Neurological consequence of industrial exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
A Barbeau
Publications and source records attributed to A Barbeau.
New amphibian models for the study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
We report the development of two animal models in amphibians (frogs and salamanders) in whom 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces the behavioral (neurological) and biochemical equivalents of the human disease and, in addition, a measurable modification in at least one form of pigment-bearing cell from the neural crest, the skin melanocyte. We propose that this new approach can become an inexpensive, easily quantifiable model for the study of the effect of MPTP on the central and peripheral nervous systems. We also demonstrate that the toxic effect of MPTP can be completely abolished in vivo by treatment with a monoamine oxidase inhibitor and potentiated by an inhibitor of catechol-O-methyltransferase. MPTP is catabolised by oxidation into toxic metabolites, but 1-methyl-4-phenylpyridinium ion (MPP+), the proposed end-metabolite, is even more toxic than MPTP in this model, possibly through a different mechanism.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Gel chromatography on a Sepharose 4B column: earlier elution of protein-sodium dodecyl sulfate complexes of low Stokes radii.
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.
Chemical Phenomena↗
The osmoregulatory function of taurine and glutamic acid.
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Animals↗
Diagnostic problems in Parkinson's disease.
The diagnosis of Parkinson's disease is not as easy as previously claimed, and presents a number of pitfalls. We present three rules, or aphorisms, to help the general practitioner in overcoming these diagnostic difficulties: Know well the basic disease and its symptoms. Use tricks to elicit apparently absent 'primary' symptoms. Beware of unusual symptoms or case histories. Examples of difficulties encountered at each level are given. Such analysis should permit the physician to classify his extrapyramidal patient within one of the many types of 'parkinsonism' as shown in Table 1.
Diagnosis, Differential↗
A clinical classification of hereditary ataxias.
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.
Ataxia↗
Origin of Friedreich's disease in Quebec.
We have been able to trace 40 cases of classical Friedreich's disease from 14 previously unrelated French Canadian kindreds to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin. One member of this couple presumably introduced one gene for Friedreich's disease into the French Canadian population. This gene has now been traced over 12 generations to both parents of the present cases. We plan to use this knowledge to study the spectrum of clinical manifestations of this gene and to carry out gene chromosomal localization studies, using the techniques of linkage and of molecular biology. Such studies in rare autosomal recessive disorders have previously been judged to be almost impossible.
Female↗
The natural history of Machado-Joseph disease. An analysis of 138 personally examined cases.
We have examined 138 cases of a disorder previously described in people of Portuguese origin and which has received many names. By computer analysis of 46 different items of a standardized neurological examination carried out in each patient, we have been able to delineate the main components of the clinical presentation, to conclude that the marked variability in clinical expressions does not negate the homogeneity of the disorder, and to describe the natural history of this entity which should be called, for historical reasons, "Machado-Joseph Disease". This hereditary disease has an autosomal dominant pattern of inheritance, presenting as a progressive ataxia with external ophthalmoplegia, and should be classified within the group of "Ataxic multisystem degenerations". When the disease starts before the age of 20, it may present with marked spasticity, of a non progressive nature but often so severe that it can be accompanied by "Gegenhalten" countermovements and dystonic postures but little frank dystonia. There are few true extrapyramidal symptoms except akinesia. When the disease starts after the age of 50, the clinical spectrum is mostly that of an amyotrophic polyneuropathy with fasciculations accompanying the ataxia. For all the other cases the clinical picture is a continuum between these two extremes, the main determinant of the clinical phenotype being the age of onset and a secondary factor, the place of origin of the given kindred. The ataxic and amyotrophic components are clearly progressive with time in contrast to the spasticity component. Although the majority of known cases are of Portuguese origin, this is not obligatory. The next research endeavour should be a search for the chromosomal site of the gene, using molecular biology technology such as those for recombinant DNA.
Adolescent↗
Recessive ataxia in Acadians and "Cajuns".
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.
Canada↗
Familial periodic ataxia responsive to acetazolamide.
Two cases, a father and son, of recurrent cerebellar ataxia in the same family are reported, suggesting a familial 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.
Acetazolamide↗
Visual evoked potentials and brain stem auditory potentials in Friedreich's ataxia--a longitudinal study.
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 P100 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.
Adolescent↗
Lysosomal enzymes in ataxia: discovery of two new cases of late onset hexosaminidase A and B deficiency (adult Sandhoff disease) in French Canadians.
We have measured in leukocytes the following lysosomal enzymes in 11 Friedreich disease cases, 11 "atypical" recessive ataxias, 13 neurological controls and 16 normal controls: hexosaminidase A and B; beta-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 Charlevoix-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.
Adult↗
Platelet taurine content in Friedreich's disease.
We have studied the concentrations of taurine and of 6 other amino acids in platelets from 12 patients with Friedreich's disease and 12 age sex-matched normal control subjects. No significant differences could be demonstrated between the two groups. The glycine/serine ratio was lower in all the patients but this change did not reach statistical significance. From these and other data, we conclude that the taurine retention deficit observed previously in Friedreich's disease cannot be the primary causal defect.
Adult↗
Hair trace elements in Friedreich's disease.
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. Although 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.
Adult↗
Distribution of apolipoprotein E phenotypes in Friedreich's ataxia.
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.
Adolescent↗
Plasma cholesteryl sulfate in Friedreich's ataxia.
Alteration of membrane fluidity and anomalies of membrane structural proteins have been suspected in Friedreich's ataxia. Plasma lecithin:cholesterol 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 micrograms/dL, 6 times the normal mean) was only 25% as high as the concentrations reported to inhibit LCAT activity.
Adolescent↗
Friedreich's ataxia: malic enzyme activity in cellular fractions of cultured skin fibroblasts.
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.
Adolescent↗
Cardiac malic enzyme in Friedreich's disease.
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.
Adult↗