A Comprehensive Screening Method for Detecting Organic Acidurias and other Metabolic Diseases in Acutely Sick Infants and Children

Chalmers, R. A.; Watts, R. W. E.; Lawson, A. M.

doi:10.1177/000456327701400134

Cited by 17 publications

(8 citation statements)

References 34 publications

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“…The possibility that the twins, Bak 1 and Bak 2 ( to Jamaican vomiting sickness (hypoglycine toxicity) is discussed elsewhere (Chalmers and Lawson, 1979;Chalmers et al, 1980b). Figure 1, which is an extension of our previously published protocol (Chalmers et al, 1977b) shows the sequence of investigation which we now suggest on the basis of present experience. This incorporates organic acid analysis and quantitative amino acid analysis relatively late in the process.…”

Section: Discussionmentioning

confidence: 70%

Screening for organic acidurias and amino acidopathies in newborns and children

Chalmers

Purkiss

Watts

et al. 1979

J of Inher Metab Disea

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This investigation was undertaken in order to define the place of multidisease screening for inborn errors of metabolism in paediatric practice with particular reference to the organic acidurias, and to compare the efficiency of organic acid screening as a detection method for inborn errors of metabolism with that of amino acid screening on urine. The clinical criteria adopted for the selection of patients were: (i) acute unexplained illness in the newborn or infant; (ii) unexplained developmental delay in infancy or early childhood.The derivatized organic acids were separated by automated gas chromatography and identified by mass spectrometry. The patients were also screened for abnormal amino acidurias by thin-layer chromatography supplemented by automated quantitative column chrolnatography when visual inspection of the thin-layer chromatography plates suggested that the result might be abnormal.Six hundred and ninety-five patients were studied. The incidence of abnormalities was higher in the material which was referred from other hospitals. We attribute this to the more extensive preliminary investigation to which these cases had been subjected before our help was sought than was the case in patients referred from our hospital.We conclude that screening for organic acidurias on the basis of the broad criteria which we originally specified is unproductive and not cost-effective and that screening for organic acidurias should be confined to acutely ill neonates and young children who have been systematically evaluated biochemically by other means. A suitable scheme of investigation which need not involve a clinically unacceptable delay is proposed.Organic acid analysis by the present methods detected about ten times more abnormalities than amino acid analysis, or three times more if one considers only the known and likely inherited metabolic abnormalities in this series. The amino acidopathies were often diagnosed more precisely by the associated organic aciduria and only a few of the known inborn errors of metabolism require amino acid analysis exclusively for their identification. The present type of urinary organic acid analysis used as part of the investigation scheme which we have described will identify about one third of the approximately 180 inherited metabolic diseases with known enzyme defects. Organic acid analysis also detects other disorders and usually provides more information about the underlying biochemical derangement than does amino acid analysis alone.

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Section: Discussionmentioning

confidence: 70%

Screening for organic acidurias and amino acidopathies in newborns and children

Chalmers

Purkiss

Watts

et al. 1979

J of Inher Metab Disea

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“…Preliminary studies in one patient indicated this 2-HG to represent predominantly the L-enantiomer. An isolated 2-HG excretion has been observed recently in a patient described by Chalmers et al (1977). However, in that case it appeared to be D-2-HG (Chalmers et al, 1980).…”

Section: -mentioning

confidence: 84%

L‐2‐Hydroxyglutaric aciduria: an inborn error of metabolism?

Durán

Kamerling

Bakker

et al. 1980

J of Inher Metab Disea

199

111

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A 5-year-old boy, excreting large amounts of 2-hydroxyglutaric acid in the urine (3.3-7.6 mmol/l), is described. The patient presented with psychomotor retardation and dystrophy. His skeletal age was delayed. The EEG was not well differentiated; it resembled that observed in 2-year-old children. There was a severe anaemia, which reacted well to iron supplements. The 2-hydroxyglutaric acid was found to have the L-configuration, as analysed by capillary gas chromatography of the O-acetylated di-(-)-2-butyl ester derivative. The relation of L-2-hydroxyglutarate excretion to known metabolic pathways is discussed.

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“…All PPA loading tests were performed after the age of 6 months [14]. Urinary phenylpropionylglycine was determined by gas-chromatography-mass spectrometry (GC-MS), according to Chalmers et al [15] . …”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes

Touw

Smit

Niezen-Koning

et al. 2013

Orphanet Journal of Rare Diseases

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BackgroundMedium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of the mitochondrial fatty acid oxidation, caused by mutations in the ACADM gene. Since the introduction of neonatal screening for MCAD deficiency, a subgroup of newborns have been identified with variant ACADM genotypes that had never been identified before in clinically ascertained patients. In vitro residual MCAD enzyme activity has been found to facilitate risk-stratification. In this study we integrated results of in vitro (residual MCAD enzyme activities) and in vivo (clinical fasting tolerance tests, and phenylpropionic acid loading tests) tests in this subgroup of newborns, defining the consequences of variant ACADM genotypes.MethodsEnzyme analyses were performed in leukocytes with: hexanoyl-CoA (C6-CoA) +/− butyryl-CoA (C4-CoA), and phenylpropionyl-CoA (PP-CoA). In vitro studies were performed in 9 subjects with variant ACADM genotypes, in vivo functional tests in 6 of these subjects.ResultsEnzyme analyses with C6-CoA, C6-CoA + C4-CoA, and PP-CoA identified significantly higher residual MCAD enzyme activities in subjects with variant ACADM genotypes when compared to patients with classical ACADM genotypes.After prolonged fasting (range 15–18.5 hours) no hypoglycaemia was observed. Increasing concentrations of free fatty acids indicated lipolysis, and ketone body concentrations were sufficient for blood glucose concentrations in 5 out of 6 subjects. Phenylpropionic acid loading clearly demonstrated in vivo residual MCAD enzyme activity in all studied subjects.ConclusionsSubjects with variant ACADM genotypes and residual MCAD enzyme activities >10% display residual MCAD enzyme activities in vitro and in vivo. Our findings support the hypothesis that the guidelines on maximal duration of fasting might be abandoned in subjects with residual MCAD enzyme activities >10% under normal conditions. An emergency regimen and parental instructions remain necessary in all subjects with MCAD deficiency, regardless of residual MCAD enzyme activity.

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A Comprehensive Screening Method for Detecting Organic Acidurias and other Metabolic Diseases in Acutely Sick Infants and Children

Cited by 17 publications

References 34 publications

Screening for organic acidurias and amino acidopathies in newborns and children

Screening for organic acidurias and amino acidopathies in newborns and children

L‐2‐Hydroxyglutaric aciduria: an inborn error of metabolism?

In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes

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