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Background:Friedreich's ataxia (FRDA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. A deficiency in the protein frataxin causes this disease. Frataxin deficiency leads to progressive iron accumulation in mitochondria, excessive free radical production and dysfunction of respiratory chain complexes. The expansion (GAA) repeat in the first intron causes decreased frataxin expression by interfering with transcription.Methods:Activity of mitochondrial respiratory chain complex I (measured as NADH ferricyanide reductase) and intracellular ATP measurement was performed on lymphocyte of FRDA patients (n=12) and control subjects (n=25).Results:Our findings showed that complex I activity and intracellular ATP were significantly reduced (P=0.001) in patients compared with controls and we found strong correlation between complex I activity and intracellular ATP content in FRDA patients (r = 0.93; PConclusions:This study suggested that a biochemical defect in complex I activity and ATP production, which may be due to iron accumulation in mitochondria, can be involved in age of onset of FRDA.

Background:Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype.Objective:To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1.Setting:Tertiary referral university hospital setting. Patients andMethods:A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact.Results:Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele.Conclusion:We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.

Introduction: Les buts de cette etude etaient de mesurer les niveaux d'acide homovanillique (HVA), un metabolite de la dopamine, d'acide 5-hydroxindoleacetique (5HIAA) , un metabolite de la serotonine, et de son precurseur, le tryptophane, ainsi que du 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), un metabolite de la noradrenaline et de la thiamine dans le liquide cephalorachidien (LCR) de patients atteints d'ataxie de Friedreich (AF), d'atrophie olivopontocerebelleuse (OPCA) et d'ataxie spastique autosomale recessive de Charlevoix-Saguenay (ARSAC) et de les comparer a ceux de sujets controles apparies pour le sexe et l'âge. Patients et methodes: Les niveaux de composes relies aux amines du LCR et les resultats de thiamine ont ete compares chez 40 patients atteints d'AF, 44 d'OPCA et neuf d'ARSAC a ceux de 94 sujets controles apparies pour le sexe et l'âge. Des examens de neuroimagerie (CT scan et tomographie a emetteur gamma i.e. SPECT) ont ete effectues chez tous les patients et les controles. Les patients atteints d'OPCA ont egalement subi des tests genetiques. Les composes relies aux amines du LCR ont ete mesures par chromatographie a haute pression en phase liquide et les niveaux de thiamine ont ete mesures par une methode microbiologique. Resultats: Les patients atteints d'AF avaient des valeurs de HVA, de 5HIAA et de thiamine du LCR significativement plus basses que les sujets controles et une tendance a des niveaux plus bas de MHPG. Chez les patients atteints d'OPCA, les valeurs de HVA, de MHPG et de thiamine du LCR etaient beaucoup plus basses, alors que les valeurs de 5HIAA du LCR avaient seulement une tendance a etre plus basses; chez les patients atteints d'ARSAC, seulement les valeurs de thiamine et de HVA du LCR etaient plus basses que celles des sujets controles. Conclusions: Les auteurs presentent les relations entre les observations neurochimiques d'une part et le degre d'ataxie et d'atrophie cerebelleuse et les observations de neuroimagerie d'autre part et ils concluent que les essais therapeutiques de remplacement et de neuroprotection chez ces patients devraient inclure deux ou trois medicaments a cause des deficits multiples en neurotransmetteurs.

SUMMARY:A computer program was developed to analyse the relative amount of EMG activity in an agonist-antagonist pair of muscles while subjects performed voluntary flexion-extension movements at the wrist to track a visual target. The data were presented to the subjects in the form of a vector display, the angle and length of which was determined from calculation of EMG power in the two muscles.This new approach to EMG biofeedback was evaluated in two hemiplegic patients and three patients with cerebellar incoordination. Over a training period of several weeks, all the subjects were able to modify the pattern of EMG activity in the muscles to reduce the amount of inappropriate coactivation of flexors and extensors and to produce more sustained and regular activation of individual muscle groups.

Seventeen patients with Friedreich’s ataxia or spastic ataxia were subjected to an urodynamic evaluation. Fifty-three per cent (53%) of the patients presented with urinary symptoms consisting of urgent micturition and urgency incontinence. Cystometric evaluation showed a lack of inhibition of the detrusor in 7 patients (41%). Abnormal electric hyperactivity of the external sphincter was documented in 6 cases (37.5%) by electromyography. Some hypotheses are presented to explain the etiology of these abnormal findings.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles epsilon 2, epsilon 3, and epsilon 4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the epsilon 2 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 epsilon 2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the epsilon 2 subset did not have significantly higher plasma triglycerides than the non-epsilon 2 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.

In the present overview an attempt is made to summarize the investigations carried out during the first part of Phase Two of the Quebec Cooperative Study of Friedreich's Ataxia. These investigations delineated the relative importance of various biochemical leads uncovered during the preliminary survey. It is possible to indicate some findings that may be primary and which should be pursued in subsequent investigations. Among these, the observation of an abnormal composition of high density lipoproteins in Friedreich's Ataxia appears to be the most important.

Auditory brainstem responses (ABRs) and cortical auditory evoked responses (AERs) were studied in a series of 16 Friedreich’s ataxia patients who varied in age, degree of clinical involvement and duration of the disorder. The ABRs were markedly abnormal in all but the youngest patient, and the abnormalities reflected the severity and duration of the disease. The latencies of the AERs were significantly longer in the Friedreich’s ataxia patients compared to normal controls, suggesting cortical as well as peripheral involvement of the auditory system. These data are discussed in terms of the neuropathology of the disorder and the similarities with the other sensory systems in Friedreich’s ataxia patients.

SUMMARY:Pyruvate dehydrogenase (PDH) activity was measured in platelets from 10 patients with Friedreich's ataxia, and 10 age-matched healthy control subjects. Both total PDH and active PDH activity were measured. There were no significant differences between the two groups.

SUMMARYAn Amerindian girl with Friedreich’s ataxia presented at the age of 14 years with intermittent bifrontal headaches and abdominal aching, often associated with nausea and recurrent vomiting and an evanescent pink, blotchy rash on the upper trunk. In these attacks she also had hypertension up to 210/160 mm Hg. Renal function studies, including intravenous pyelogram and angiography, were normal. Plasma renin activity (2.5 ng/ml/hr) was also normal. Total body CT scan was negative for phaeochromocytoma, and repeated estimations of 24-hour excretion of urinary VMA were normal or borderline high. Levels of total catecholamines in 24-hour urine were normal twice, but two random specimens during the paroxysmal episodes contained abnormally high levels of norepinephrine and dopamine. Plasma catecholamine concentrations were increased but not as high as with phaeochromocytoma. Blood pressure monitoring demonstrated marked fluctuations with position and temperature. A clonidine suppression test showed a substantial fall of plasma catecholamine levels, consistent with dysautonomia and not with phaeochromocytoma. It is concluded that the patient has dysautonomia of central origin, probably as a manifestation of Friedreich’s ataxia. These findings are discussed in relation to the recent demonstration of increased levels of plasma catecholamines in that disease.

The hypothesis is that an abnormal oxygen-hemoglobin dissociation curve is a primary or a secondary defect in patients with Friedreich's ataxia was investigated in 12 subjects with this disease. Hemoglobin and P50 were measured and compared with age and sex matched controls. The mean hemoglobin concentration was 14.2 g% and the P50 was 26.25 torr for the patients and 13.8 g% and 26.27 torr in the controls. These results indicate that the oxygen transport system is normal in this disease and likely exclude an abnormal oxygen dissociation curve as a primary or a secondary factor in the pathophysiology of the cardiomyopathy and the neuromyopathy found in this disease.

The general outline of the complete prospective study of 50 cases of spino-cerebellar degeneration is given. The general protocol followed, the criteria for inclusion and the mode of analysis are described. The aim of this study was to establish a base of clinical, physiological and biochemical facts upon which a logical and systematic approach to pathogenesis and treatment of Friedreich's ataxia could be attempted.

SUMMARY:Echocardiographic examination of 21 patients with Friedreich's ataxia (age 7 to 28 years) showed cardiac abnormalities in 90% of the cases. They were characterized by varying degrees of septal hypertrophy in 81%, left ventricular free wall hypertrophy in 61%, and a slight reduction of left ventricular internal dimension in 57% of the cases. Asymmetric septal hypertrophy (ASH) with a septal/left ventricular free wall ratio of over 1.3 was found in 29% of the cases, and systolic anterior motion (SAM) of the mitral valve in three patients. Two other patients showed evidence of a different type of cardiomyopathy with marked symmetric left ventricular hypertrophy and marked left ventricular enlargement.

SUMMARY:The preliminary results based on a three year retrospective study in cavus foot deformity of forty-four Friedreich ataxia patients regularly seen at the Neuromuscular Disease Clinic of Sainte-Justine Hospital have been presented. An accurate “weight-bearing” foot stereoradiographic technique has been recently developed by our group. Since the follow-up period with this device is not sufficient to provide statistical information, the conventional non-weight bearing technique has been utilized in this study to enable a possible comparison between the radiographs of ambulant and non-ambulant patients. Due to the present technique, the results of this study must be interpreted with caution.For 132 pairs of radiographs, 28 parameters have been analyzed. Four of these, namely the calcaneal inclination angle, the first metatarsal inclination angle, the inferior cortex of calcaneus-first metatarsal angle and the first-fifth metatarsals angle, were of particular interest. From these parameters, a preliminary quantitative description of cavus foot deformity in Friedreich’s ataxia has been attempted. Three stages of evolution have been tentatively identified for this type of neurological disorder.

SUMMARY: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.

SUMMARY:Leucocyte Glutamate Dehydrogenase (GDH) activity was measured in 44 patients with various forms of ataxia and 44 age and sex-matched normal controls. The only significant change found was a moderate decrease in activity in Freidreich's ataxia and a few patients with OPCA. This decreased activity is not primary to the disease but probably reflects a regulatory defect affecting mitochondrial membranes in these patients.

SUMMARY:In a study of the fatty acid composition of erythrocyte membrane phospholipids in Friedreich's 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 LCA Tactivity 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

SummaryIn a study of the lipid composition of erythrocyte membranes in Friedreich's ataxia, the concentration of the major membrane components (phosr pholipids, cholesterol and protein) in ataxie 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 P E in Friedreich's ataxia patients).

SUMMARY: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.

Fourteen Friedreich patients (F group) who had undergone a first electronystagmogram (E.N.G.) reported in 1978, had the same test 12 to 24 months after the first one. In the second study, there are more patients with bilateral hypoactive caloric nystagmus failure of fixation suppression, ocular dysmetria, irregular pendulum tracking and ocular flutter. These signs are probably most representative of the progression of the disease. Nineteen unaffected relatives of these patients (H group) also had an electronystagmogram but no special “familial” electronystagmographic pattern could be identified. Irregular ocular poursuit, nearly invariable in the F group but absent in the H group, was one of the most important differences between patients and their relatives.

The physician exposed to a large number of patients with a recessive form of ataxia, will occasionally observe slower progression forms which lack many of the severe features or cardinal symptoms of Friedreich's disease. We have studied 31 such cases in Acadians of the Maritime Provinces of Canada, and in their separated “cousins” from Louisiana, now called “Cajuns”. These patients are compared to a consecutive series of 22 Friedreich's disease cases in French Canada.It is shown that the age of onset is slightly later, but the progression much slower and the age at death older in the Acadian patients. These cases develop signs of pyramidal and posterior column involvement gradually and later than the classical Friedreich. As a result, pes cavus and scoliosis are less marked, as well as muscle weakness and cardiomyopathy. On the other hand, the rate of progression of areflexic ataxia, the “core disease”, is identical in both groups. The main difference in progression rates of the disorders occurs after 10-12 years of evolution, thus after the period of hormono-ponderal growth.These differences, coupled to the diverging genetic and genealogical backgrounds, are sufficiently large for the presumption of distinct disorders. Whether they are due to allelic mutations, linked but different genes, genes affecting the same metabolic pathway, but elsewhere or to completely distinct entities, will have to be left to further studies, but their existence in completely different populations and milieux is worthy of report.

HLA antigen typing was carried out in a family with an autosomal dominant form of spinocerebellar degeneration [possibly olivoponto cerebellar atrophy (O.P.C.A.)--Type 1]. Eleven ataxic patients, three possibly ataxic subjects, two unrelated spouses and 13 clinically normal at risk siblings were typed for ABO and Rh blood groups, HLA-A and HLA-B antigens, C4 component of the complement and a number of other serum proteins (Clq, beta-1A, beta-1C, C5, beta-lipoproteins). No solid evidence for linkage between the ataxia gene and the HLA or C4 loci could be demonstrated in this family. Certain serum proteins, and particularly beta-lipoproteins were found to be significantly reduced in some sub-groups of subjects.

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.

SummaryGlutamic 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.

SUMMARY:We made an electroretinographic (ERG) and visual evoked potential (VEP) study of 12 patients with Friedreich’s ataxia whose diagnosis was established using the Quebec diagnostic criteria. ERGs and VEPs were elicited to the same stimulating conditions. Flash evoked luminance changes and pattern-specific evoked potentials to check and diamond stimuli were used. Statistical analysis of the data was made using independent sample t-tests. Significant VEP delays were present under all test conditions. The presence of significant interocular and interhemispheric delays as well as evidence of abnormal temporal dispersion of the VEP response suggest there to be both diffuse anterior visual system disease and retrochiasmal involvement in Friedreich’s ataxia. The implicit times of the ERG b-waves were statistically within normal limits but the waveforms were of low amplitude and deformed and there were significant interocular implicit time differences. These ERG results suggest there are retinal conduction abnormalities in Friedreich’s ataxia which possibly play a role in the genesis of the abnormal VEPs.

SUMMARY:The authors present a simple system for disability scoring and functional staging of an ataxic patient, based on modifications of a previous scheme advocated by De Falco and collaborators (1979). This system was tested under field conditions in 47 ataxic subjects and found to be useful and functional.

The combined metabolic stresses of fasting and the intravenous injection of 50 mg nicotinic acid in Friedreich's ataxia resulted in the delineation of two sub-groups of responses. High bilirubin ataxics maintained abnormally elevated levels of bilirubin, while normal bilirubin ataxics behaved like the normal control group. It is postulated that this finding infers the possible linkage of the gene for Friedreich's ataxia and that for Gilbert's disease.

SUMMARY:Eighteen patients with the presumptive diagnosis of Friedreich's ataxia were studied. Clinical, neurophysiological and biochemical data were concordant in 14 patients and led to the diagnosis of typical Friedreich's ataxia in this group of patients. The remaining 4 patients differed from the typical patients in several respects, but mainly in the cardiological findings. It is concluded that no single clinical or laboratory finding is typical of F.A. Multidisciplinary approaches are essential to the diagnosis of Friedreich's ataxia.

Vigabatrin (ɣ-vinyl GABA; GVG), an irreversible inhibitor of GABA-transaminase, at a daily dose of 2-4 g, and a placebo were each administered orally for 4 months to 14 patients with cerebellar ataxia (9 with Friedreich's ataxia, 5 with olivopontocerebellar atrophy), in a double-blind, placebo-controlled crossover study. For the group as a whole, there was no significant difference between the GVG and placebo periods in any of the parameters of cerebellar symptomatology measured. Individually, one patient showed some improvement after 3 months of treatment with 2 g/day GVG. Tolerance to 4 g/day GVG was poor, whereas 2 g/day was well tolerated. The results suggest that agents which increase central GABA concentrations are not likely to be of benefit to patients with Friedreich's ataxia or olivopontocerebellar atrophy.

SummaryThe evolution of 15patients initially evaluated during Phase One of the Quebec Cooperative Study of Friedreich's ataxia has been studied approximately three years later. It is concluded that the deterioration of cardio-pulmonary function in Friedreich's ataxia is multi-factorial. The neuromyopathy (or the underlying metabolic or cellular defect) appears to be the main contributing factor to the deterioration of cardio-pulmonary function, which is exacerbated by the scoliosis and varying severity of the cardiomyopathy.

SUMMARY:A preliminary genealogical investigation of all the known ancestors from the year 1608 of 4 apparently unrelated French Canadian kindreds with Friedreich’s ataxia reveals that the original ataxia gene in the province of Quebec was present within a core of no more than 10 families living in Quebec City in the mid-1600's.

SummaryTwenty four ataxie patients were investigated with electromyography and nerve conduction studies. They were divided in two groups according to the area they came from, the evolution of the disease, and the clinical signs. Group I patients from the Rimouski area displayed all the clinical and electrophysiological signs of Friedreich's ataxia. Group II comprised patients who presented with a new syndrome known as the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Although the clinical evolution was better in the latter, there were more electromyographic signs of denervation and the motor conduction velocities were slower. Both groups showed identical and important abnormalities in sensory nerve conduction.The results of electrophysiological studies in spastic ataxia have not been reported to our knowledge. They underline the place of spastic ataxia as distinct f rom Friedreich's ataxia, spastic paraplegia, and the known familial neuropathies.

SUMMARY: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.

SUMMARY:Lipoamide dehydrogenase was measued in cultivated skin fibroblasts from twelve patients with Friedreich's ataxia and nine normal controls. No difference in specific activity, subcellular distribution and Vmax or Km was observed between patients and controls.

A systematic study of plasma lipids and lipoproteins was carried out in 11 cases of Friedreich's ataxia and 6 cases of familial spastic ataxia (Charlevoix-Saguenay disease) using 11 healthy normolipidemic volunteers of comparable age and sex as controls. No differences were noted in the fatty acid profile of the total lipid fraction, in the total cholesterol and phospholipids or in the percentage distribution of the individual phospholipid classes. The triglycerides were significantly higher in Friedreich's ataxia, but remained within the normal range. Although no systematic abnormalities could be detected in the electrophoretic pattern of plasma lipoproteins or in the apolipoprotein profile on polyacrylamide gel electrophoresis, major differences were found in the high density lipoprotein (HDL) fraction. Their total amount was reduced and their composition was abnormal in both neurological diseases. In Friedreich patients, the relative proportion of cholesterol and triglycerides was increased while the relative protein content was greatly reduced. In Charlevoix disease, a similar abnormality was seen except for the excess of triglycerides. The proportion of phospholipids in HDL was the same in the three groups of patients. In addition, the low density lipoprotein (LDL) fraction was slightly reduced in both diseases. This anomaly of the HDL fraction could indicate that the HDL apolipoprotein moiety has a greater affinity for cholesterol and triglycerides in Friedreich's ataxia than its normal counterpart.

SummaryDetailed 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.

SummaryAn estimate is given of the frequency of pathological changes (assessed by cell populations and from myelin staining) in the brains of 15 cases of Friedreich's ataxia. Mention is made of the special problem of distinguishing primary degenerative lesions from those due to circulatory disturbances arising from the patients cardiac disease.

SUMMARY: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.

A new syndrome of autosomal recessive spastic ataxia has been isolated in the Charlevoix-Saguenay region of Quebec. This syndrome is remarkably homogeneous and includes: spasticity, dysarthria, distal muscle wasting, foot deformities, truncal ataxia, absence of sensory evoked potentials in the lower limbs, retinal striation reminiscent of early Leber's atrophy and the frequent presence (57%) of a prolapse of the mitral valve. Biochemically, many cases show impaired pyruvate oxidation, others have hyperbilirubinaemia and some have low serum beta-lipoproteins and HDL apoproteins. These features are similar to those found in typical Friedreich's ataxia.

SummaryThe 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.

SUMMARY:Twenty-six of 50 patients were investigated with nerve conduction studies and electromyography using a standard protocol and were compared to the findings in 50 normal control subjects. Almost all cases of typical Friedreich's ataxia had absent sensory action potentials (SAP) in the digital (92%) or sural (96%) nerves. The others had markedly decreased S.A.P's. In these same patients motor conduction auvelocities were either normal or only slightly decreased. In the second, atypical group of 9 patients, the motor conduction velocities were considerably decreased.Because of the absence of sensory action potentials in Friedreich's ataxia, and that the absence was noted in our very mild cases, it is proposed that this measure be used to facilitate early diagnosis.

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.

SummaryIn 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.

In a previous study we reported low values of taurine and aspartic acid in the CSF of patients with Friedreich's 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 Friedreich's ataxia. GABA levels are also normal in Friedreich's ataxia CSF.

SUMMARY:Treatment of rats with asparagine or glutamine caused substantial increases in glutamine concentrations in cerebellum and medulla oblongata. Insulin treatment caused a diminution of glutamate and GA BA in these regions of brain. Since it is now well-established that glutamine is a very efficient precursor of the neurotransmitter pool of glutamate in mammalian brain, treatment with asparagine or glutamine could be of therapeutic (replacement) value in the treatment of neurological disorders such as Friedreich's ataxia, in which cerebral glutamate concentrations have been found to be diminished.

SUMMARY:In our studies, high total bilirubin values in the plasma were noted in cases of Friedreich's 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 Gilbert's 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.

In a detailed investigation of nucleotide synthesis, interconversion and degradation, no difference was found between subjects with Friedreich's Ataxia and normal controls. It appears improbable that this disorder is related to a primary defect in purine metabolism.

SUMMARY:This study consists of two parts: I. A detailed genetic analysis of 35 sibships in which 58 individuals were affected with Friedreich’s ataxia; and 2. Clinical and laboratory examinations of parents and siblings, in an attempt at carrier detection and diagnosis of the pre-clinical state.The increased parental consanguinity, the lack of affected individuals in other generations, and the lack of significance of extrinsic etiological variables, all suggested an autosomal recessive mode of inheritance, and this was confirmed by formal genetic analyses, employing several different methods.Associated abnormalities in our series of 58 patients included cardiomyopathy (51.7%), diabetes melitus (19.0%), optic atrophy (5.2%), nerve deafness (5.2%) and congenital malformations (6.9%). The incidence of diabetes mellitus. congenital malformations, and epilepsy and lor febrile convulsions was elevated in first degree relatives of patients with Friedreich’s ataxia.Examinations in first degree relatives revealed an increased frequency of neurological and skeletal abnormalities (26.3%). but no abnormalities on neuro-ophthalmological examination. Frequent EMG abnormalities were noted in parents (56.3%). but not in siblings; and these could usually be attributed to extrinsic causes. There was an increased incidence of ECG abnormalities in both parents (50.0%) and siblings (25.0% and some of these abnormalities may represent cardiomyopathy. An increased frequency of EEG abnormalities was also recorded in parents (14.3%) and siblings (27.2%). but these were not specific. None of these examinations resulted in a practicable method of carrier detection or preclinical diagnosis.Since carrier detection is still not feasible, genetic counselling remains the only possible means of prevention of Friedreich’s ataxia.