Molecular prenatal diagnosis of 3‐hydroxy−3‐methylglutaryl coa lyase deficiency

We report the first molecular prenatal diagnosis of 3‐hydroxy‐3‐methylglutaryl CoA lyase (HL) deficiency. The proband had a classic but severe 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 frameshift mutation N46fs (+1), which yields a distinct pattern on single‐strand conformation polymorphism (SSCP) analysis. In two subsequent pregnancies, molecular prenatal diagnosis was performed using SSCP. In the first, chorionic villus biopsy was normal. In the second pregnancy, amniocentesis revealed an affected fetus. In both pregnancies, the diagnosis was confirmed enzymatically. HL activity was less than 7 per cent of control values in amniocytes and fetal liver of the affected pregnancy. In the second pregnancy, amniotic fluid metabolite measurements by stable isotope dilution‐selected ion monitoring mass spectrometry showed greater than 100‐fold increases of 3‐hydroxy‐3‐methylglutaric acid and of 3‐methylglutaconic acid levels compared with controls.