PRENATAL-DIAGNOSIS OF MITOCHONDRIAL FATTY-ACID OXIDATION DEFECTS

Amniocytes isolated from two pregnancies at risk for fatty acid oxidat ion defects were incubated with stable isotopically labelled palmitate , in the presence of L-carnitine, to probe that pathway. The labelled acylcarnitines were then quantitated using tandem mass spectrometry. A mniocytes from a pregnancy at risk for medium-chain acyl-CoA dehydroge nase (MCAD) deficiency produced a characteristic acylcarnitine profile with increased levels of octanoylcarnitine and decanoylcarnitine, ind icative of MCAD deficiency. DNA analysis confirmed that the fetus was homozygous for the MCAD A985G mutation. Acylcarnitine and DNA analysis of the infant's blood obtained post-partum confirmed MCAD deficiency. Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced increased levels of long-chain acylcarnitines consiste nt with a deficiency in very-long-chain acyl-CoA dehydrogenase (VLCAD) . Measurements of the enzymatic activity confirmed VLCAD deficiency in amniocytes. Acylcarnitine profiles of the infant's blood obtained pos t-partum in addition to enzyme activities measured in fibroblasts conf irmed VLCAD deficiency. The successful prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty acid oxidation in fi broblasts suggests that this approach can potentially recognize many m itochondrial fatty acid oxidation defects even if no prior diagnosis i s determined in the family at risk.