Dennis Shapcott

Pyruvate metabolism in Friedreich's ataxia.

Friedreichs ataxia patients show evidence of an abnormally elevated and prolonged response of pyruvate and lactate to a glucose load, with normal fasting levels. However, ther is a bimodal distribution of this response with high and low pyruvate responders. This trait appears to be determined genetically, However, although in vivo tests suggest low oxidation of pyruvate, we were unable to confirm any in vitro impairment of each of the components of the pyruvate dehydrogenase (PDH) complex. We conclude that the defect is in the metabolic regulation of PDH, probably at the E3 (lipoamide dehydrogenase) step.

Glucose and insulin metabolism in Friedreich's ataxia.

Our prospective survey of 50 ataxic patients confirms the previous finding of frequent clinical or chemical diabetes in Friedreichs ataxia. Eighteen percent of our typical cases have clinical diabetes and 40% at least an abnormal glucose tolerance curve. However, this finding does not appear to be specific to that form of ataxia. Furthermore, we have shown that most patients with ataxia have normal or low fasting insulin levels, but a hyperinsulinic response to a glucose load.

Amino acid metabolism in Friedreich's ataxia.

A study of amino acids determined by sequential Multi-sample Amino Acid Automatic Analyzer in plasma, urine and cerebrospinal fluid (CSF) in patients with Friedreichs 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 presence 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 beta-amino acids in Friedreichs ataxia.

Erythrocyte membrane lipids in Friedreich's ataxia.

In a study of the lipid composition of erythrocyte membranes in Friedreichs ataxia, the concentration of the major membrane components (phospholipids, cholesterol and protein) in ataxic 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 PE in Friedreichs ataxia patients).

Taurine in cerebrospinal fluid in Friedreich's ataxia.

In a previous study we reported low values of taurine and aspartic acid in the CSF of patients with Friedreichs ataxia, when the results were compared to the literature. Further studies have revealed that unforetold difficulties with the advertised methodology of sequential multi-sample amino acid analysis were responsible for low values in the determination of these two amino acids in the small volumes necessary for CSF. A corrected method is presented. With the latter method the differences disappear for CSF taurine and aspartic acid, but they remain valid for the previously reported blood and urine values in Friedreichs ataxia. GABA levels are also normal in Friedreichs ataxia CSF.

Zinc and taurine in Friedreich's ataxia.

Zinc and taurine were measured in urine in the fasting state and following a 4mg/kg load of taurine in subjects with Friedreichs 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.

Clinical laboratory findings in Friedreich's ataxia.

All clinical laboratory tests carried out in 4 groups of patients with the diagnosis of typical or atypical Friedreichs 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.

Simple and rapid system for screening andidentification of reducing sugars in urine

As part of our screening programme for metabolic disorders we needed a rapid, simple, inexpensive means to detect reducing sugars in urine, with a simple but precise test for their identification. Our system comprises a bismuth reduction test for reducing sugars, with unidimensional thin layer chromatography on silica gel and color development with diphenylamine--aniline for definitive identification.

The measurement of rivotril in whole blood by gas liquid chromatography

Rivotril is extracted from blood into an organic solvent mixture, Mogadon, (Nitrazepam) is used as internal standard. The drugs are then back-extracted into acid which is heated to produce the corresponding benzophenones. These are extracted into benzene and separated by gas liquid chromatography with electron capture detection.

Studies on the role of taurine in Friedreich's ataxia

New studies were undertaken to verify the previous findings of increased urinary excretion of taurine, in the basal state and after challenge with a taurine load, in Friedreichs disease. Particular attention was paid to possible causes of error such as weight, muscle mass, creatine and creatinine excretion, variability with time and appropriate control groups. Although the overall findings were confirmed, their interpretation is open to question because of all these factors of error. Many possibilities must still be further explored to account for the apparent taurine retention defect observed in many cases of Friedreichs disease.