Electroencephalographie studies have heen done in two groups of hereditary ataxia: a group hearing the classical features of Friedreich's ataxia and a group clinically different described as autosomal recessive spastic ataxia of Charlevoix-Saguenay (A RSA CS). The qualitative anomalies observed in the two Ķroups were similar and were comparable with the data reported in the literature. However, the main difference between the two groups is the greater incidence of EEG abnormalities in the A RSA CS group, which suggests more involvement of the cortical and subcortical structures. This is reinforced by the lower I.Q. performance in the latter patients. Some comments are made about focal EEG findings, behavior and I.Q. In general, EEG was not considered a valuable instrument for diagnosis since no qualitative electric pattern could be identified. With regard to prognosis, EEG cannot be used as a criterion, since there is no relation between the degree of anomalies and the severity of the disease and since EEG does not worsen with the progression of the disease.

Nine cases of Friedreich's ataxia and seven cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) were submitted to neuroradiological procedures to determine the extent of atrophie processes in the central nervous system. All cases had a computerized cerebral tomography and five were studied with pneumencephalo-graphy. The results show a correlation between the two tests and the comparison between Friedreich's ataxia and ARS ACS.

In Friedreich's ataxia, the radiological signs are variable and discrete in most of the cases. In A RSA CS there are constant signs of cerebellar atrophy almost limited to the superior parts of the vermis and anterior lobes.

Two female patients aged 30 and 40 years with the Charlevoix-Saguenay ataxia were studied. Both had absent sensory action potentials in upper and lower extremities but, unlike typical cases of Friedreich's ataxia, they displayed a marked slowing of motor conduction velocities. Sural nerve biopsies taken from calf and ankle revealed a severe loss of large my elina ted axons contrasting with a normal myelinated fiber density. Evidence for active axonal degeneration was scarce, with no indication of axonal regeneration.

Teased myelinated fibers revealed an increased variability of internodal length but no evidence for myelin breakdown. These findings support, as a primary defect, a developmental abnormality of peripheral nerve, namely a lack of maturation of large myelinated axons and possibly a faulty myelination of nerve fibers. We think it is unlikely to represent a progressive axonal atrophie or dystrophic process, as suggested in Friedreich's ataxia.

We described a cluster of 8 independent sibships of Friedreich's ataxia in the ShFabien parish of Rimouski and have shown that they are all related within 6 generations. The study of this geographic and genetic isolate permitted the investigation of certain unusual features of the disease such as constant myopia, delayed reaction times to pain, flexor spasms, anda rapid evolution.

The purpose of the present study was to design a standard battery of tests capable of quantitatively characterizing ataxia and concomitant neurological signs in the rat. In addition to a systematic analysis of the walking gait of animals, tests for activity, catalepsy, rigidity, and various reflexive responses were included in the battery. The standardization and validation of the test system was performed by determining and comparing profiles of neurobehavioral effects produced by 3-acetyl pyridine, acrylamide, pyrithiamine, and thiamine deficiency, four experimental treatments reported to induce ataxia in animals. Results indicate that profiles of neurobehavioral disturbances accompanying ataxia in animals varied distinctively with each experimental treatment.

Thiamine-deficient encephalopathy in the rat is characterized by ataxie gait, loss of righting reflex and curvature of the spine. N euro chemie ai changes include a diminished activity of cerebral pyruvate decarboxylase leading to abnormal pyruvate oxidation. The present study shows that this defective pyruvate oxidation produces a significant depletion of three important amino acid neurotransmitters, namely gamma aminobuiyrie acid (GABA), glutamic acid, andaspartic acid. Such changes could lead to severe neuronal dysfunction and the observed neurological symptoms of thiamine deficiency. Some implications for the pathogenesis of Friedreich's ataxia are discussed.

In light of the available information on the cardiomyopathy of Friedreich's ataxia, the cardiomyopathic Syrian hamster may be an appropriate laboratory model. Cardiomyopathy in these animals is a result of calcium accumulation. We analyzed the atria and right and left ventricles from cardiomyopathic (CM) and random bred (RB) animals for calcium, magnesium, and iron concentrations at 30-40 and 60-70 days of age (age of maximum lesioning). There are no significant differences in the concentration of iron or magnesium among age-matched groups. The concentration of calcium in the left ventricles of the CM animals at 60 days old is 14 fold higher than that of R B animals. Although there is a significant difference in the concentration of calcium in the left ventricles of younger animals, it is not as pronounced as the difference in older animals. Analysis of the taurine concentration in 30-40 day old animals revealed that the CM animals show slightly higher taurine concentrations than RB in the whole heart. In 60 day old CM hamsters the ß-adrenergic receptor density of the ventricles is unchanged. This indicates that calcium overload is not due to a drene rg i c super sensitivity.

Of 13 patients with Fried-reich's ataxia (Type la) and 17 with type Ila recessive ataxias, all were found to have levels of “free erythrocyte protoporphyrin “ (FEP) above the normal range. The rise in FEP in Friedreich's ataxia correlated well with the age of the individual and thus appears to be related to the course of the disease. Subjects with olivo-ponto-cerebel-lar atrophy, Charlevoix syndrome, Duchenne muscular dystrophy, and Parkinson's disease were also found to have significantly elevated FEP, although the distribution overlapped with the normal range.

The finding of elevated FEP may indicate a relative heme deficiency in ataxia due to inhibition offerrochelatase leading to a state of ineffective, persistent erythropoiesis. The possibility of a prosta-glandin abnormality being related to this defect and to the pathogenesis of ataxia is considered.

Detailed in vivo and in vitro studies of glucose and insulin metabolism in Friedreich's ataxia patients and unaffected family members have further defined the extent of the abnormalities in carbohydrate metabolism. The high incidence of glucose intolerance and a hyper-insulinemic response to a glucose challenge in a high percentage of Friedreich's ataxia patients has been confirmed. An increased incidence of glucose intolerance among hétérozygotes is suggested, while the siblings show a more normal distribution of diabetes and a nearly normal insulin response to the glucose tolerance test. Human growth hormone patterns are normal for all groups.

Preliminary studies of insulin binding to erythrocytes suggest a difference in the binding characteristics among diabetic Friedreich's ataxia patients, while the binding in the non-diabetic Friedreich's ataxia group is similar to that of non-diabetic controls. Results from a small group of non-diabetic siblings suggest a normal insulin binding, while a tendency toward increased binding at low insulin concentrations among diabetic family members is noted.

The activity of lipoamide dehydrogenase and two closely related enzymes was studied simultaneously in early, mid, and late passage fibroblast cultures. Friedreich's ataxia fibroblasts tended to lose pyruvate dehydrogenase and citrate synthase activities, while lipoamide dehydrogenase activity remained constant with aging of the cells. Mean pyruvate dehydrogenase activity was lower over-all in fibroblasts from ataxies. Mean citrate synthase activity was higher in ataxie fibroblasts. Present tissue culture media do not represent the best conditions in which to reproduce cofactor binding defects such as those found in other genetic diseases with structural enzyme mutations.

Taurine resembles G ABA in its synaptic effects in the cockroach cereal nerve giantfiber synapse where it exerts a depressant action upon synaptic transmission. Both taurine and G A B A produce an increased conductance of pre- and postsynaptic membranes through changes in the permeability of chloride ions.

Taurine and ß-alanine uptake kineiics were studied in cultured skin fibroblasts from 9 patients with Friedreich's Ataxia and 8 controls. No significant difference was observed. The data support the presence of normal ß-amino acid carrier protein in Friedreich's Ataxia cell membrane.

The distribution of amino acids in two Friedreich's ataxia brains is compared to 4 control brains. Glutamate and G A BA were decreased in the ce r ebe l-lar hemispheres and/or in the vermis. Taurine concentrations were uniformly elevated throughout the areas studied. Taurine /glutamate and taurine/ GABA ratios were consistently elevated in Friedreich's ataxia brains, whereas glutamate/ glutaminę ratios were consistently decreased (with normal glutaminę concentrations).

The binding of ‘H-quinu-clidinyl henzilate. a muscarinic cholinergic antagonist, of xH-dihydroalprenolol, a beta adrenergic antagonist, and of ﹜H-flunitrazepam, a ligand which labels benzodiazepine receptors, was examined in several regions of control and Fried-retch's ataxia (FA) brains. yH-Quinuclidi-nyl henzilate binding appeared to increase in the inferior olivory nucleus, anterior and posterior cerebellar vermi but was unaltered m the dentate nucleus and cerebellar hemisphere of FA brain. The binding of 1 H-dihydroalprenolol seemed to increase in the inferior olivary nucleus yet was not different from controls in the dentate nucleus, cerebellar hemisphere, anterior and posterior cerebellar vermi of FA brains. * H-Flunitrazepam binding was slightly lowered in the inferior olivary and dentate nuclei but was unchanged in the other FA brain regions examined. The present study suggests possible trends in neurotransmitter receptor alterations in post-mortem brain tissue of FA patients.

Glutamic and aspartic acid uptake was measured in skin fibroblasts from patients with Friedreich's Ataxia, dicarboxylic aminoaciduria, and normal individuals. The results showed no difference in uptake kinetics of either dicarboxylic amino acids between Friedreich's Ataxia and normal cells, but reduced uptake velocities in dicarboxylic aminoaciduria fibroblasts. Friedreich's Ataxia fibroblasts were, however, less calcium-dependant and more magnesium and phosphate-dependent than controls in glucose-free incubation mixture. This difference might be related to some degree of glucose intolerance by Friedreich's Ataxia fibroblasts in culture.

Studies were undertaken to further characterize plasma lipids and lipoprotein abnormalities in Friedreich's ataxia. The high density lipoprotein (HDL) apo AI/All ratio was quantitated by densitometry and found to be normal. The free to esterified cholesterol ratio in HDL was lower in Friedreich's ataxia because of a reduction in the amount of free cholesterol in this lipoprotein class. The fatty acid profile of the cholesteryl-ester (CE) fraction was markedly deficient in linoleic acid (18:2) in both total plasma and HDL· There was a compensatory increase in saturated acids. The HDL phospholipid (PL) fraction also showed a reduction in the proportion of 18:2 with a concomitant increase in stearic (18:0) and oleic acid (18:1) while the HDL triglycéride (TG) fraction showed only an increase in palmi t oleic (16:1) and oleic acids. Feeding of soya lecithin rich in 18:2 failed to increase significantly the 18:2 content of HDL-CE and HDL-PL but lowered the percentage of 16:1 and 18:1 in all 3 lipid classes of HDL. Although the total plasma CE fatty acid profile was perturbed in Friedreich's Ataxia, total plasma PL and TG fatty acid patterns were unaffected. Among the plasma lipoprotein fatty acid profiles, that of the low density lipoprotein (LDL) was most affected, then that of the HDL. The very low density lipoprotein (VLDL) fatty acid composition showed an increase in 16:1 and a decrease in 18:2 which were entirely corrected by lecithin feeding. These results suggest the existence of a metabolic defect in the incorporation of 18:2 into chylomicron phospholipids within the intestinal mucosa.

The observed anomalies in high density lipoproteins in Friedreich's ataxia led us to investigate the state of cellular membranes in this illness. As a preliminary screening program, we studied the shape of erythrocytes; the phospho-lipid content of platelets and the transport properties of these membranes as indirectly reflected in the absorption of Vit E and the renal handling of orally injected taurine. All these investigations were normal, except for a tendency towards more echinocytes in Friedreich's ataxia and the significant increase in taurine urinary excretion after an oral load. We concluded that the possible membrane abnormalities are not major and will have to be searched for with more subtle and specific tests.