Antioxidant Treatment of Friedrich’s Ataxia
Abstract & Commentary
Source: Lodi R, et al. Ann Neurol. 2001;49:590-596.
Patients with ataxia present a diagnostic and therapeutic challenge for the neurologist. It is helpful to divide the inherited ataxias into 2 groups, those that are autosomal recessive and those that are likely autosomal dominant (also known as the spinocerebellar ataxias or SCAs). Unlike the SCAs, symptoms of autosomal recessive ataxia typically begin within the first 2 decades of life. This group includes Friedrich’s ataxia, ataxia from vitamin E deficiency, the Ramsay-Hunt syndrome, Unverricht-Lundborg disease, and Ataxia Telangiectasia.
Friedrich’s ataxia is the most common form of inherited ataxia, with an incidence of 1 in 20,000. Starting before the age of 25, progressive limb ataxia, gait disturbance, and scoliosis usually bring the patient to medical attention. Friedrich’s is a multisystem disorder, and cardiomyopathy and diabetes are frequent findings. Most patients have absent reflexes and up-going toes, and in nearly all cases a GAA repeat expansion in the first intron of the frataxin gene is found.
Increasing evidence indicates that patients with Friedrich’s ataxia have a heightened susceptibility to oxidative stress. Using phosphorus magnetic resonance spectroscopy, Lodi and colleagues previously measured phosphocreatine and ATP levels in living muscle. They demonstrated that patients with Friedrich’s ataxia have defects in both cardiac and skeletal muscle metabolism.
The present study tested the hypothesis that treatment with high-dose antioxidants could improve measures of oxidative stress in these patients. Ten patients with genetically proven Friedrich’s ataxia were treated with oral Coenzyme Q10 (400 mg/d) and vitamin E (2100 IU/d) for 6 months. Patients were evaluated by physical and neurological examination, echocardiography, and magnetic resonance spectroscopy of cardiac and skeletal muscle. All patients were able to tolerate CoQ10 and vitamin E. Echocardiographic measures of left ventricular hypertrophy did not change. Similarly, neurologic examinations and clinical ratings on a standard ataxia scale did not change. In virtually all patients, however, a dramatic and statistically significant improvement in spectroscopic measures of energy metabolism occurred in both skeletal and cardiac muscle. The improvement was greatest in patients without left ventricular hypertrophy (ie, those treated earlier in their disease course), and greater in patients with longer GAA repeat length (ie, more severe disease).
Commentary
This first study shows that high-dose oral antioxidant therapy improves cellular bioenergetics in Friedrich’s ataxia. Improvements were sustained over 6 months of treatment, and the treatment was easy to tolerate. Patients who were treated earlier in the courses of their disease, and those with more severe metabolic deficits, were most likely to improve.
Skeptics might criticize this study because Lodi et al failed to demonstrate a clinically significant change with therapy. Although echocardiographic parameters and neurologic exams were unaffected by treatment, these are relatively insensitive measures of disease progression. The improvement in energy metabolism was robust and sustained, raising the possibility that long-term prophylactic treatment of presymptomatic patients might demonstrate an improvement in the forthcoming neurologic exams.
This study is important for patients with Friedrich’s ataxia and also for patients with other neurodegenerative diseases. Based on the power of this study, on the lack of alternative treatments, and on the benign nature of oral antioxidants, it would seem reasonable to recommend high-dose antioxidant treatment for Friedrich’s patients as well as those at risk for the disease. Whether these promising results can be extended to other disorders of oxidative stress (such as Parkinson’s disease) remains to be seen. —Steven Frucht
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