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This double blind cross-over study, involving 9 chronic spinal cord injured (SCI) patients (6 paraplegic and 3 paretic), was a first attempt to investigate the effects of the noradrenergic agonist, clonidine, on the modulation of the locomotor pattern and spasticity in patients with spinal cord lesions. Electromyographic (EMG), footswitch and video recordings were made as the patients walked on a treadmill with the support of an overhead harness if needed. Overground locomotion was also assessed in the paretic patients. All 3 spastic paretic patients had kinematic deviations and abnormal EMG recruitment profiles during the premedication or placebo sessions. With clonidine therapy one patient demonstrated a marked improvement in locomotor function. This patient progressed from non-ambulation to limited independent ambulation as the extent of coactivation in antogonist muscles decreased. The other 2 paretics who presented limited spasticity showed minimal changes while on clonidine. In the paraplegic patients, clonidine did not elicit locomotor activity, although there were marked reductions in stretch reactions and clonus during assisted locomotion. They remained incapable of locomotion, either during the control period or during the clonidine therapy. These results indicate that clonidine may be a potentially useful medication for both locomotion and certain manifestations of spasticity in SCI patients but further investigation is warranted.

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.

SUMMARY:We report a clinical and biochemical survey of 23 patients with Friedreich's ataxia from southern Italy. They were studied clinically and by means of a clinical rating scale devised by us (Inherited Ataxias Clinical Rating Scale). Laboratory tests, based on the Quebec Cooperative Study, were also performed on our patients. No major clinical or biochemical differences were found between Italian and Canadian patients. Investigation of CSF monoamine metabolites showed that HVA decreased after probenecid and metoclopramide loading

SUMMARY:Pyruvate dehydrogenase (PDH), α -keto gluturate dehydrogenase (α -KGDH) and lipoamide dehydrogenase (LAD) were measured in platelets of II patients with typical Friedreich's ataxia and 10 normal control subjects. Serum LAD was also evaluated in the same patients. No statistically significant changes were found in platelets for the group as a whole, although some patients had low values (more than one standard deviation below control mean). Serum LAD was significantly reduced in the patients with Friedreich's ataxia. This was not due to associated diabetes.

SUMMARY: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, (β -1A, (β-1C, C5, (β -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 β -lipoproteins were found to be significantly reduced in some sub-groups of subjects.

SUMMARY:We evaluated 15 patients with Friedreich's ataxia (FA) to define the incidence of myocardial involvement and the type of cardiomyopathy observed.All patients with FA had either ECG, vectocardiographic or echocardiography abnormalities, suggesting some degree of myocardial involvement. In contrast to reports indicating that asymmetric septal hypertrophy (ASH), often obstructive, is associated with FA, symmetric, concentric hypertrophic cardiomyopathy (SCH) was the predominant abnormality (sixty-seven percent of patients). Echocardiograms should be performed periodically in all FA patients since this technique allows the detection of cardiac hypertrophy.

SUMMARY:All clinical laboratory tests carried out in 4 groups of patients with the diagnosis of typical or atypical Friedreich's ataxia have been found to be within the normal range. In this prospective study of 50 patients, a number of findings previously reported to be abnormal in the literature, have not been confirmed.

We present a working and flexible classification of inherited ataxic syndromes based on the use of simple tools available to every clinician: a good history (particularly pinpointing the age of onset, the rate of progression and the mode of inheritance) and a neurological examination (identifying the presence of ataxia, deep tendon reflexes in the knee, optic nerve, retinal and/or 8th nerve signs). This classification is easily coded for computer translation on any personal computer. The place occupied by a given disorder may, by contiguity, give a clue to its pathophysiology.

SummaryWe 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.

We have measured in leukocytes the following lysosomal enzymes in II Friedreich disease cases, 11 “atypical” recessive ataxias, 13 neurological controls and 16 normal controls: hexosaminidase A and B; (3-galactosidase and neuraminidase (labile and cold stable, or A and B). The lysosomal enzyme deficiencies known to produce certain forms of spinocerebellar degeneration were not present in Friedreich's disease or the Charievoix-Saguenay syndrome. The very small scale survey of “atypical” recessive ataxias revealed 3 cases of severe deficiencies in hexosaminidase activity. Two adult brothers presenting with the clinical phenotype of Kugelberg-Welander disease (one also with ataxia), were shown to have a severe deficiency of both HEX A and HEX B activity (Sandhoff biochemical pattern). This is the first such report. A further adult female patient, unrelated to the others, had a severe isolated deficiency of HEX B and presented with a very slowly progressive and mild ataxia with severe internal strabismus. These patients and their families are being studied clinically and biochemically in greater detail and will be reported elsewhere. However these preliminary findings justify screening for such lysosomal defects in all cases of “atypical” recessive ataxia.

SUMMARY: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 β-lipoproteins and HDL apoproteins. These features are similar to those found in trypical Friedreich's ataxia.

SUMMARY:Angiograms of 12 patients with typical Friedreich's ataxia were analyzed. The results corroborate previous reports and justify the conclusion that the cardiomyopathy is of the hypertrophic type. In 10 of 12 cases, the hypertrophy is concentric, and non obstructive. Less frequently (2 cases), this hypertrophy is accompanied by diffuse hypokinesis and depressed ejection fraction.

SUMMARY: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.

We analysed the clinical features of 82 patients with dominantly inherited ataxia in a cohort survey. All patients fulfilled the diagnostic criteria for Machado-Joseph disease. The mean age of onset of symptoms was 39.8 (± 12.5) years and the duration of the disease was 9.2 (± 6.7) years. Ataxia, peripheral neuropathy, and fasciculation scores correlated with age of onset and duration of disease. Upper motor neuron scores failed to correlate with age of onset. In a follow-up study we analysed the clinical data of 46 patients two years after the first examination. A paired ttest was used to compare differences between observations. The results are in agreement with those of the cross-section in time, suggesting a deterioration of the symptoms with the evolution of the disease. We conclude that dynamic definition of the disease according to age of onset and duration of symptoms is preferable to subdivision into classical types.

SUMMARY:The suppressive effect of various amino acids against ouabaininduced seizures was investigated in young female rats. The amino acids were injected into the left lateral ventricle 10 minutes prior to the intraventricular administration of 5 μg. of ouabain. Animals receiving 1.9 x 10-1M solutions of hypotaurine and of β- alanine were almost completely protected from the ouabain seizures. Administration of L-alanine and of glycine was also effective, although running and leaping seizures still occurred to some extent. Betaine reduced only clonic-tonic and whole body flexion and extension seizures. In contrast, L-proline exclusively suppressed clonic-tonic and focal clonic seizures. Rats injected with isethionic acid showed increases in incidence of running and leaping seizures while L-arginine in high concentrations caused aggravation in clonic-tonic seizures. L-cysteine, even in low concentrations, also brought about an increase in the occurrence and incidence of clonic-tonic seizures. The ED50of hypotaurine was 10.11 x 10-2M for running seizures and 4.63 x 10-2, M for clonictonic seizures; that of β -alanine was 14.01 x 10-2M for running seizures and 5.50 x 10-2M for clonic-tonic seizures. However, hypotaurine and β -alanine, the most effective compounds tested in the present studies, provided less protection than taurine previously examined by us under similar conditions (Izumi et al., 1973).

SUMMARY:Dynamic muscle function was evaluated in nine patients with Friedreich's ataxia (FA) and eight with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The measurement of torque throughout maximum voluntary isokinetic knee movements was used to quantitatively describe muscle weakness in the ataxic patients. Both FA and ARSACS patients were shown to have decreased dynamic strength in comparison to normal values during knee extension and flexion movements at 30% /s. In the FA patients a lower torqueproducing capacity was seen in the older patients.The electromyographic (EMG) activity was recorded in lower extremity muscles during the movements. In the vastus lateralis (VL), deviations from the normal EMG activation pattern were described in both groups of patients. A reduced amplitude in the EMG activity in the medial hamstrings (MH) was seen in the majority of the patients. An index of coactivation was defined by comparing the EMG activity when a muscle lengthened (antagonistic) to the EMG activity when the same muscle shortened (agonistic) during the isokinetic contractions. In comparison to normal values increased coactivation indexes were present in the VL and MH in patients of both groups. The characteristics of dynamic muscle strength and the activation of agonistic and antagonistic muscles described in the present study will provide the basis of evaluation for the effects of therapy in these patients.

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.

Six patients with Friedreich's ataxia, 4 males and 2 females, their ages ranging from 13 to 33 years, were studied. The early manifestations started between age 7 and 13 with an evolution time between 6 and 20 years. Serial visual and brain stem auditory evoked potential recordings were made. A progressive increase in latency, reduction in amplitude and in latency inter-ocular difference of PlOO were observed. The pattern of the reversal checker-board visual evoked potential was preserved. A disorganized BAEP pattern, a well defined potential I, a very small potential V and a delay in the interpeak latency were constant findings. The assumption is made of a progressive involvement of both visual and central auditory pathways. Pathophysiological mechanisms are discussed.

SUMMARY:A systematic study of plasma lipids and lipoproteins was carried out in II cases of Friedreich's ataxia and 6 cases of familial spastic ataxia (Charlevoix-Saguenay disease) using II 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.

SUMMARY: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 tinforetold 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.

SummaryElectron spin resonance, scanning electron microscopic, and SDS-polyacrylamide gel electrophoretic studies of erythrocytes in Friedreich's ataxia have been performed. No alteration in the physical state of membrane lipids, in morphology, or in the staining profile of erythrocytes in Friedreich's ataxia could be demonstrated. An altered conformation and I or organization of proteins in ery-throcyte membranes in this disorder was suggested by spin labeling studies(P < 0.025), favoring the possibility of a generalized membrane abnormality in Friedreich's ataxia. These findings are discussed in relation to other inherited neurological diseases where similar studies have been performed.

We have measured the activity of malic enzyme NADP+ dependent in the nuclear, mitochondrial, lysosomal and cytosolic fractions of cultured skin fibroblasts from twelve patients with Friedreich's ataxia and nine control subjects. Hexosaminidase, cytochrome-C-oxidase, lactate dehydrogenase and malic enzyme NAD+ dependent were used as marker enzymes. The activity of malic enzyme NADP+ dependent was not significantly reduced in the mitochondrial fraction of patients with Friedreich's ataxia as compared with controls. When corrected for possible contamination between mitochondrial and cytosolic fractions, malic enzyme NADP+ dependent activity was still not significantly reduced in patients with Friedreich's ataxia. Unless critical methodological differences were overlooked in this or previously published studies, we conclude that mitochondrial malic enzyme deficiency is not the primary genetic defect underlying Friedreich's ataxia.

Twocases,afather and son, of recurrent cerebellarataxiain the same family are reported, suggestingafamilial trait for the dysfunction. In the older male the onset of each episode (30-90 min.) was signalled by dysarthria which then progressed towards gait ataxia; the son presented closely similar clinical symptoms. Physical examination and blood chemistry revealed no obvious neurological deficit or biochemical abnormalities, with the exception of I-III and III-IV evoked auditory wave interpeak latencies, which were found markedly abnormal on the left side in the father but not in the son; the EEG of both individuals showed some diffuse, slow wave abnormalities. A low dose of acetazolamide, 250 mg daily, has successfully repressed recurrence of the attacks over the past six months. Temporary withdrawal for 14 days of the carbonic anhydrase inhibitor in the father coincided with two observed ataxic episodes.

SummaryThe binding of ‘H-quinu-clidinyl henzilate. a muscarinic cholinergic antagonist, ofxH-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 of1H-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.

SUMMARY: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:The present paper analyses the new data accumulated since 1972 concerning the etiology and pathogenesis of Huntington’s chorea. Particular attention is paid to the respective roles of the dopaminergic and GABA-ergic systems.

The effects of mechanically supporting a percentage of body weight on the gait pattern of spastic paretic subjects during treadmill locomotion was investigated. Electromyographic (EMG), joint angular displacement and temporal distance data were simultaneously recorded while 7 spastic paretic subjects walked at 0% and 40% body weight support (BWS) at their maximal comfortable treadmill speed. Forty percent BWS produced a general decrease in EMG mean burst amplitude for the lower limb muscles investigated with instances of more appropriate EMG timing in relation to the gait cycle. The joint angular displacement data at 40% BWS revealed straighter trunk and knee alignment during the weight bearing phase especially at initial foot-floor contact and midstance. An increase in single limb support time and a decrease in percentage total double support time were evident at 40% BWS. An increase in stride length and maximum comfortable walking speed was also seen with BWS. The use of BWS during treadmill locomotion as a therapeutic approach to retrain gait in neurologically impaired patients is discussed.

SummaryElectroencephalographie 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.

In this paper the author reviews the progress accomplished in the understanding of Friedreich's disease since the start of the “Quebec Cooperative Study of Friedreich's Ataxia” in 1974. The last ten years have indeed seen important strides taken in the definition and nosography of the hereditary ataxias and the characterization of a number of new entities. Biochemically, the principal leads uncovered during the initial prospective survey, have been pursued to great detail. Unfortunately no clear-cut constant and severe enzyme block in the principal metabolic pathways has yet been identified, despite intensive studies. It is postulated that the defect may instead be a regulatory one and involve a decreased availability or utilization of one of the vitamin cofactors that are known experimentally, or clinically, to produce central nervous system damage with ataxia: Vitamin E, Biotin or Pantothenic Acid. Studies in that direction and in molecular genetics to localize the Friedreich's disease gene are being untertaken for the next phase of the Cooperative Study.

SUMMARY:A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreich's ataxia and control subjects has revealed a number of mathematically significant variations from normal. Of practical physiological importance are the following: a high urinary excretion of alanine with slightly elevated plasma levels; a low plasma and CSF concentration of aspartic acid in the resence of normal urinary values and finally a low CSF concentration of taurine accompanied by normal plasma levels, but elevated urinary output and renal clearance rates. We postulate that the modifications in alanine and aspartic acid are less specific and probably secondary, but there could be a genetic defect in the membrane transport of taurine and the other β-amino acids in Friedreich's ataxia.

SummaryThiamine-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.

SUMMARY: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.

Threonine supplementation (500 mg/day) was given to 6 patients with genetic spasticity syndromes for a period of 12 months, followed by a 4-month observation period without medication. All 6 patients showed partial improvement of spasticity, intensity of knee jerks and muscle spasms without changes in true pyramidal tract signs. The improvement in motor performance, objectively measured, averaged 29% (19% in upper limbs and 42% in lower limbs). The range of overall improvement was 19–35% (7–30% for upper limbs; 25–67% for lower limbs). No toxic clinical or biochemical side effects were encountered. Thus threonine, a precursor of glycine, produced the same effect on spasticity than that previously observed with glycine. It is concluded that threonine supplementation is feasible and safe and that it deserves a controlled trial in well defined (preferably genetic) cases of spasticity.

SummaryOf 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.

SUMMARY:This paper reviews some recent developments concerning the “non-essential” amino acid Taurine. It is shown that taurine is important in metabolic regulations within the heart, muscle and brain. Particular attention is paid to the neuropharmacology of taurine, such as its possible role in epilepsy.

SUMMARY:We investigated the clinical and metabolic characteristics of Parkinsonian patients whose illness started before the age of 40. A pilot study of 32 of our own such cases revealed the existence of 3 subgroups: 1. Post-Encephalitic, 2. Onset and course with predominant tremor, 3. Onset and course with akinesia and rigidity. In this early onset group of patients, there was a 46% incidence of familial cases (as opposed to 10-15% in the general Parkinson population). The cases with tremor onset had a high prevalence of essential tremor in their families, while those with an akinetorigid onset had a high familial incidence of other cases of Parkinson’s Disease. Familial grey hair, hypertension, diabetes and thyroidopathies appeared to be in higher than expected frequency.These trends were confirmed in a larger series of 135 cases of early onset Parkinson obtained through a mail survey. When the same clinical material was analysed for the familial cases only, two new genetic subgroups emerged: 1) a familial metabolic akineto-rigid syndrome (with hypertension, familial diabetes, hypothyroidism and a more severe course) and, 2) a familial essential tremor-related Parkinsonian syndrome (with familial grey hair trait and hyperthyroidism). These new genetic syndromes along with the recently described “Familial juvenile Parkinsonism” require many further prospectives metabolic and clinical investigations for full characterization, but confirm our hypothesis that “idiopathic” Parkinson’s disease is not a single homogeneous entity.

SUMMARYIn this essay I present a new “global approach hypothesis” to explain the pathophysiology of Parkinson’s disease: “Susceptibility to Parkinsonism is genetically determined and is reflected in all cells. I propose that idiopathic Parkinson’s disease is the combined result of a generalized cell aging process accelerated, in susceptible individuals, by a variety of often repetitive trigger factors. These factors have in common the fact that they cause a transient increase in turnover within catecholamine producing neurons, centrally as well as peripherally. This results in accumulation within these neurons of free radicals. When the level of the toxic substances, in quantity or in time of exposure, exceeds the scavenging capacity of the cell, damage to organelles and to membranes results, leading to the formation of Lewy bodies through an autoimmune reaction to damaged filaments and to cell death, particularly in the pigmented neurons of the brainstem. The progressive cell depletion leads to a compensatory increase in catecholamine turnover in the remaining pigmented cells, and an ever-accelerating degenerative process. The resulting neurotransmitter imbalance in the basal ganglia explains the symptoms of Parkinson’s disease”. In the light of this hypothesis, our research objectives should be (1) to delineate the limits of true Parkinson’s disease from all phenocopies; (2) to identify individuals susceptible to parkinsonism and the most common trigger factors; (3) to reduce the metabolic effects of unavoidable trigger factors and (4) to protect susceptible individuals by increasing the functional availability of free radical trapping agents.

We have investigated the influence on the excitability of lumbar motoneurons of 5-hydroxytryptamine (5-HT), substance P and thyrotropin releasing hormone (TRH), three substances which coexist in the same bulbospinal descending pathway and end in large part around motoneurons. We have also studied the effect of clonidine, an alpha 2 noradrenergic agonist. This was done in spinalized rats (T5) treated three weeks before with 5-7-dihydroxytryptamine. Under those circumstances 5-HTP (LP.), 5-HT (intrathecally) TRH (LP. or I.T.) and substance P (I.T.) all elicited a strong excitation of motoneurons as measured by integrated EMG of the hindlimb muscles. Substance P reduced by almost half the subsequent response to 5-HTP, 1 hour and 24 hours later. TRH given acutely did not modify the response to 5-HTP but given chronically for twenty one days by means of Alzet minipump, markedly increased the response to 5-HTP. Clonidine by itself decreased the excitability of motoneurons and antagonized the excitatory effect of 5-HTP and TRH. In a pilot trial, cyproheptadine, a 5-HT antagonist was shown to decrease the manifestations of spasticity in patients with a partial spinal lesion. Clonidine also appears to be of potential use in the treatment of spasticity.

SUMMARY:The 50 patients in this survey were classified by a panel of neurologists into 4 clinical sub-groups: Group la (“typical” Friedreich's ataxia, complete picture), Group lb (“typical” Friedreich's ataxia, incomplete picture), Group Ila (“atypical” Friedreich's ataxia, possible recessive Roussy-Levy syndrome), Group lib (heterogeneous ataxias). The clinical symptoms and signs were analyzed for each of these groups. A constellation of signs constantly present in Friedreich's ataxia and obligatory for diagnosis was described. Other important symptoms, such as the Babinski sign, kyphoscoliosis and pes cavus were found to be progressive, but not essential for the diagnosis at any given time. Finally, a host of other symptoms can only be called accessory. The progression of scoliosis was found to be an important tool in the differential diagnosis of ataxias. Our study also indicates, in contrast to the opinion of some authors, that absent deep tendon reflexes in the lower limbs and early dysarthria are essential in “typical” Friedreich's ataxia.

SummaryCoded erythrocyte samples from ten individuals with Friedreich*š ataxia, from parents of five of these individuals, and from five unrelated control individuals were subjected to lecţin agglutination tests at three temperatures; before and after trypsinization; and before and after treatment with echinocyte-producing sodium salicylate and stornato^ cyte-pröducing tetracaine followed by shape-fixation with glutaraldehyde. The aġglutinins tested were the polycationic poly-L-lysirie (PLL) and four lectins with different saccharide specificities: soybean agglutinin, wheat germ agglutinin, Ufex europeus agglutinin (VEA) and concana-valin A. Altogether, over 45,000 individual test wells were scored, the status of each blood donor with respect to diagnosis being disclosed to the experimenters only after all results were tabulated.The majority of these tests revealed no significant difference among the three groups of blood samples. A few tests did reveal statistically valid (p

SUMMARY:The histories of seven consecutive cases of Gilles de la Tourette's syndrome are presented to exemplify the range of clinical manifestations in this disease and to collate preliminary results with the new benzodiazepine, clonazepam, as a possible adjuvant therapy of this disorder. Controlled trials with clonazepam alone and in association with haloperidol are now justified. Five of our 7 patients had a positive family history of tics, and 2 a confirmed family history of gout. Because clonazepam improves myoclonia and tics and because its mechanism of action possibly involves serotonin, we thought it worthwhile to study simultaneously the relative roles of serotonin and dopamine metabolism in the production of tics, and their relationship to possible defects in purine metabolism in Gilles de la Tourette's syndrome.

SUMMARY: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.

SUMMARY:Thirteen patients with classical Friedreich's ataxia underwent cardiac catheterization with recordings of retrograde cardiac pressures, measurements of cardiac output and calculation of the left ventricular volumes and mass. The cardiomyopathy in Friedreich's ataxia falls into the hypertrophic group of cardiomyopathies with decreased compliance of ventricular myocardium, varying degrees of concentric and asymmetric hypertrophy and outflow tract obstruction. Although there is no clear parallel between the degree of abnormal hemodynamic findings and the degree of neurological impairment, severely handicapped patients may present a diffusely hypertrophied and hypokinetic left ventricular myocardium.

SUMMARY: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.

SummaryStudies 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.

SUMMARY: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.

SUMMARY: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.