Response from members of the Griffiths inquiry.
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Consent Forms↗
Biomedical subjects
T E Stacey
Publications and source records attributed to T E Stacey.
Carnitine therapy and metabolism in the disorders of propionyl-CoA metabolism studied using 1H-NMR spectroscopy.
1H-NMR spectroscopy has been used to study metabolic perturbations in patients with disorders of propionyl-CoA metabolism during the administration of oral and intravenous L-carnitine. The administration of L-carnitine either in the form of a challenge or as a therapeutic measure resulted in an increased excretion of propionylcarnitine, consistent with the removal of accumulated intramitochondrial propionyl-CoA esters. Additionally, during the therapeutic administration of L-carnitine excretion of acetylcarnitine occurred, coincident with an improvement in clinical condition and confirming the intracellular propionyl-CoA depletion. An additional benefit from the formation of acylcarnitines may be an accompanying intracellular alkalinisation.
Acyl Coenzyme A↗
Congenital intestinal pseudo-obstruction associated with a giant platelet disorder.
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Abnormalities, Multiple↗
Creatine metabolism during metabolic perturbations in patients with organic acidurias.
Creatine excretion was measured in two patients with methylmalonic aciduria and two patients with 3-hydroxy-3-methylglutaric aciduria. During periods of metabolic decompensation the creatine/creatinine ratio increased and fell during recovery. Prolonged periods of metabolic decompensation may result in the loss of a large proportion of the creatine pool. In one study, measurements of total daily urinary output of metabolites demonstrated that the absolute creatine excretion followed a similar qualitative pattern to the creatine/creatinine ratio. However, apparent fluctuations in methylmalonate excretion when expressed as methylmalonate/creatinine ratio were absent when absolute methylmalonate excretion was calculated. The increased creatine excretion during metabolic perturbations may result from loss from creatine containing tissues such as muscle and may represent an underlying defect in energy metabolism. Alternatively creatine transport may be disrupted by accompanying acidosis. The use of metabolite/creatinine ratios as a measure of metabolite excretion rates during metabolic decompensation whilst qualitatively sound may need a re-appraisal.
3-Hydroxybutyric Acid↗
Measurement of L-carnitine and acylcarnitines in body fluids and tissues in children and in adults.
We have developed a reliable and validated radio-enzymatic method for the assay of L-carnitine and acylcarnitines, using a modification of existing methods. The sensitivity of the assay is 10 mumol/l using 10 microliters of plasma or urine. It is also suitable for measurements of carnitine in a 10 mg sample of liver or muscle obtained by percutaneous biopsy. The use of N-ethylmaleimide in the reaction mixture together with an excess of [1-14C]acetyl CoA ensures that the reaction proceeds to completion and a linear response is obtained. Using this method control ranges have been established for plasma and urine carnitine concentrations in healthy children and adults, and for the carnitine content of liver and muscle in adults. No significant difference was found between fasting and post-prandial plasma carnitine levels. An age-related increase was found in urinary total carnitine and acylcarnitine concentration throughout childhood. These data provide a reliable basis for studies of patients with abnormal carnitine and acylcarnitine metabolism, distribution and excretion.
Acetylcarnitine↗
Dietary treatment eliminates succinylacetone from the urine of a patient with tyrosinaemia type 1.
Over an 18-month period serial observations of plasma tyrosine, methionine and urinary tyrosine metabolites were made and compared with urinary succinylacetone excretion in an infant with tyrosinaemia type 1 treated by diet alone. Despite broadly similar profiles there were significant temporal and quantitative differences between each of these metabolic parameters. Only when plasma tyrosine was kept in the low-normal range by strict phenylalanine restriction (10-15 mg phenylalanine/kg body weight) was detectable succinylacetone consistently eliminated from the urine. Urinary succinylacetone is the only measure of metabolite accumulation immediately proximal to the enzyme defect and its routine measurement will allow more effective control of dietary treatment.
Amino Acid Metabolism, Inborn Errors↗
Permeability of the human placenta in vivo to four non-metabolized hydrophilic molecules.
1. Permeability of the human placenta to four permeants of different molecular size was measured at Caesarean section in seven normal full-term pregnancies. 2. Placental clearance for mannitol was 8.7 +/- 1.1 ml min-1 (mean +/- S.E.M.), lactulose 6.3 +/- 0.8, chromium ethylenediaminetetraacetic acid (CrEDTA) 3.7 +/- 0.5, and inulin 0.98 +/- 0.1. 3. The permeability data were analysed in terms of restricted diffusion through 'notional' water-filled pores and found to be incompatible with a single population of uniform pores.
Adult↗
Dietary restriction and methylmalonicaciduria.
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Child↗
Prenatal diagnosis of 3-hydroxy-3-methylglutaric aciduria by GC-MS and enzymology on cultured amniocytes and chorionic villi.
This paper reports the prenatal diagnosis of HMG CoA lyase deficiency at 16 weeks' gestation by direct chemical analysis of cell-free amniotic fluid and by measurement of HMG CoA lyase activity in cultured amniocytes. Termination of an affected fetus allowed study of chorionic villus tissue, the results providing the basis for future first trimester prenatal diagnoses of this condition. An abstract report of this work has appeared elsewhere.
Amino Acid Metabolism, Inborn Errors↗
Maternal alloimmunization to HLA, platelet and granulocyte-specific antigens during pregnancy: its influence on cord blood granulocyte and platelet counts.
In order to obtain an estimate of the frequency of platelet-specific and granulocyte-specific antibodies and of the effect of such antibodies on the platelet count and granulocyte count of the newborn infant, serum from 147 women in their second or subsequent pregnancies was tested. No platelet-specific antibodies were found but 29 of the women had granulocyte-specific antibodies and the corresponding infants had granulocyte counts which were significantly lower than those of infants without antibodies. HLA antibodies were found in the sera of 57 women but were not associated with diminished platelet or granulocyte counts in the corresponding infants. Maternal granulocyte antibodies may be an underestimated contributory factor in the pathogenesis of neonatal neutropenia.
Blood Platelets↗
Urinary C6-C12 dicarboxylic acylcarnitines in Reye's syndrome.
C6-C12 dicarboxylic acylcarnitines have been identified for the first time in urine from a 2-year-old girl presenting with Reye's syndrome. The acylcarnitines were extracted by ion-exchange chromatography and analysed, both underivatised and as methyl esters using high-resolution fast-atom-bombardment mass spectrometry and B/E-linked scanning. The acylcarnitines were quantified by capillary gas chromatography of the acids extracted after hydrolysis of the acylcarnitine esters. Dodecandioylcarnitine was present in the highest concentration (35.9 mmol/mol creatinine) which exceeded the urinary free dodecandioic acid concentration. The adipic, suberic and sebacic acylcarnitine concentrations were less than 10% of the respective free acid concentrations. It is possible that beta-oxidation of dicarboxylic acids is partially inhibited in Reye's syndrome leading to accumulation of precursor dodecandioyl CoA which is metabolised to dodecandioylcarnitine. The accumulation of these metabolic intermediates may be significant in the pathogenesis of Reye's syndrome.
Carnitine↗
Contribution of gut bacterial metabolism to human metabolic disease.
Metronidazole, an antibiotic with specific activity against anaerobic bacteria, was of clinical and biochemical benefit in two patients with methylmalonic aciduria. The virtual elimination of propionic acid from the stool suggested that propionic acid derived from faecal bacterial metabolism contributes substantially to methylmalonate production. These findings point to a novel avenue of treatment for these disorders of intermediary metabolism, and indicate the importance of microbial gut flora in normal human metabolism.
Bacteria, Anaerobic↗
In vivo permeability of the human placenta to inulin and mannitol.
1. Permeability of the term human placenta to inulin and mannitol was measured in six normal pregnancies. 2. Bolus and continuous infusion of inulin and mannitol to the mother for 1-2 h before delivery by Caesarean section achieved steady-state maternal serum concentrations. Net accumulation of inulin and mannitol in the fetus was measured by the subsequent neonatal urinary excretion. 3. Transplacental clearance was calculated by dividing the net flux by the time-averaged transplacental concentration gradient. Clearance for inulin was 0.86 +/- 0.1 ml min-1 (mean +/- S.E.M.) and for mannitol 7.3 +/- 0.8 ml min-1 (n = 6 in both cases).
Female↗
Effect of diazoxide or glucagon on hepatic glucose production rate during extreme neonatal hypoglycaemia.
The relation between hepatic glucose production rate (HGPR) and plasma concentrations of insulin and glucagon was investigated in four term neonates who had severe hypoglycaemia. The hepatic glucose production rate was less than 20% of normal for fasting term neonates in all four babies and yet insulin concentrations were never greater than 12 microU/ml; two babies had very low glucagon concentrations (less than 60 ng/l). Two further neonates with similar histories also had plasma glucagon concentrations that were also extremely low (less than 20 ng/l). A single intravenous bolus of glucagon caused a rapid rise in hepatic glucose production rate towards the normal range, which was sustained for many hours after the bolus had been given. Diazoxide given to one baby suppressed previously 'normal' insulin concentrations still further (4.2 to less than 1.6 microU/ml) and thereby restored the hepatic glucose production rate to normal. In view of the normal plasma insulin concentrations at a time when the hepatic glucose production rate was reduced, we feel that the absolute concentration of insulin may be less important than the insulin/glucagon molar ratio in the control of glucose homeostasis in this group of infants. The changing of this ratio by means of boluses of glucagon may be useful in preventing rebound hypoglycaemia, which so often occurs when dextrose infusions are reduced either accidentally or in an attempt to restart oral feeds.
Blood Glucose↗
Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing.
A male infant, whose parents were first cousins, presented at 6 mo of age with hypotonia, microcephaly, and delayed development. He was found to have large amounts of fumaric and succinic acids present in the urine. In lysed cultured skin-fibroblast preparations, the activity of fumarase was found to be 22.7% of that in controls. Cell fractionation by homogenization and by digitonin treatment indicated that the residual activity in the cells of the patient was primarily located in the mitochondrial fraction rather than in the cytosolic fraction. Isoelectric focusing of fibroblast extracts showed that six bands of fumarase activity were discernible in control cell lines, two of them cytosolic with pI's of 5.53 and 5.60 and four of them mitochondrial with a pI of 5.65-6.8. In contrast, isoelectric focusing of fibroblast extracts from the fumarase-deficient patient showed only a single band of activity with a pI corresponding to the mitochondrial type seen in the controls. Immunoprecipitation of proteins with rabbit antifumarase antibody in (35S)-methionine-labeled fibroblasts indicated that a protein of correct size (Mr = 44,000 daltons) corresponding to fumarase was synthesized in similar amounts in both the patients and controls. It is proposed that in the patient's cells a single active species of fumarase that is mitochondrial in location is synthesized. Since it is known that mitochondrial and cytosolic fumarases are encoded by the same gene but differ slightly in amino acid sequence, it is possible that a point mutation might explain these findings.
Abnormalities, Multiple↗
Patient-triggered ventilation in the newborn.
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Evaluation Studies as Topic↗
The response to L-carnitine and glycine therapy in isovaleric acidaemia.
The profound metabolic disturbances which occur in isovaleric acidaemia are due to the intramitochondrial accumulation of isovaleryl coenzyme A (CoA) with a consequent reduction in the availability of free CoA. Secondary carnitine insufficiency is also a feature of this and other disorders of organic acid metabolism. A patient who presented at 2.5 years of age was diagnosed using capillary GC-MS as having isovaleric acidaemia. She showed the full spectrum of abnormal organic acids previously associated with the 'neonatal' form of the disease despite her late presentation, indicating that it is inappropriate to refer to acute early and late onset forms of isovaleric acidaemia. Instead, a spectrum of disease exists, determined by environmental factors, residual enzyme activities and modifying effects of different phenotypes in different individuals. She also showed evidence of carnitine insufficiency. An oral challenge with L-carnitine resulted in the excretion of large amounts of urinary acylcarnitines which were shown by use of fast atom bombardment mass spectrometry to be primarily isovalerylcarnitine. Regular glycine supplementation caused no significant increase in urinary isovalerylglycine and had to be stopped because of side-effects after 5 days. An oral L-carnitine challenge during glycine supplementation resulted in a marked increase in isovalerylglycine excretion, again associated with the excretion of large amounts of isovalerylcarnitine. Carnitine acts by removing (detoxifying) intramitochondrial isovaleryl groups and, in the presence of glycine, it promotes the formation of isovalerylglycine. We believe L-carnitine supplementation is of value in the treatment of isovaleric acidaemia and that, in the present case, L-carnitine together with a moderate dietary restriction has proved to be the optimum form of therapy.
Amino Acid Metabolism, Inborn Errors↗
Radioiodide transfer across sheep placenta.
Unidirectional transplacental clearances of radioiodide were calculated from the net radioiodide fluxes after injection into fetal and/or maternal circulations of 33 catheterized conscious sheep. Maternofetal potential difference (PD) was also recorded. Clearance reached a steady state 20 min after bolus injection. Fetomaternal clearance was related to PD. Bidirectional clearance ratios measured in five experiments showed a significant divergence from the value for passive flux predicted from the measured PD, and in four experiments these ratios were also significantly different from unity, this result being incompatible with passive flux even if the transplacental PD is assumed to be zero. Injection of thiocyanate or iodide reduced radioiodide clearance. Fetomaternal clearance of radioiodide was halved by an increase in fetal plasma iodide concentration of approximately 0.1 mM. There appears to be an inhibitable iodide-transporting site capable of active transport in either direction.
Animals↗