A clinical and biochemical evaluation of twenty-two patients with Friedreich’s Ataxia and ten normal controls was undertaken in 1980 to assess the effect of lecithin and linoleic acid supplements on the course of the disease. The trial consisted of two consecutive six months periods on either supplements in a double-blind crossover fashion. Clinical appraisal was performed with regards to the following parameters: joints mobility, muscle strength, equilibrium, coordination, motor accuracy, speech and numerous day to day activities. Blood samples were obtained at the beginning and in the course of the trial for enzymatic determinations. This paper describes the methodology of the study.

Twenty-two patients with Friedreich’s Ataxia and ten normal controls were followed for one year and assessed as to their clinical performance after two successive six-month periods of lecithin or safflower oil. Results demonstrated no significant difference in performance scores according to group assignation, neither in patients nor in controls. According to stages, two patients in stage I and to a lesser degree, one patient in stage IV showed better scores for muscle strength and some motor accuracy and coordination tests with lecithin. Controls as groups maintained positive scores in all tests. Patients as groups showed negative mean values in nine out of eleven tests. Again as groups, patients receiving safflower oil demonstrated a mean 8% less deterioration than patients receiving lecithin. This study demonstrates that objective clinical tests and the participation of normal controls are a must in a therapeutic trial implicating patients with a progressive disorder such as Friedreich’s Ataxia. The possible role of linoleic acid as the active factor from which clinical improvement proceeded in some specific patients and with early functional stages of the disease, has to be considered and reevaluated in the near future.

Lecithin and sqfflower oil brought about the same changes in serum LAD activity and kinetics in patients with Friedreich’s Ataxia as in controls when results of this double-blind crossover study were analyzed according to group assignation. According to functional stages, pretrial LAD activity decreased with advancing severity while Km for lipoamide increased. Lecithin and sqfflower oil supplements corrected the elevated Km for lipoamide but produced a further reduction in LAD activity. These changes may have been due to the increased intake of linoleic acid, a precursor of lipoic acid, which is present in high percentage in both lecithin and safflower oil. Results of the biochemical study thus agreed with the clinical data gathered during the course of the one-year trial in suggesting that linoleic acid may well have been the active factor through which biochemical and clinical improvement was previously observed in patients with Friedreich’s Ataxia supplemented with lecithin.

Gamma-Vinyl GABA, an irreversible inhibitor of GABA-transaminase, was administered orally in two daily doses of 250 mg to 10 patients with cerebellar ataxia (9 with Friedreich’s ataxia, one with olivo-ponto-cerebellar atrophy) for at least one month in an open study. No significant difference occurred in the disability scores of cerebellar symptomatology for the group as a whole, but seven patients showed some improvement in scores with treatment and two patients claimed marked subjective amelioration. Tolerance to Gamma-Vinyl-GABA treatment was excellent. These preliminary results suggest that further studies with well-tolerated agents which enhance CNS GABA-ergic function are warranted in patients with cerebellar ataxia.

The purpose of the present study was to examine the ability of nicotinamide to prevent the appearance of neurobehavioral symptoms induced by 3-acetyl pyridine (3-AP) in rats. Nicotinamide in doses of 5,50 and 500 mg/kg was injected immediately after administration of 65 mg/kg 3-AP, and neurobehavioral measurements were made at 6, 12, 24, 48 and 72 hours after injections. The effects of 500 mg/kg nicotinamide injected at 3 and 6 hours after 3-AP treatment were also investigated. The results indicate that, starting at 50 mg/kg, nicotinamide can protect animals against most of the neurobehavioral effects of 3-AP. However, the muscular rigidity induced by 3-AP can only be reversed by 500 mg/kg nicotinamide, and the depressing influence of 3-AP on locomotor activity is not blocked by any of the doses of nicotinamide tested. In terms of time course, the protective action of 500 mg/kg is seen when injected 3, but not 6 hours after 3-AP.

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.