61 PRENATAL DIAGNOSIS OF MEVALONIC ACIDURIA BY STABLE ISOTOPE DILUTION GCMS

Abstract

Prenatal diagnosis of the organic acidurias that are life threatening or cause mental retardation is an important part of genetic counseling and may permit prenatal therapy. Eight different organoacidopathies have been successfully diagnosed prenatally by stable isotope dilution GCMS assays; there are 15 others potentially diagnosable. This methodology has been applied to mevalonic aciduria, the first documented inherited disorder of cholesterol and nonsterol isoprene biosynthesis in man. In a mother at risk for this disease the urinary excretion of mevalonic acid at 16 weeks of pregnancy of 5.6 mmol/mol creatinine was 35 times the mean normal level (range 0.09 - 0.22 mmol/mol creatinine, 5 control females). The analysis of amniotic fluid at this time indicated a 3000-fold elevation of mevalonic acid (240 μmol/l; range in 4 control amniotic fluids: 0.054 - 0.11 μmol/l), indicating the presence of an affected fetus. The diagnosis was confirmed by demonstration of deficient mevalonate kinase in amniocytes and ultimately in liver from the abortus. Mevalonic acid was found to be highly elevated in the abortus tissues. Concentrations ranged from 840 to 1120 μmol/kg in adrenals, gonads, liver, lymph nodes and spleen. An even higher level was detected in the brain, where the concentration was 1810 μmol/kg (control< 1 μmol/kg). This may reflect a particular need for cholesterol in brain development and is consistent with the severe developmental delay of the index patient with mevalonic aciduria. After termination of the pregnancy the mother's urinary excretion of mevalonic acid fell to 0.20 mmol/mol creatinine, within the normal range.