Concentrations of zinc, copper, manganese, chromium, cobalt and selenium were measured in the hair obtained from subjects with Friedreich’s disease, other inherited ataxias and neurological control patients. Althought zinc and copper concentrations were significantly higher in Friedreich than in the two control groups, the mean values for all groups were well within the normal range. No major deficiency in zinc or selenium was demonstrated in Friedreich’s disease using the approach. This does not, however, indicate that there is no defect in zinc and selenium metabolism, availability or transport in this disorder.

Zinc and taurine were measured in urine in the fasting state and following a 4mg/kg load of taurine in subjects with Friedreich's Ataxia (FA), and healthy controls (C), and subjects with Duchenne type muscular dystrophy (MD). Of the FA, 25% had increased fasting excretion of zinc, and 50% had increased excretion of zinc following the taurine load. The MD subjects all had increased zinc excretion at all times. The increased zinc excretion did not correlate with increased excretion of taurine. As an index of zinc deficiency, uptake of zinc by erythrocytes was measured in all subjects and in heterozygotes for FA. The pattern of uptake was abnormal for FA and heterozygotes. Hair analysis for zinc showed that 10 of the 12 FA subjects had low values.

We conclude that significant abnormalities in zinc metabolism exist in some, but not all cases of FA. The evidence available does not permit definition of the cause of these abnormalities, whether zinc deficiency or abnormal zinc transport is the primary factor.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles ɛ2, ɛ3 and ɛ4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the ɛ2 allele in the genotype tends to be associated with higher triglyceride levels, a study was undertaken to determine if a higher frequency of this allele could account for the presence of higher plasma triglycerides in subsets of patients with Friedreich's Ataxia. The frequency of the apo E phenotypes was determined in 37 subjects with Friedreich's Ataxia and compared with that of 102 normolipidemic and 102 hyperlipidemic individuals. There was no increased prevalence of the E3/2 phenotype and the ɛ2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the ɛ2 subset did not have significantly higher plasma triglycerides than the non-ɛ2 subset and the hypothesis was rejected. On the other hand, there was a trend for a decreased frequency of the E4/3 phenotype in the Friedreich's sample relative to the hyperlipidemic group but the difference did not reach statistical significance. The apo E phenotype distribution was also measured in a smaller sample of Charlevoix-Saguenay disease; this led to the discovery of two siblings with the relatively rare E2/2 phenotype and unexpectedly low levels of plasma lipid and lipoprotein concentrations. Plasma apolipoprotein E concentrations in both diseases were within the normal range except for subjects bearing the E2/2 phenotype.

Alteration of membrane fluidity and anomalies of membrane structural proteins have been suspected in Friedreich's ataxia. Plasma lecithinxholesterol acyltransferase (LCAT) activity is also lowered in this disease, presumably because of a substrate effect. The membrane-stabilizing effect of cholesteryl sulfate (CS) and its inhibitory effect on LCAT activity prompted us to measure this substance in the plasma of Friedreich's ataxia patients as well as in normal subjects and in patients with Charlevoix-Saguenay disease. Plasma cholesteryl sulfate concentrations were significantly higher in Friedreich's ataxia, with levels above the upper limit of normal in nearly half of the cases. This increase was unrelated to age, sex or plasma cholesterol levels, but closely associated with the severity of the disease and thus considered to be secondary. A similar phenomenon (except the association with severity) was observed in Charlevoix-Saguenay ataxia. Levels also tended to be higher in first-degree relatives of Friedreich cases. The significance of these findings is discussed in the light of recent knowledge and experimental data obtained in this laboratory on rats made deficient in essential fatty acids. The highest concentrations of CS observed in Friedreich's ataxia (1097 µ-g/dL, 6 times the normal mean) was only 25% as high as the concentrations reported to inhibit LCAT activity.

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.

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.

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.