MOLECULAR PRENATAL-DIAGNOSIS OF 3-HYDROXY-3-METHYLGLUTARYL COA LYASE DEFICIENCY

We report the first molecular prenatal diagnosis of 3-hydroxy-3-methyl glutaryl CoA lyase (HL) deficiency. The proband had a classic but seve re presentation with hypoketotic hypoglycaemia and acidosis, secondary mental retardation, and epilepsy, and HL deficiency was documented in cultured fibroblasts. We found him to be homozygous for the frameshif t mutation N46fs (+1), which yields a distinct pattern on single-stran d conformation polymorphism (SSCP) analysis. In two subsequent pregnan cies, molecular prenatal diagnosis was performed using SSCP. In the fi rst, chorionic villus biopsy was normal. In the second pregnancy, amni ocentesis revealed an affected fetus. In both pregnancies, the diagnos is was confirmed enzymatically. HL activity was less than 7 per cent o f control values in amniocytes and fetal liver of the affected pregnan cy. In the second pregnancy, amniotic fluid metabolite measurements by stable isotope dilution-selected ion monitoring mass spectrometry sho wed greater than 100-fold increases of 3-hydroxy-3-methylglutaric acid and of 3-methylglutaconic acid levels compared with controls.