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.

We define the meaning of early and late treatments and present arguments opposed to early treatment with levodopa. These are based on the development of complications with long-term Sinemet which include clinical fluctuations, loss of efficacy, and painful dystonic cramps. By delaying the onset of levodopa therapy until the symptoms require this most potent of antiparkinsonian agents, we can delay the onset of these disabling problems. Also, using as low a dosage as possible should reduce the risk of any long-term complication related to accumulative dose.

We also present the serial evaluations of 26 patients followed for as long as 7.5 years before levodopa therapy was initiated. Three scoring scales on these patients are compared. Arguments are presented which suggest that the Columbia University and the ADL scales are superior to the UCLA scale, and more closely approximate the curve of the progressive clinical disability of the disease as assessed by global evaluation. We conclude that the ultimate answer to any clinical debate must come from well-designed, controlled studies to assess the differences between two treatment modalities.

Complete withdrawal of all levodopa compounds “drug holiday” for a period of at least one week in severely disabled, unresponsive Parkinson patients may influence receptor blockade by resensitizing and can alter denervation hypersensitivity.

Twenty four patients with 31 holidays were evaluated. Transient improvement was noted in most patients, however significant long term benefit of over 1 years duration occurred in only 6 individuals.

In view of the unpredictability and limited responsiveness, drug holiday has not yet been established as a satisfactory treatment for the severe, intractable problems associated with chronic levodopa administration in Parkinson patients. Further trials appear to be warranted.

Zinc and taurine were measured in urine in the fasting state and following a 4mg/kg load of taurine in subjects with Friedreich's Ataxia (FA), and healthy controls (C), and subjects with Duchenne type muscular dystrophy (MD). Of the FA, 25% had increased fasting excretion of zinc, and 50% had increased excretion of zinc following the taurine load. The MD subjects all had increased zinc excretion at all times. The increased zinc excretion did not correlate with increased excretion of taurine. As an index of zinc deficiency, uptake of zinc by erythrocytes was measured in all subjects and in heterozygotes for FA. The pattern of uptake was abnormal for FA and heterozygotes. Hair analysis for zinc showed that 10 of the 12 FA subjects had low values.

We conclude that significant abnormalities in zinc metabolism exist in some, but not all cases of FA. The evidence available does not permit definition of the cause of these abnormalities, whether zinc deficiency or abnormal zinc transport is the primary factor.

Parkinson’s disease is associated with a variety of neurotransmitter disturbances which may be further altered by its treatment with dopamine agonists. Based on this information a wide range of pharmacological approaches have been used in search of newer treatment alternatives and in hopes of reducing complications of long-term levodopa use. This paper reviews the various therapies which have had some success in the management of Parkinson’s disease, other than levodopa and dopamine agonists. Special emphasis is placed on the many unresolved questions and controversies that exist in this area of neuropharmacology.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles ɛ2, ɛ3 and ɛ4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the ɛ2 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 ɛ2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the ɛ2 subset did not have significantly higher plasma triglycerides than the non-ɛ2 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.

Dopamine agonists have yielded two important advances to our understanding of the basal ganglia – they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons – a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect.

The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson’s disease, but as yet there is no firm evidence.

In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.

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.