Search

Recent systematic studies of Friedreich's ataxia, a hereditary degenerative disease, have uncovered a number of previously unsuspected biochemical defects, pieces of a puzzle which may in fact be closely related: a decrease in the activity of lipoamide dehydrogenase in the serum; a decrease in the protein content of high density lipoproteins and in their essential fatty acid composition; a marked decrease in glutamic acid and aspartic acid concentrations in the cerebellum and spinal cord; and a renal loss of taurine and β-alanine.

Administration of zinc into the left lateral ventricle of rats elicited yawning-stretching behavior. Yawning and stretching was not observed after injection of the metal ions manganese, copper and cadmium. Intraventricular injection of β1–24-ACTH, synthetic α and β-LPH also evoked yawning and stretching after a latent period of 40–60 minutes. The administration of L-glutamate and D, L-glycine was ineffective in producing yawning-stretching behavior.

An observation is presented of unusual variations in dentition during the same day in a patient undergoing Ievodopa treatment for Parkinson’s disease. These variations were documented during normal, free, and rigid periods with the aid of plaster casts of the occlusion, radiographs of the arches, pantographic measurements of the arches, and bitewing radiographs.

Over a two-year period one hundred and sixty-two patients with Parkinson's disease have been treated with L-DOPA in a cooperative study involving four hospitals in the Montreal area. The clinical results for the first consecutive one hundred patients treated for longer than three months are reviewed. These observations warrant the conclusion that L-DOPA is by far the best currently available treatment for Parkinson's disease. Some potentially troublesome side effects still exist and these require further investigations.

Previous observations on clonic and tonic seizures in rats induced by intraventricular injections of ouabain, Zn2+, or Cu2+ have been expanded and confirmed. Tritiated ouabain was injected intraventricularly to rats and its regional distribution studied in the brain. The hippocampus and hypothalamus were found to be the regions with highest accumulation of radioactivity. This was supported by the in vitro finding that synaptosomes from both these regions demonstrate the highest uptake of the labelled ouabain. Subcellular fractionation experiments following in vivo injection of 3H-ouabain revealed that maximal radioactivity is associated with synaptosomal membrane fractions rich in Na+–K+-ATPase.

3,4-dimethoxyphenylethylamine (DIMPEA) was injected into Rhesus monkeys and the pattern of excretion of urinary catecholamines and metabolites was studied for three days post-injection. A selective increase in urinary dopamine excretion was demonstrated following a single injection of 20 mg/Kg DIMPEA. In male albino Sprague-Dawley rats, a single injection of DIMPEA (100 mg/Kg) caused an increase in the concentration of dopamine in the central grey masses of the brain. DIMPEA was shown not to decrease the activity of rat COMT, MAO and dopamine-β-hydroxylase. It is postulated that DIMPEA acts in competition with dopamine at specific dopaminergic nerve endings, in areas where dopamine is the end-point of catecholamine metabolism (e.g: striatum, lungs) and where it probably has an independent physiological function.

We measured the activity of cytosolic and of mitochondrial malic enzyme in the hearts from 4 patients with Friedreich's disease and from two non-ataxic control subjects. There was a wide variability in the results and the slight overall decreases in both enzyme activities were not considered to be statistically significant. From these and other results, we conclude that deficient mitochondrial malic enzyme activity is not a constant or primary feature of Friedreich's disease.

SUMMARY:The cardiovascular signs and symptoms were recorded in 36 patients with typical Friedreich's Ataxia (Group la, lb). Seventeen patients were asymptomatic and this did not correlate with the severity of the disease. No pathognomonic clinical constellation was found to reveal the underlying cardiomyopathy.

SUMMARY:Rats rendered diabetic by alloxan monohydrate were studied to investigate the effect of increased blood glucose upon the concentration of various putative neurotransmitter amino acids in the cerebellum. No modification was found in the concentrations of glutamate, gamma aminobutyric acid (GABA), glutamine, glycine or taurine, but there was a significant decrease in the cerebellar concentration of aspartate in the diabetic animals. This raises the question of the specificity of the aspartic acid defect found in some form of ataxia.

SUMMARY:A single intraperitoneal injection of 3-acetyl pyridine produces, within 24 hours of administration, signs of cerebellar ataxia and damage to the medulla oblongata and to the climbing fibers of the cerebellum. These changes are accompanied by changes in the concentration of certain amino acids in the appropriate areas. Glutamic acid is decreased in cerebellum, medulla, cortex, striatum, hippocampus, retina and olfactory bulbs, while taurine is specifically decreased in the cerebellum and medulla oblongata and aspartic acid in the retina. The concentrations of GABA and glycine are not modified in any of the areas studied. Glutamine is generally increased in concentration in areas of cell damage.

The distribution of apomorphine following subcutaneous injection of 20 mg/kg (as the hydrochloride) was measured spectrofluorometrically in specific regions of rat brain. Measurable concentrations were found in the brain within a few minutes of injection, the drug was still detectable for at least 60 min in all regions, and maximum concentration was observed 20 min after injection. Stereotyped behavior, characteristic of apomorphine action, followed a time course parallel to accumulation of the drug in the brain.

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.

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: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:The main purpose of this study was to examine the effects of intraventricular injections of glutamate and aspartate on the walking gait of rendered ataxic by the administration of 3-acetyl pyridine. Both amino acids significantly improved the walking gait of these animals. The effects of other substances known to have a stimulatory influence on locomotor activity in rats were also investigated. Amphetamine, apomorphine and thyrotropin releasing hormone (TRH) had no effect on the ataxic gait of 3-AP treated animals. Substance P significantly improved the gait of ataxic animals, but to a lesser extent than that seen with glutamate and aspartate.

Methionine enkephalin, the amino acid sequence 61–65 (Tyr-Gly­Gly-Phe-Met) of β-lipotropin, and the related peptide leucine enke­phalin (Tyr-Gly-Gly-Phe-Leu) are endogenous ligands for the opiate receptor in the brain (12). These peptides administered icv in rats (2) and mice (6) possess short-lasting and naloxone-sensitive anal­gesic properties. D-Ala2-Met-enkephalinamide (DAME, Tyr-D-Ala-Gly­Phe-Met-CONH2) is an enkephalin analogue and is pharmacologically similar to morphine and β-endorphin (β-LPH61–91); DAME is more potent in the induction of analgesia than methionine enkephalin (24) and elicits the same catalepsy in rats (29) as β-endorphin (4,17,19, 22) .

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).

Intraventricular injections of substance P, TRH and somatostatin were administered to rats rendered hypokinetic by bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus, Only substance P in a dose of 0.30 micrigrams/rat significantly increased motor activity as determined by photocell counts in a 5 min test session immediately after administration of the peptide. Behavioral observations indicated that grooming and not locomotion was mainly responsible for the greater activity scores. None of the three peptides at the doses examined potentiated or reduced the increased activity induced by 1 mg/kg apomorphine. Stereotyped behavior was also not affected by previous injections of substance P and somatostatin but was enhanced in animals which had received 5 micrograms/rat TRH 30 min prior to apomorphine.

SUMMARY:We have studied the brain regional distribution of methyl mercury following intravenous administration of CH3203HgCl in rat. Early peak levels were obtained in cerebellum, medulla oblongata and midbrain. The efficacy of removal of 203Hg by different chelators is also region dependent. The most efficient chelator for brain mercury proved to be mesodimercaptosuccinic acid.

A procedure is described for the determination of the Stokes radius of a detergent micelle by gel chromatography. It was observed that different lots of Sepharose 4B can exhibit a wide variation in the permeation of their gel pores. It is shown that this variation is due to differences in their pore size distribution. It has been observed that protein-sodium dodecyl sulfate (SDS) complexes of high Stokes radii eluted on a Sepharose 4B column with Stokes radii lower than the theoretical, as it has been previously reported but that protein-SDS complexes of low Stokes radii (less than 70 A), contrary to what might have been expected, eluted with Stokes radii higher than the theoretical. Evidence was obtained that their anomalous elution is due to an interaction of the detergent SDS with the gel pores of small diameter.

Friedreich’s ataxia is a recessively inherited spino-cerebellar ataxia appearing in childhood and relentlessly progressing to invalidity or death in middle age at the latest. A number of signs and symptoms have been found to be present in 100% of patients and are obligatory for a diagnosis, while other signs are definitely of a progressive nature (19). Incoordination of limbs (ataxia) is linked to evidence of damage to the posterior columns of the spinal cord and of dorsal root ganglia (loss of vibration and position sense), and of the pyramidal tract (absence of knee and ankle jerks, trophic changes). Most of these symptoms first appear in the lower limbs. Also observed are skeletal deformities (pes cavus, kyphoscoliosis). Electrically, almost all cases of the typical disease have absent or considerably diminished sensory action potentials in the sural nerves, while motor conduction velocities are either normal or only slightly decreased. Retinitis pigmentosa is not usually seen in typical Friedreich’s ataxia, but it is often present in association with a variety of other forms of hereditary ataxia. A final feature of Friedreich’s ataxia that must be stressed is the constant presence of a cardiomyopathy as evidenced by abnormal echocardiograms, vectocardiograms or electrocardiograms, singly or in combination. This cardiomyopathy is usually hypertrophic in type and occasionally obstructive; it appears to be an integral part of Friedreich’s ataxia, and not a phenomenon secondary to the disease process. The most important histological changes are myocardial fibrosis and foci of degeneration of the cardiac muscle cells. Granular deposits of calcium or iron salts can occasionally be found in these muscle cells.

Acetylcholinesterase (AChE, EC 3.1.1.7) of rat retina was studied with respect to its kinetic and other properties, and a comparison was made with the enzyme from brain. The subcellular distribution of the retinal AChE showed that the enzyme was concentrated in the synaptosomal–mitochondrial fraction although in the brain the AChE was distributed more evenly between the fractions studied. The enzyme from both retina and brain was easily solubilised and exhibited a Km of the order of 10−4 M. The pH optimum was 8.3–8.6 for the AChE from both tissues for both the soluble and particulate enzyme.

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.

Concomitant measurements of circadian variations in the urinary excretion of dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), epinephrine (E) as well as of creatinine, sodium and potassium under controlled dietary conditions during relative physical and emotional rest in 13 volunteers have shown that maximum excretion of all these substances occurred in the afternoon period between 14:30h and 18:00h, and minimum excretion in the morning between 4:00h and 5:00h. The changes were in some cases progressive from one collection period to the other, and synchronized for NE and E. DA and HVA excretions fluctuated from subject to subject. Excretory rhythms of sodium and potassium were found to be similar to those of the catecholamines. This can be explained by diurnal changes in renal blood flow and different renal excretory mechanisms of catecholamines. None of the catecholamines correlated with the urinary volume but urinary NE and E positively correlated with urinary creatinine, urinary NE and E with urinary DA and urinary sodium with urinary E. There are some common patterns in the diurnal rhythms of catecholamines and electrolytes but their interrelationship is different for individual catecholamines.

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.

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.

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.

Peptides have found a progressively more important role in the biochemistry and physiology of the brain in recent years. Many possess neurological and behavioral actions in addition to their function in endocrinology. This paper reviews the formation and distribution, as well as the neurological action, of peptides probably involved in Parkinson’s disease: β-LPH and its derivatives (MSH, ACTH4+10, β-endorphin). It also recounts the experience of many authors with prolyl-leucyl-glycine-amide (PLG) in that disease. Finally we propose a new theory of the etiology of Parkinson’s disease, based on a postulated deficiency in the important trophic function upon catecholaminergic neurons of A.P.U.D. cells.

Veratramine produces a characteristic excitatory action on the central nervous system, producing both tremor and a characteristic “struggling” behavior. This behavioral excitation is accompanied by changes in serotonin content in hypothalamus. The central serotonin agonist methysergide in doses of 5–15 mg per kg produces a dose-dependent inhibition of veratramine's action, while parachlorophenylalanine has no effect. These results are consistent with a serotonin agonist mechanism to explain veratramine's action.

The effect of 1-methyl-4-phenyl-pyridinum (MPP+), the main toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonism-causing neurotoxin, upon the activity of nicotinamide adenine dinucleotide (NADH) cytochrome c reductase (EC 1.6.99.3) and upon that of glutathione reductase (EC 1.6.4.2) was monitored spectrophotometrically. For the cytochrome c reductase, the increase in absorbance of reduced cytochrome c was measured at 550 nm; for evaluating glutathione reductase, the absorbance of nicotinamide adenine dinucleotide phosphate (NADPH) was followed at 340 nm. MPP+ but not MPTP reversibly inhibited NADH cytochrome c reductase, but not glutathione reductase. This may be a direct mechanism of cell toxicity by this neurotoxin.

A method for the quantitation of Coomassie blue-stained proteins in cylindrical polyacrylamide gels is described. It involves an elution of the dye with an 80% methanol solution in a sealed Pyrex tube at 100 degrees C for 3 h and a measurement of its concentration at 585 nm. Using a 6.5% polyacrylamide gel and bovine serum albumin as a protein standard, the curve of absorbance of the dye solution as a function of the amount of protein was observed to be linear up to 30-40 micrograms of protein and as little as 0.8-1.0 micrograms of protein could be measured. The validity of the method was indicated by the values obtained for the relative proportions of the human erythrocyte membrane proteins. Using this method, the color yields of several proteins varying widely with respect to their size, amino acid composition, and carbohydrate content were determined in a 6.5% polyacrylamide gel. The results showed that they were generally the same except for proteins having a high carbohydrate content which were significantly lower.

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.

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.

The effects of intraventricular injections of various doses (20.00, 5.00, 1.25, 0.30 and 0.07 μg) of synthetic Substance P on motor activity in rats were investigated. Activity scores as determined by photocell counts recorded for a 15 min test period were significantly increased in animals injected with 0.30 and 1.25 μg/rat Substance P. The other doses examined did not affect activity. Doses in the range of 40–80 μg produced immobility, rigidity and barrel rotations. Hypersalivation as indicated by a wet fur following an episode of grooming was observed in several animals. Administration of Substance P, in a dose of 0.60 μg, in combination with or 30 min after injections of 2 mg/kg d-amphetamine and 1 mg/kg apomorphine did not potentiate or reduce the increased activity and stereotypy induced by these two drugs.

SUMMARY: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 ataurine 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 istheprimary genetic event still has to be determined.

SummaryThe 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.

A combination of levodopa and a peripheral dopa-decarboxylase inhibitor, benzerazide (Ro 4-4602), was studied over a 75-month period of observation in 132 patients with Parkinson's disease. The combined therapeutic approach was without biological toxicity, was well tolerated by 95 percent of patients, and was highly effective: 72 percent of patients improved by more than 50 percent on a functional activity scale and the group as a whole improved on an objective battery by a mean of 46 percent. Neurologic side effects of abnormal involuntary movements, falls, and oscillations in performance were not improved over levodopa used alone. The combined therapy is to be preferred over the use of levodopa alone in the symptomatic management of Parkinson's disease.