Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection

Georg F. Hoffmann, Lawrence Sweetman, Hans J. Bremer, Donald H. Hunneman, Josef Hyánek, Victor Kožich, Willy Lehnert, William L. Nyhan, Ines Speidel, Friedrich K. Trefz, Kenneth M. Gibson

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

A stable isotope dilution assay using D3-mevalonic acid was developed and applied to the study of mevalonic aciduria. The method also appears to be suitable for the evaluation of different therapeutic regimens in patients with hypercholesterolemia. Mevalonic acid was isolated by liquid partition chromatography and quantified as the underivatized lactone by means of ammonia chemical ionization selected ion monitoring capillary gas chromatography-mass spectrometry. In heterozygotes there was significantly greater urinary excretion of mevalonic acid, while the range of enzymatic activity of mevalonate kinase showed an overlap with that of controls. The analysis of amniotic fluids of two pregnancies at risk for mevalonic aciduria showed a 3277-fold elevation as compared to controls in the first case, diagnostic of an affected fetus, and a normal value in the second one. Mevalonic acid concentration was much increased in tissues of the affected and aborted fetus. Concentrations ranged from 840 to 1120 μmol/kg in various tissues and were as high as 1810 μmol/kg in brain. Concentrations in control fetal tissues were ≈ 1 μmol/kg.

Original languageEnglish (US)
Pages (from-to)209-227
Number of pages19
JournalClinica Chimica Acta
Volume198
Issue number3
DOIs
StatePublished - May 15 1991
Externally publishedYes

Keywords

  • Carrier detection
  • Cholesterol biosynthesis
  • Mevalonic aciduria
  • Prenatal diagnosis
  • Stable isotope dilution assay

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical

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