Barbeau A

Pyruvate metabolism in Friedreich's ataxia.

Friedreichs ataxia patients show evidence of an abnormally elevated and prolonged response of pyruvate and lactate to a glucose load, with normal fasting levels. However, ther is a bimodal distribution of this response with high and low pyruvate responders. This trait appears to be determined genetically, However, although in vivo tests suggest low oxidation of pyruvate, we were unable to confirm any in vitro impairment of each of the components of the pyruvate dehydrogenase (PDH) complex. We conclude that the defect is in the metabolic regulation of PDH, probably at the E3 (lipoamide dehydrogenase) step.

Glucose and insulin metabolism in Friedreich's ataxia.

Our prospective survey of 50 ataxic patients confirms the previous finding of frequent clinical or chemical diabetes in Friedreichs ataxia. Eighteen percent of our typical cases have clinical diabetes and 40% at least an abnormal glucose tolerance curve. However, this finding does not appear to be specific to that form of ataxia. Furthermore, we have shown that most patients with ataxia have normal or low fasting insulin levels, but a hyperinsulinic response to a glucose load.

Amino acid metabolism in Friedreich's ataxia.

A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreichs ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the presence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other beta-amino acids in Friedreichs ataxia.

Lecithin: cholesterol acyltransferase activity and fatty acid composition of erythrocyte phospholipids in Friedreich's ataxia.

In a study of the fatty acid composition of erythrocyte membrane phospholipids in Friedreichs ataxia, a lower percentage of linoleic acid in phosphatidylcholine was demonstrated. An enzyme involving the exchange of lipids between plasma and erythrocyte membrane, lecithin: cholesteryl acyltransferase (LCAT) was also studied. It was found that the LCAT activity had a trend towards low values. However, crossing-over studies indicated that when the LCAT enzyme of patients was exposed to its own substrate it gave low activity values but that the result reverted to normal when control substrate was used.

Erythrocyte membrane lipids in Friedreich's ataxia.

In a study of the lipid composition of erythrocyte membranes in Friedreichs ataxia, the concentration of the major membrane components (phospholipids, cholesterol and protein) in ataxic patients, family members, and control subjects were found to be the same. The total fatty acid distribution was also normal. However, an altered distribution of phospholipid classes in erythrocytes was noted (an increase of PI + PS and a decrease of PE in Friedreichs ataxia patients).

Platelet taurine uptake in spinocerebellar degeneration.

The uptake of 14C-taurine was studied in the platelets of 20 ataxic patients and 20 age-matched normal control subjects. No significant differences were found in uptake or kinetics of taurine between the two groups of subjects. If a transport defect in taurine exists in Friedreichs ataxia, it is not present in all tissues. Preliminary indication was obtained in favor of heterogenity of the uptake pattern between ataxic individuals.

Taurine in cerebrospinal fluid in Friedreich's ataxia.

In a previous study we reported low values of taurine and aspartic acid in the CSF of patients with Friedreichs ataxia, when the results were compared to the literature. Further studies have revealed that unforetold difficulties with the advertised methodology of sequential multi-sample amino acid analysis were responsible for low values in the determination of these two amino acids in the small volumes necessary for CSF. A corrected method is presented. With the latter method the differences disappear for CSF taurine and aspartic acid, but they remain valid for the previously reported blood and urine values in Friedreichs ataxia. GABA levels are also normal in Friedreichs ataxia CSF.

Bilirubin metabolism - preliminary investigation.

In our studies, high total bilirubin values in the plasma were noted in cases of Friedreichs ataxia. A bimodal distribution of the values indicated the possible presence of two subgroups of patients. In these kindred, we demonstrated an elevation in unconjugated bilirubin with features similar to those reported in Gilberts syndrome: normal liver function tests, elevation after fasting and day to day variability. We also report preliminary experiments indicating that bilirubin levels may be taurine dependent. We postulate that the defect could be a secondary component of the ataxic disease, possibly indicating a defect in membrane transport.

Clinical laboratory findings in Friedreich's ataxia.

All clinical laboratory tests carried out in 4 groups of patients with the diagnosis of typical or atypical Friedreichs ataxia have been found to be within the normal range. In this prospective study of 50 patients, a number of findings previously reported to be abnormal in the literature, have not been confirmed.

Origin of Friedreich's disease in Quebec.

We have been able to trace 40 cases of classical Friedreichs disease from 14 previously unrelated French Canadian kindreds to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin. One member of this couple presumably introduced one gene for Friedreichs disease into the French Canadian population. This gene has now been traced over 12 generations to both parents of the present cases. We plan to use this knowledge to study the spectrum of clinical manifestations of this gene and to carry out gene chromosomal localization studies, using the techniques of linkage and of molecular biology. Such studies in rare autosomal recessive disorders have previously been judged to be almost impossible.