MOLECULAR-BASIS OF HUMAN MITOCHONDRIAL VERY-LONG-CHAIN ACYL-COA DEHYDROGENASE-DEFICIENCY CAUSING CARDIOMYOPATHY AND SUDDEN-DEATH IN CHILDHOOD

beta-Oxidation of long-chain fatty acids provides the major source of energy in the heart, Defects in enzymes of the beta-oxidation pathway cause sudden, unexplained death in childhood, acute hepatic encephalop athy or liver failure, skeletal myopathy, and cardiomyopathy, Very-lon g-chain acyl-CoA dehydrogenase [VLCAD; very-long-chain-acyl-CoA:(accep tor) 2,3-oxidoreductase, EC 1.3.99.13] catalyzes the first step in bet a-oxidation. We have isolated the human VLCAD cDNA and gene and determ ined the complete nucleotide sequences, Polymerase chain reaction ampl ification of VLCAD mRNA and genomic exons defined the molecular defect s in two patients with VLC;ID deficiency who presented with unexplaine d cardiac arrest and cardiomyopathy, In one, a homozygous mutation in the consensus dinucleotide of the donor splice site (g(+1) --> a) was associated with universal skipping of the prior exon (exon 11), The se cond patient was a compound heterozygote, with a missense mutation, C- 1837 --> T, changing the arginine at residue 613 to tryptophan on one allele and a single base deletion at the intron-exon 6 boundary as the second mutation, This initial delineation of human mutations in VLCAD suggests that VLCAD deficiency reduces myocardial fatty acid beta-oxi dation and energy production and is associated with cardiomyopathy and sudden death in childhood.