We have measured the activity of malic enzyme NADP+ dependent in the nuclear, mitochondrial, lysosomal and cytosolic fractions of cultured skin fibroblasts from twelve patients with Friedreich's ataxia and nine control subjects. Hexosaminidase, cytochrome-C-oxidase, lactate dehydrogenase and malic enzyme NAD+ dependent were used as marker enzymes. The activity of malic enzyme NADP+ dependent was not significantly reduced in the mitochondrial fraction of patients with Friedreich's ataxia as compared with controls. When corrected for possible contamination between mitochondrial and cytosolic fractions, malic enzyme NADP+ dependent activity was still not significantly reduced in patients with Friedreich's ataxia. Unless critical methodological differences were overlooked in this or previously published studies, we conclude that mitochondrial malic enzyme deficiency is not the primary genetic defect underlying Friedreich's ataxia.

The results obtained with high and low dose bromocriptine therapy were compared in a review assessing the per cent of patients showing improvement (not taking account of the extent of improvement). It is concluded that the response rate with low dose bromocriptine is as good as that obtained with high dose therapy for both de novo and levodopa treated patients. The incidence of adverse effects is similar in the high and low dose treatment groups: More levodopa reduction results in a higher daily bromocriptine requirement. A statistical analysis of 61 bromocriptine-levodopa treated patients showed no positive correlation between bromocriptine dose and severity or duration of Parkinson’s disease.

The long term consequences of the use of a dopamine agonist, bromocriptine, in the treatment of Parkinson’s disease are reported. In a first study in 82 patients showing late side effects of levodopa, bromocriptine permitted a significant decrease of the gastro-intestinal adverse effects. In contrast, no significant improvement of end of dose deterioration from levodopa was noted. In cases where levodopa had ceased to be active, bromocriptine produced an improvement in the clinical state. The drug was ineffective in the very advanced stages of the disease or in the cases of dyskinesias without “on-off” effects. Bromocriptine did not significantly improve freezing or “on-off” effects, but reduced other side effects of levodopa, in particular dystonia. In a second group of 29 patients who had never received levodopa treatment, bromocriptine was shown to be very effective as a first treatment of the disease. The most important finding was the absence of long term side effects similar to those usually observed under levodopa: in this group and in comparison with 38 patients taking levodopa, dyskinesia, dystonia, oscillations in performance and especially “on-off” effects were not noted. However, a partial loss of efficacy of bromocriptine was observed in 27% of cases. In a third group of 10 patients, bromocriptine introduced according to a low and slow protocol was found to be active in a limited number of patients only.

We measured the activity of cytosolic and of mitochondrial malic enzyme in the hearts from 4 patients with Friedreich's disease and from two non-ataxic control subjects. There was a wide variability in the results and the slight overall decreases in both enzyme activities were not considered to be statistically significant. From these and other results, we conclude that deficient mitochondrial malic enzyme activity is not a constant or primary feature of Friedreich's disease.

Experience with bromocriptine in 106 patients treated over nine years was reviewed. Most of the patients were already being treated with levodopa (combined with a peripheral decarbosylase inhibitor). These patients, after having initially achieved a good response to levodopa, were no longer responding satisfactorily. Most of the patients were also experiencing diurnal oscillations in performance: “wearing off” and “on-off” phenomena. In these patients previous attempts at changing the dose (increasing or decreasing) or changing the scheduling of levodopa had been unsuccessful. Bromocriptine was added to levodopa beginning at a dose of 5mg/day, and each week was increased by another 5mg/day. At a dose of bromocriptine of at least 25 mg/day, there was a decrease in disability in the majority of patients with a decrease in the severity of the diurnal oscillations in performance (especially “wearing off” phenomena). In most patients, the addition of bromocriptine resulted in an approximately 10% reduction in the dose of levodopa. The majority of patients sustained their improvement at least one year. In some patients improvement was sustained for up to five years. The therapeutic efficacy of bromocriptine was limited in many patients by the occurrence of adverse effects including mental changes, dyskinesias, orthostatic hypotension, and nausea. These adverse effects could often be minimized by reducing the dose of bromocriptine or levodopa. All adverse effects were reversible upon stopping the drug. We have found bromocriptine to be a valuable adjunct in the treatment of these patients.

In this paper the author reviews the progress accomplished in the understanding of Friedreich's disease since the start of the “Quebec Cooperative Study of Friedreich's Ataxia” in 1974. The last ten years have indeed seen important strides taken in the definition and nosography of the hereditary ataxias and the characterization of a number of new entities. Biochemically, the principal leads uncovered during the initial prospective survey, have been pursued to great detail. Unfortunately no clear-cut constant and severe enzyme block in the principal metabolic pathways has yet been identified, despite intensive studies. It is postulated that the defect may instead be a regulatory one and involve a decreased availability or utilization of one of the vitamin cofactors that are known experimentally, or clinically, to produce central nervous system damage with ataxia: Vitamin E, Biotin or Pantothenic Acid. Studies in that direction and in molecular genetics to localize the Friedreich's disease gene are being untertaken for the next phase of the Cooperative Study.