Isotope dilution analysis of methylcitric acid in amniotic fluid for the prenatal diagnosis of propionic and methylmalonic acidemia

Naylor, Gordon S.; Sweetman, Lawrence; Nyhan, William L.; Hornbeck, Cecil L.; Griffiths, John C.; Mörch, Lars; Brandänge, Svante

doi:10.1016/0009-8981(80)90445-3

Cited by 57 publications

(26 citation statements)

References 16 publications

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“…Prenatal diagnosis by amniotic fluid analysis using a stable isotope dilution method have been reported in several organic acidurias such as methylmalonic acidemia (22)(23)(24), isovaleric acidemia (25), and glutaric aciduria type I (26). In many of these cases, a substantial difference in concentration of the diagnostic compounds between normal controls and the affected fetus has been detectable.…”

Section: Control Patientmentioning

confidence: 99%

Prenatal Diagnosis and Neonatal Monitoring of a Fetus with Glutaric Aciduria Type II Due to Electron Transfer Flavoprotein (β-Subunit) Deficiency

et al. 1991

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ABSTRACT. The prenatal diagnosis of a male fetus with glutaric aciduria type I1 and the time course of metabolite urinary excretion, starting immediately after birth, are described. Prenatal diagnosis was undertaken at the 17th wk of gestation by irnmunoblot analysis and pulse labeling experiments of amniocytes and, retrospectively, by stable isotope dilution analysis of six metabolites in amniotic fluid. The results were as follows: I) The immunochemical analysis on cultured amniocytes showed that the fetus, as the previous index case in this family, was affected with a deficiency of the P-subunit of electron transfer flavoprotein. 2) Glutarate concentration was significantly increased in the cell-free supernatant of the amniotic fluid. In the postnatal period, most of the organic acids and acylglycines characteristic of the disorder appeared in urine within a week, although an increased excretion of hexanoylglycine was the only biochemical abnormality detectable in the first urine sample collected at 9 h after birth. Growth and development of this infant were normal during the following 6 mo of life, when he was receiving oral supplementation with L-carnitine and riboflavin. It should be underscored that transient abnormalities in routine blood tests (glutamic oxaloacetic transaminase, lactate dehydrogenase, and creatine phosphokinase) were present soon after birth, despite his asymptomatic clinical course. Early detection and aggressive treatment could be effective in such a form of glutaric aciduria type 11. (Pediatr Res 30: [439][440][441][442][443] 1991) Abbreviations GAII, glutaric aciduria type I1 ETF, electron transfer flavoprotein a-ETF, a-subunit of ETF P-ETF, P-subunit of ETF GC/MS, gas chromatography mass spectrometry GOT, glutamic oxaloacetic transaminase LDH, lactate dehydrogenase

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Section: Control Patientmentioning

confidence: 99%

Prenatal Diagnosis and Neonatal Monitoring of a Fetus with Glutaric Aciduria Type II Due to Electron Transfer Flavoprotein (β-Subunit) Deficiency

et al. 1991

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“…Affected fetuses produced relatively smaller elevations in urinary MMA excretion (3%-9-fold) compared to the elevations observed in amniotic fluid MMA concentrations from pregnancies carrying affected fetuses (125-250-fold), and one of the urines (Case 12) was not obtained until 23 weeks gestation. Nevertheless, these urinary elevations are significant (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) standard deviations above the mean), and it remains to be seen if similar elevations in urinary MMA excretion will be observed in other at-risk pregnancies. Presently we do not advocate the use of urinary MMA excretion as the sole determinant for prenatal diagnosis.…”

Section: Discussionmentioning

confidence: 97%

“…During the course of these studies, Naylor et al (15) reported a method for measurement of methylcitric acid by stable isotope dilution GC-MS and its successful application to the prenatal diagnosis of propionic acidemia and methylmalonic acidemia. There are important differences between the method which they describe and our own.…”

Section: Discussionmentioning

confidence: 99%

The Stable Isotope Dilution Method for Measurement of Methylmalonic Acid: a Highly Accurate Approach to the Prenatal Diagnosis of Methylmalonic Acidemia

et al. 1982

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SummaryWe report a stable isotope dilution method for the accurate measurement of methylmalonic acid (MMA) in amniotic fluid and its successful application to the prenatal diagnosis of methylmalonic acidemia. The stable isotopically-labeled analogue of MMA, (2-[2H3]methyl)malonic acid, was synthesized and used as an internal standard. Samples were extracted, methylated, and analyzed by chemical ionization gas chromatography-mass spectrometry (CI-GC-MS) operated in the selected ion monitoring (SIM) mode. The analytical method is rapid (8 h), ultrasensitive (lower limit -10 ng/ml), linear over three orders of magnitude, and reproducible. The concentration of MMA in amniotic fluids from normal pregnant women was 38 2 15 ng/ml (mean + 1 S.D.). This value is 20-fold less than our previous estimate by gas chromatographic analysis, indicating that interference by co-eluting materials was eliminated by use of SIM in the present method. Amniotic fluids from eight at-risk pregnancies were examined. MMA concentration in six of the pregnancies was in the normal range whereas the concentration in the remaining two pregnancies was elevated by greater than two orders of magnitude (125-250-fold). Analysis of urine from ten at-risk pregnancies showed a smaller (3%-9-fold) but significant increase in urinary MMA excretion in two women carrying affected fetuses. A control group of normal pregnant women had a mean urinary MMA excretion of 1.7 + 0.5 pg/mg creatinine, in excellent agreement with previous estimates. There was concordance in prenatal diagnosis of fetal status in all cases between amniotic fluid cell studies and MMA measurements in amniotic fluid and/or maternal urine. Amniotic fluid MMA determination by the stable isotope dilution technique provides a highly accurate technique for prenatal diagnosis of methylmalonic acidemia that is complementary to amniotic fluid cell studies, and may supplant such studies in selected instances. SpeculationThe stable isotope dilution method may be extended to prenatal diagnosis of other inborn errors of metabolism in which low molecular weight metabolites accumulate in amniotic fluid. The concentrations of metabolites, which accumulate in some of these disorders, are below the sensitivity limits of currently available analytical techniques and it is thus impossible to distinguish differences that may be present in pregnancies carrying affected and unaffected fetuses. The enhanced sensitivity of the stable isotope dilution method may permit the desired discrimination.The inherited methylmalonic acidemias are a group of metabolic disorders characterized clinicallv bv rotei in intolerance.

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“…The prenatal diagnosis of propionic acidaemia (propionyl CoA carboxylase 1 ) deficiency), and of the methylmalonic acid rias (methylmalonylCoA mutase 1 ) deficiency and cobalamine disorders) can be rapidly established by quantifying methylcitrate in the amniotic fluid obtained at the 15 -16th week of pregnancy (1,2) or perhaps even earlier (L. Sweetman, personal communication). The method of choice for the quantification of methylcitrate (2-hydroxy-l,2,3-butanetricarboxylic acid), normally present at concentrations below 1 μπιοΐ/ΐ, is nowadays gas chromatography mass spectrometry (GC-MS) with stable isotope dilution.…”

Section: Introductionmentioning

confidence: 99%

“…In order to circumvent the resulting low sensitivity, chemical ionisation methods have been applied (1,3 Another possibility would be El with lower ionisation energy, which however needs more expensive mass spectrometers.…”

Section: Introductionmentioning

confidence: 99%

Methylcitric Acid Determination in Amniotic Fluid by Electron-Impact Mass Fragmentography

Kretschmer

Bachmann²

1988

Clinical Chemistry and Laboratory Medicine

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Summary:Methylcitric acid, a metabolite of abnormal propionyl-CoA metabolism, is elevated in amniotic fluid when the fetus is affected with propionic acidaemia or methylmalonic aciduria. We developed a method for quantifying methylcitric acid in amniotic fluid by solid-phase extraction, derivatisation to the /-butyldimethylsilylester, and gas chromatography-mass spectrometry with electron-impact ionisation, using the deuterated analogue of methylcitric acid as an internal standard. The main advantages are a good sensitivity, simple sample preparation, and feasibility on instruments equipped with mass specific detectors.

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Isotope dilution analysis of methylcitric acid in amniotic fluid for the prenatal diagnosis of propionic and methylmalonic acidemia

Cited by 57 publications

References 16 publications

Prenatal Diagnosis and Neonatal Monitoring of a Fetus with Glutaric Aciduria Type II Due to Electron Transfer Flavoprotein (β-Subunit) Deficiency

Prenatal Diagnosis and Neonatal Monitoring of a Fetus with Glutaric Aciduria Type II Due to Electron Transfer Flavoprotein (β-Subunit) Deficiency

The Stable Isotope Dilution Method for Measurement of Methylmalonic Acid: a Highly Accurate Approach to the Prenatal Diagnosis of Methylmalonic Acidemia

Methylcitric Acid Determination in Amniotic Fluid by Electron-Impact Mass Fragmentography

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