The purpose of this experiment was to examine the effects of intraventricular injections of glutamate and aspartate on the gait of animals rendered ataxic by the administration of acrylamide. Contrary to their previously reported corrective Influence on ataxia induced by 3-acetyl pyridine, these amino acids did not modify the ataxic gait of acrylamide treated animals. This suggests that glutamate and aspartate can act in cerebellar but not in peripheral types of ataxia in animals.

A preliminary survey of tissue lipid composition in acrylamide intoxicated rats is reported. The animals were injected intraperitoneally with acrylamide 50 mg/kg body weight per day for 10 days. Liver cholesterol, mainly in the ester fraction, was decreased in treated rats. When fatty acid composition of liver cholesterol esters was examined, the proportions of linoleate and stearate were found to be decreased and were compensated by the increase of palmitate. Atrophy of epididymal fat pad resulted in severe triglyceride depletion and a relative increase in the proportion of phospholipids and cholesterol. There was also a reduction of linoleate, palmitate and palmitoleate in triglycerides and phospholipids of this tissue. There were, however, only minor changes in the fatty acid profile of the sciatic nerve.

An autosomal recessive mutant strain of mouse with a progressive neurological disorder is described. Histopathology is dramatic in the sensory afferents and in the red nucleus. In the cerebellar vermis the concentrations of glutamate, aspartate, glycine and GABA are significantly reduced, and in the cerebellar hemispheres the taurine/glutamate ratio is elevated. These mice may provide a useful experimental model of Friedreich’s ataxia.

Oral glucose tolerance, thyroid function tests, as well as thyrotropin, prolactin and growth hormone release after administration of thyrotropin releasing hormone, were evaluated in patients with Friedreich’s ataxia and unaffected family members. Impaired glucose tolerance was found in the majority of family members, affected or not. Thyroid hormone levels and PRL and TSH responses to TRH, were similar in all and normal. However, GH responses to TRH were abnormal in half of the patients, but in none of the unaffected family members. Paradoxical responses to neuropeptides may characterize some Friedreich’s ataxia patients, and may predict the possibility of therapeutic maneuvers with such peptides in these patients.

Plasma triglycerides although within the normal range have been shown to be higher in Friedreich’s ataxia than in control subjects. To determine whether this difference could be ascribed to a reduced catabolism of triglyceride-rich lipoproteins, the activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HL), released into plasma after an heparin injection, were measured in 13 cases of Friedreich’s ataxia and 14 control subjects of comparable signs. LPL was found to be significantly lower in the ataxic patients. Moreover about half of the cases clustered below the normal range for both lipase activities. This subgroup of Friedreich’s patients had significantly higher plasma triglycerides than those with normal lipase activities. Further studies are needed to relate these findings to other characteristics of the disease.

We studied free plasma catecholamines in 23 patients with Friedreich’s ataxia, having a mean age of 22 ± 9.6 (SD) years. Conjugated catecholamines were also studied in 10 patients. Mean plasma norepinephrine and epinephrine were significantly higher than controls both in the supine and standing positions. In total 15 out of 23 patients (65%) had increased free and/or conjugated plasma catecholamines. The increase in plasma catecholamines was more marked in patients with severe neuromotor impairment. Among the patients with left ventricular concentric hypertrophy (wall thickness >12 mm), only 3 had no demonstrable sympathetic hyperfunction.

Since the high local concentrations of norepinephrine at the site of release from sympathetic nerve terminals may serve as a trigger for the hypertrophic response of the myocardial cell, it is suggested that early pharmacological intervention could prevent or limit the cardiomyopathic process or its clinical consequences.

Resting levels of plasma norepinephrine, epinephrine and dopamine were determined in 9 patients diagnosed as having Friedreich’s Ataxia using a relatively new assay method, HPLC with electrochemical detection. Levels of norepinephrine and dopamine were found to be significantly elevated in patients as compared to controls while epinephrine, though increased, was not significantly higher. These results confirm in most parts previous findings of Pasternak et al. of increased plasma catecholamines and demonstrate the sensitivity and utility of the present method for the routine assay of plasma catecholamines.

The taurine urinary excretion pattern, before and after an oral load of 250 mg taurine, was studied in normal control subjects and in patients with typical Friedreich’s ataxia. It was demonstrated that in both situations the ataxic patients fell within the sub-types of “intermediate” and “high taurine excretors”, while none were “low taurine excretors”. It was also demonstrated that the excretion of taurine after a load in the obligate heterozygotes parents of the ataxic patients was intermediate between normal controls and patients. It is postulated that patients with Friedreich’s Ataxia lack normal regulation of the high affinity-low capacity uptake system for taurine (the TH system) in the brush border of kidney tubules. The low affinity-high capacity uptake system in the same membranes (the TL system) appears to be normal in Friedreich’s patients. The normal allele could be called THN and the variant THF and this trait would be inherited in an autosomal recessive fashion if it is linked to the Freidreich phenotype. Whether this finding is or is not the basic genetic defect in Friedreich’s Ataxia will require more studies to clarify, but it is of interest to note that a similar pattern appears to be present in the fibroblasts of these patients.

We have observed a markedly decreased formation of hippuric acid after benzoic acid load in patients with typical Friedreich’s Ataxia compared to normal control subjects. Since there is evidence for normal or even enhanced tauro-conjugation in the bile of patients with this disease, with a decreased G/T ratio, it is unlikely that co-factor or enzyme concentrations are the cause of this defect. We postulate decreased availability of the enzyme for glycine conjugation either to bile acids in the usual situation or to benzoic acid in the artefactual test condition. This could be due to the enzyme’s preference for an increased amount of taurine substrate in the liver. The relationship of this observation to the other biochemical changes observed in Friedreich’s Ataxia must still be established.

The present experiment was carried out using the following diets: FF, fat-free, and LP the same diet with 0.7% sunflower oil - given to the progeny of females kept on the FF diet since the mating. After 10 mM Mg2+ activation of the PDH phosphatase, the rate of [1-14C] pyruvate decarboxylation into acetyl-CoA ester units was determined in the liver, brain and adipose-tissue of the pair-fed developing rats. Results: In the male progeny, pyruvate dehydrogenase (PDH) activity was higher (61%) in the LP group livers than in the FF group livers, at the end of the 13 week experiment. Such a difference was not observed in the two group brains up to the 91 days postweaning, but was even larger (94%) between adipose-tissues of the LP and FF groups. In the female progeny kept 12 weeks on the diets, PDH activity in the LP group tissues was also higher than in the FF group tissues: 63% in the liver, 43% in adipose-tissues, and less than 10% in the brain. Therefore, a minute amount of lipids high in linoleic acid appeared to increase PDH activity, and especially in the liver and adipose-tissues of animals kept on a strictly fat-free diet. This stimulation of the PDH activity seems closely related to the phospholipid rehabilitation in the tissues (decrease in the trienoic: tetraenoic acid ratio values).

The plasma distribution of α-keto acids was measured in 26 subjects including 8 patients with Friedreich’s ataxia, 8 with the recessive spastic ataxia of Charlevoix-Saguenay and 10 healthy volunteers. The groups were matched with regards to age, sex, weight and the study was conducted under standardized dietary intake. The results indicate significant differences in α-keto acids distribution between the groups.

We studied the activity of valine dehydrogenase (VDH) in leukocytes of 14 Friedreich’s ataxia patients and of 14 normal control subjects. There was a significant 26% mean decrease in enzyme activity in the patients, a finding which could be responsible for the chronic accumulation of some α-keto acids with toxic metabolic consequences in that disease. However the deficiency was not present in all patients with the typical symptoms, nor was its magnitude sufficient to be considered the primary genetic defect in Friedreich’s A taxia.

To test the physiological significance in vivo of our previous in vitro finding of reduced valine dehydrogenase (VDH) activity inpatients with Friedreich’s Ataxia, we subjected ataxic patients and controls to an oral valine load test (1.0g) and measured the levels of branched chain α-keto acids in the plasma for 24 hours. We demonstrated a significantly higher peak for α-keto isovaleric acid in Friedreich’s Ataxia and a general trend towards higher than control values in all other α-keto acids measured, and at all times in the experiment. These changes are compatible with the postulated defect in regulation of the activity of VDH in this illness, but because of their small amplitude, they also indicate that a VDH – deficiency is not the genetic defect in Friedreich’s A taxia.

The author reviews the arguments for and against the four etiologic hypotheses in Friedreich’s disease that have been proposed since 1974: the “pyruvate hypothesis”, the “lipidmembrane hypothesis”, the “energy-defect hypothesis” and finally the “taurine hypothesis”. While none of these hypotheses are mutually exclusive, the author shows that all of these mechanisms play some role in the pathophysiology of the symptoms, but that only the “taurine hypothesis” appears to be compatible with all the known facts and the biochemical abnormalities reported. The author proposes that a taurine retention defect (possibly due to a block in the high affinity-low capacity transport of taurine – The TH System) is a primary event in Friedreich’s disease. Whether it is the primary genetic event still has to be determined.