvious. Since FRDA treatment strategies preferentially target at an early disease stage, 7 we aimed to associate paediatric FRDA muscle and ataxia parameters. The present paediatric dynamometry and ultrasound parameters reveal a similar pattern of muscle impairment.…”

Section: Discussionmentioning

confidence: 99%

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In children with Friedreich ataxia, muscle and ataxia parameters are associated

Sival

Pouwels

Brederode

et al. 2011

Developmental Medicine &Amp; Child Neurology

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FRDA Friedreich ataxia ICARS International Cooperative AtaxiaRating Scale MUD Muscle ultrasound density MUV Muscle ultrasound volume SEP Sensory evoked potential AIM In children with Friedreich ataxia (FRDA), ataxia is assessed using the surrogate marker the International Cooperative Ataxia Rating Scale (ICARS). We aimed to determine whether ICARS scores in children with FRDA are confounded by muscle weakness.METHOD In 12 children with FRDA (10 males, two females; mean age 13y 6mo, SD 2y 6mo) and 12 age-matched children without FRDA (nine males; three females), we determined the association between muscle and ataxia parameters (i.e. muscle ultrasound density (MUD), muscle force, sensory evoked potentials, and ICARS scores). Children with FRDA were included on the basis of FXN gene analysis. Children in the comparison group were included on basis of uneventful pregnancy and normal cognitive and neurological development. RESULTSIn children with FRDA, muscle ultrasound density was homogeneously increased in the biceps, quadriceps, and tibialis anterior muscles (median 4SD). FRDA muscle weakness was significantly more pronounced in proximal than in distal muscles ()2SD vs )0.5SD respectively; p=0.004), with a stronger impairment of leg muscles than of arm muscles ()2SD vs )0. SD respectively; p=0.001). Comparing MUD between children with FRDA and an age-matched comparison group revealed a relatively strong increase in MUD in the proximal leg muscles in the FRDA group. Under the condition of persistently absent sensory evoked potentials, leg ICARS subscores in the FRDA group appeared to be positively associated with leg muscle force until a maximal plateau level of ICARS subscores was reached.INTERPRETATION In children with FRDA, ataxia scales based on ICARS are confounded by muscle weakness. Longitudinal ICARS evaluations in children with FRDA do not necessarily indicate altered ataxia.Friedreich ataxia (FRDA) is an autosomal, recessively inherited disorder that is associated with progressive ataxia, muscle weakness, and hypertrophic cardiomyopathy. In about 98% of affected individuals, FRDA is associated with a homozygous GAA trinucleotide expansion in the first intron of the FXN gene on chromosome 9q13; in the remaining 2%, FRDA is associated with a heterozygous GAA expansion in intron 1 on one allele and another inactivating mutation on the other allele.1 The genetic defect hampers frataxin transcription, resulting in deficient mitochondrial iron-sulphur-containing enzymes, respiratory chain dysfunction, and oxidative stress. Frataxin is strongly expressed in the central and peripheral nervous system and muscles. Consequently, disturbed central and peripheral innervation 3,4 and oxidative muscle stress 5 may influence FRDA disease manifestation. This could explain why FRDA encompasses a variety of disease symptoms involving motor and sensory neuropathic, myopathic, spastic, choreatic, and ataxic features. To achieve optimal therapeutic gain, medication strategies for ataxia should be introduced at an early stage....

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In children with Friedreich ataxia, muscle and ataxia parameters are associated

Sival

Pouwels

Brederode

et al. 2011

Developmental Medicine &Amp; Child Neurology

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“…In these studies, idebenone consistently improved cardiac hypertrophy, which is an important feature of FRDA. Neurological symptoms have not been improved as much as cardiac problems, however higher doses of idebenone especially in younger patients seem to be much more promising for neurological efficacy [76,[85][86][87].…”

Section: Idebenonementioning

confidence: 99%

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Miotto¹,

Striebel²,

Cho

et al. 2013

Drug and Alcohol Dependence

121

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Abstract:Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.

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“…One small, open-label trial in young FA patients found an improvement in overall neurological function that was related to plasma idebenone concentrations. 11 This suggests that treatment may be eff ective if given early in the disease course, and that improvement may be dependent on higher doses of idebenone. This suggestion is supported by the fi nding in two other trials that patients who still had cardiac hypertrophy after treatment with 5 mg/kg idebenone daily subsequently responded when the dose was increased to 10 mg/kg daily.…”

Section: Introductionmentioning

confidence: 99%

Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial

Prospero¹,

Baker²,

Jeffries³

et al. 2007

The Lancet Neurology

279

161

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SummaryBackground 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 defi nite improvement in neurological function has not been shown.

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Friedreich's Ataxia: Idebenone Treatment in Early Stage Patients

Cited by 114 publications

References 15 publications

In children with Friedreich ataxia, muscle and ataxia parameters are associated

In children with Friedreich ataxia, muscle and ataxia parameters are associated

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial

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