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Biomedical subjects

G N Thompson

Publications and source records attributed to G N Thompson.

At least 37 records · Page 2Linked to original sources
PubMed1990

The use of metronidazole in management of methylmalonic and propionic acidaemias.

Gut bacteria have been implicated as an important source of propionate in children with inborn errors of propionate metabolism. We have investigated the value of oral metronidazole (10-20 mg/kg per day) in five children with methylmalonic acidaemia (MMA) and four with propionic acidaemia (PA). Urinary excretion of propionate metabolites fell significantly during the treatment in all subjects, the mean decrease being 41% (range 12-76, P less than 0.01), while mean plasma propionate was reduced from 45.0 mumol/l to 25.1 mumol/l (P less than 0.05). Substantial reduction of the gut bacterial population was confirmed by lactulose breath hydrogen tests and by stool culture, and stool propionate concentration was reduced in most subjects. Clinical improvement was noted in three children. These results suggest that long-term antimicrobial therapy may offer significant clinical benefit to children with inborn errors of propionate metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

In vivo propionate oxidation as a prognostic indicator in disorders of propionate metabolism.

Biochemical markers such as plasma and urinary metabolite concentrations and in vitro enzyme activity are of limited prognostic value in the most common disorders of propionate metabolism, methylmalonic acidaemia (MMA) and propionic acidaemia (PA). In vivo propionate oxidation was compared with conventional prognostic measures as predictors of clinical severity in seven children with MMA and six with PA. Propionate oxidation was measured using a continuous infusion of [1-13C]propionate and was expressed as the rate of appearance of 13CO2 as a percentage of the propionate infusion rate. Children with MMA (mean oxidation 51.2%, range 17.5-91.6, P less than 0.05) and with PA (mean oxidation 36.3%, range 3.0-91.1, P = NS) oxidised substantially less propionate than controls (mean oxidation 81.9%, range 69.4-101.0, n = 5). Percentage oxidation was a better predictor of the clinical severity score (r = 0.75, P less than 0.01) than was in vitro enzyme activity, plasma propionate or methylmalonate concentration or urinary metabolite excretion. Studies were repeated after an interval of 1-3 weeks in six of the subjects; the percentage oxidation in each subject was virtually unchanged between studies (coefficient of variation 8.6%). These results suggest that in vivo oxidation measurements using [13C]propionate are both reproducible and prognostically useful in disorders of propionate metabolism.

Adolescent↗
PubMed1990

The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Leucine and protein metabolism were studied using stable isotope techniques in 6-year-old twins with 3-hydroxy-3-methylglutaric aciduria during acute metabolic decompensation. The decompensation was preceded by prolonged fasting in twin 1 and by an upper respiratory infection in twin 2. Twin 2 was also studied when well (control study). During infection, leucine oxidation (36 mumol/kg per hour), protein catabolism (6.0 g/kg per day) and urinary excretion of major leucine metabolites (104 mumol/kg per hour) were all increased compared with the control study (16 mumol/kg per hour, 4.7 g/kg per day and 28 mumol/kg per hour respectively). During fasting, leucine oxidation (18 mumol/kg per hour) was unchanged and protein catabolism (4.1 g/kg per day) was decreased despite substantially increased urinary metabolite excretion (87 mumol/kg per hour) compared with the control study. These results indicate that protein mobilisation and leucine oxidation played important roles in metabolic decompensation during infection but not during fasting. It is likely that the increased metabolite excretion during fasting arose primarily from fatty acid catabolism, indicating the importance of this substrate in metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Sources of propionate in inborn errors of propionate metabolism.

Amino acids are widely regarded as the most important sources of propionate in disorders of propionate metabolism. Propionate production was measured in the fasting state by continuous infusion of sodium [1-13C]propionate in three children with methylmalonic acidemia (MMA) and three with propionic acidemia (PA). The contribution of isoleucine, valine, threonine, and methionine catabolism to total propionate production was estimated by extrapolation from the hydroxylation of phenylalanine determined by a continuous-infusion [2H5]phenylalanine technique. The contribution of gut bacterial propionate production was determined by measuring total propionate production before and after treatment with oral metronidazole (10 to 20 mg/kg/d for 1 week). Amino acid catabolism accounted for a mean of 51.7% (range, 24.5% to 66.4%) of total propionate production. The mean decrease in propionate production after metronidazole was 22.2% +/- 8.5 (P less than .02); this percentage is likely to represent the minimum propionate production attributable to gut bacteria. Approximately 30% of total propionate production was unaccounted for, and is likely to arise primarily from odd-chain fatty acid catabolism in the fasting state. These results indicate that sources of propionate other than from protein catabolism are important in disorders of propionate metabolism, and explain the generally disappointing response to dietary protein restriction.

Amino Acids↗
PubMed1990

In vivo enzyme activity in inborn errors of metabolism.

Low-dose continuous infusions of [2H5]phenylalanine, [1-13C]propionate, and [1-13C]leucine were used to quantitate phenylalanine hydroxylation in phenylketonuria (PKU, four subjects), propionate oxidation in methylmalonic acidaemia (MMA, four subjects), and propionic acidaemia (PA, four subjects) and leucine oxidation in maple syrup urine disease (MSUD, four subjects). In vivo enzyme activity in PKU, MMA, and PA subjects was similar to or in excess of that in adult controls (range of phenylalanine hydroxylation in PKU, 3.7 to 6.5 mumol/kg/h, control 3.2 to 7.9, n = 7; propionate oxidation in MMA, 15.2 to 64.8 mumol/kg/h, and in PA, 11.1 to 36.0, control 5.1 to 19.0, n = 5). By contrast, in vivo leucine oxidation was undetectable in three of the four MSUD subjects (less than 0.5 mumol/kg/h) and negligible in the remaining subject (2 mumol/kg/h, control 10.4 to 15.7, n = 6). These results suggest that significant substrate removal can be achieved in some inborn metabolic errors either through stimulation of residual enzyme activity in defective enzyme systems or by activation of alternate metabolic pathways. Both possibilities almost certainly depend on gross elevation of substrate concentrations. By contrast, only minimal in vivo oxidation of leucine appears possible in MSUD.

Adult↗
PubMed1990

Protein and leucine metabolism in maple syrup urine disease.

Constant infusions of [13C]leucine and [2H5]phenylalanine were used to trace leucine and protein kinetics, respectively, in seven children with maple syrup urine disease (MSUD) and eleven controls matched for age and dietary protein intake. Despite significant elevations of plasma leucine (mean 351 mumol/l, range 224-477) in MSUD subjects, mean whole body protein synthesis [3.78 +/- 0.42 (SD) g.kg-1. 24 h-1] and catabolism (4.07 +/- 0.46) were similar to control values (3.69 +/- 0.50 and 4.09 +/- 0.50, respectively). The relationship between phenylalanine and leucine fluxes was also similar in MSUD subjects (mean phenylalanine-leucine flux ratio 0.35 +/- 0.07) and previously reported adult controls (0.33 +/- 0.02). Leucine oxidation was undetectable in four of the MSUD subjects and very low in the other three (less than 4 mumol.kg-1.h-1; controls 13-20). These results show that persistent elevation in leucine concentration has no effect on protein synthesis. The marked disturbance in leucine metabolism in MSUD did not alter the relationship between rates of catabolism of protein to phenylalanine and leucine, which provides further support for the validity of the use of a single amino acid to trace whole body protein metabolism. The minimal leucine oxidation in MSUD differs from findings in other inborn metabolic errors and indicates that in patients with classical MSUD there is no significant route of leucine disposal other than through protein synthesis.

Child↗
PubMed1990

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Indirect measurements have previously suggested that patients with classical phenylketonuria (PKU) do not convert significant amounts of phenylalanine to tyrosine. Low-dose continuous infusion techniques employing [2H5]phenylalanine and [2H2]tyrosine were used to quantitate in vivo phenylalanine hydroxylation in 10 subjects with classical phenylketonuria, 2 with hyperphenylalaninemia (HPA), and 7 controls. Plasma phenylalanine concentration ranged from 523 to 1,540 mumols/liter in PKU, 402 to 533 in HPA, and 49 to 54 in controls. Subjects with classical PKU hydroxylated mean +/- SD 4.8 +/- 2.2 mumols/kg per h (range 0.9-8.4) of phenylalanine to tyrosine and those with HPA 4.4 and 5.3, respectively. These rates were substantial in comparison with those in controls (6.3 +/- 1.6, 3.2-8.2). The significant hydroxylation in PKU and HPA subjects is likely to result from induction of activity of tyrosine hydroxylase towards phenylalanine by the greatly elevated phenylalanine concentration. The presence of such activity in PKU suggests that therapy aimed at promotion of this usually latent hydroxylating capacity may be a future alternative to dietary treatment of PKU.

Adult↗
PubMed1990

Increased urinary metabolite excretion during fasting in disorders of propionate metabolism.

Odd-chain fatty acids are recognized precursors of propionate in man, but their clinical significance in disorders of propionate metabolism has not been well studied. Urinary excretion of methylmalonate, methylcitrate, propionylglycine, and 3-hydroxypropionate was measured in five children with methylmalonic acidemia and three with propionic acidemia during frequent or continuous feeding and after 10-18 h of fasting. There was a significant (p less than 0.01) increase in the mean total measured metabolite excretion during fasting (fed 38.1 mumol/kg/h, fasting 54.6 in methylmalonic acidemia, fed 1.45, fasting 2.98 in propionic acidemia). Percentage rises in each subject were similar for all measured metabolites. These increases in metabolite excretion are most easily explained by mobilization and oxidation of odd-chain fatty acids in the fasting state. Prolonged fasting should be avoided in children with disorders of propionate metabolism.

Adult↗
PubMed1990

Protein metabolism in phenylketonuria and Lesch-Nyhan syndrome.

Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of [13C]leucine and, in Lesch-Nyhan subjects, [2H5]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 mumol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 mumol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, [13C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With [13C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 +/- 0.74 (SD) and catabolism 4.85 +/- 0.57 (g/kg/24 h, n = 5). Similar results were obtained in Lesch-Nyhan subjects using [2H5]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Measurement of propionate turnover in vivo using sodium [2H5]propionate and sodium [13C]propionate.

The outcome for children with inherited disorders of propionate metabolism is poor. To facilitate development of improved treatment in these conditions, we described techniques for the estimation of the rate of production and removal of propionate in vivo. Propionate turnover was determined in 4 healthy adults using continuous infusions of sodium [2H5]propionate and sodium [13C]propionate. The mean fasting plasma propionate concentration measured by a sensitive technique employing high performance liquid chromatography, following a two-stage extraction procedure and derivatisation with bromophenacyl bromide, was 3.3 mumol/l (SD 0.5). The isotopic enrichment of the bromophenacyl propionate derivative was measured by gas chromatography/mass spectrometry and mean propionate turnover was calculated to be 17.6 mumol/kg per h (SD 5.9). These methods allow rapid (less than 3 h) assessment of propionate turnover in man and are suitable for application in children with inherited disorders of propionate metabolism.

Adult↗
PubMed1989

Contribution of aminoacid catabolism to propionate production in methylmalonic acidaemia.

The rates of propionate production and aminoacid catabolism in 5 children with methylmalonic acidaemia were measured by use of stable isotope techniques. Total propionate production was 55-186 mumol/kg per h, to which the maximum contribution of protein catabolism was 10-35 mumol/kg per h (5-40%). These findings indicate important sources of propionate other than protein catabolism, which may account for the limited efficacy of dietary protein restriction in treatment of methylmalonic acidaemia.

Acyl Coenzyme A↗
PubMed1989

Practical considerations in the use of stable isotope labelled compounds as tracers in clinical studies.

Increasingly widespread usage of stable isotope tracers to aid clinical diagnosis and support basic research has stemmed from both advances in mass spectrometry and the availability of competitively priced labelled compounds. Stable isotopes have been used generally to investigate normal and abnormal metabolic pathways, to estimate energy expenditure and body composition and to quantitate substrate flux and oxidation rates. Despite the fact that the underlying principles relating to the use of stable isotopes for in vivo studies are straightforward, careful consideration must be given to all aspects of human studies. This review highlights some of these, including choice of label and tracer molecule, mode of tracer administration and sampling site, analytical instrumentation, interpretation of data and ethical constraints.

Carbon Isotopes↗
PubMed1989

Relationships between essential fatty acid levels, pulmonary function and fat absorption in pre-adolescent cystic fibrosis children with good clinical scores.

Twenty-one pre-adolescent cystic fibrosis (CF) children with good clinical scores had significant (P less than 0.001) deficiencies of arachidonic (mean 3.8% of total plasma fatty acids +/- SD 1.4) and linoleic (18.1 +/- 6.3) acids compared with controls (6.0 +/- 1.0, and 27.6 +/- 3.9, respectively). Despite the presence of pulmonary involvement of varying severity in all the CF children, neither arachidonic nor linoleic acid levels correlated significantly with pulmonary function measured by spirometry. All children had adequate caloric and fat intakes, and the coefficient of fat absorption correlated with none of the deficient fatty acid levels. These findings suggest that deficiencies of arachidonic and linoleic acids are of minor importance in the early development of pulmonary involvement in CF, and that factors other than fat malabsorption and decreased dietary intake probably contribute to fatty acid deficiency.

Child↗
PubMed1989

Substrate disposal in metabolic disease: a comparison between rates of in vivo propionate oxidation and urinary metabolite excretion in children with methylmalonic acidemia.

The relative importance of endogenous metabolism and urinary metabolite excretion was assessed in vivo in six children with methylmalonic acidemia by examining the kinetics of the immediate precursor to methylmalonate, propionate. Total production and oxidation of propionate were measured by means of a continuous infusion of (1-13C)propionate and were compared with the urinary excretion of propionate metabolites. Propionate oxidation was substantial (mean 48.9 mumol/kg/hr +/- SD 18.0) and, in four children, exceeded urinary metabolite excretion (mean urinary excretion in all subjects 40 mumol/kg/hr +/- 25). The sum of urinary excretion and oxidation rates (88 mumol/kg/hr +/- 29) approximated the total propionate production (93.4 +/- 37.0), suggesting that these routes together constitute the major mechanisms of propionate disposal. These results suggest that propionate oxidation is an important route of disposal in methylmalonic acidemia. Variations in the relative proportions of propionate disposal through oxidation and urinary excretion may be one reason for the often poor correlation between clinical status and urinary metabolite excretion. Measurement of urinary metabolite concentration alone may not always reflect clinical status and responses to treatment accurately.

Humans↗