Antioxidants and other pharmacological treatments for Friedreich ataxia
Abstract
Background
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.
Objectives
To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia.
Search methods
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.
Selection criteria
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.
Data collection and analysis
Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria.
Main results
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.
Authors' conclusions
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.
PICOs
Plain language summary
Antioxidants and other pharmacological treatment for Friedreich ataxia
Friedreich ataxia is a rare progressive condition that causes damage to the nervous system. It is inherited in an autosomal recessive pattern, meaning that an affected gene must be inherited from each parent for the disease to develop in their child. It is the most common recessively inherited ataxia worldwide. It usually presents between the ages of five and 15 years with clumsiness of movement, progressing to unsteadiness in standing and walking. Speech usually becomes slurred. Most people with the condition become wheelchair‐dependent in their late teens or early twenties. Heart abnormalities may cause premature death in 60 to 80% of people with the disorder. Other significant problems which may develop include scoliosis, and pes cavus (high arched foot deformity). The progression of the disease cannot be easily assessed by clinical examination or a laboratory test. Evaluation of disease progress using standard neurological scales is made more difficult when the person is wheelchair bound.
Recent studies have suggested that a synthetic antioxidant, idebenone, may help the most frequent heart abnormality, enlargement of the left ventricle. Antioxidants occur naturally in foods but do not reach a level that would be considered necessary to alter the progress of Friedreich ataxia.
A review of the medical literature revealed that there was only one small randomised controlled trial (RCT) with 29 participants which used idebenone for a sufficient period, 12 months. RCTs are studies in which people are allocated at random to receive one of several clinical interventions. One of these interventions is a control. The control may be a standard practice, a placebo (sugar coated pill) or no intervention at all. RCTs are generally accepted as the most valid method of determining the efficacy of a treatment, because the biases associated with other experimental designs can be avoided. Other clinical trials using antioxidants were identified but were not randomised or did not last long enough to be included in the review.
The included RCT showed that idebenone did not help the ataxia but did have a significant effect on the heart abnormality. No research on clinical relevance of this heart change has been done. Other pharmacological treatments being considered for Friedreich ataxia include deferiprone, erythropoietin, pioglitazone and histone deacetylase (HDAC) inhibitors but no RCTs have been completed using these treatments (www.curefa.org). A collaborative project using gene therapy in Friedreich ataxia mouse models and human brain cells is also in progress (www.ataxia.org.uk).
