Abstract
3-Hydroxy-3-methylglutaric (HMG) aciduria is a disorder of L-leucine metabolism and ketone body biosynthesis characterised by recurrent acute life-threatening episodes resembling Reye's syndrome. Prenatal diagnosis was requested by the parents of a child with this condition and was carried out by amniocentesis at 16 weeks’ gestation. Amniotic fluid concentrations (capillary GC and GC-MS) (μmole/L) were for HMG 34.6 (n=1.21±0.38), 3-hydroxyisovalerate (HIV) 33.9 (n=4.78±1.91), 3-methylglutaconate (3MΔG) 31.7 (n=0.62-0.90) and 3-methylglutarate(3MG) 1.23 (n=0.12-0.26) consistent with an affected fetus. Termination was carried out on the basis of these data. The diagnosis was confirmed immediately by analysis of fetal plasma for organic acids:concentrations of HMG, HIV, 3MΔG and 3MG were 67.3, 36.9, 31.3 and 11.3μmoles/L respectively. Subsequent enzymology on cultured amniocytes gave mean results for isovalerate incorporation into protein (pmol/h/mg protein) of 48 compared to simultaneous controls of 252; direct HMG CoA lyase activity (nmoles HMG CoA removed/min/mg protein) was 0.05 compared to simultaneous controls of 9.16. Direct HMG CoA lyase measurements on chorionic villus tissue obtained at termination gave mean activities of 0.87 compared to controls of 8.04. These results provide the first prenatal diagnosis of HMG aciduria, demonstrate the rapid, accurate and unambiguous diagnosis at 16 weeks using direct GC-MS analysis of amniotic fluid and indicate the suitability of chorionic villus biopsy for future earlier (9 weeks) prenatal diagnoses of this condition.
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Chalmers, R., Tracey, B., Mistry, J. et al. THE PRENATAL DIAGNOSIS OF 3-HYDROXY-3-METHYLGLUTARIC ACIDURIA BY GC-MS AND ENZYMOLOGY ON CULTURED AMNIOCYTES AND ON CHORIONIC VILLI. Pediatr Res 19, 1075 (1985). https://doi.org/10.1203/00006450-198510000-00041
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DOI: https://doi.org/10.1203/00006450-198510000-00041
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