THE MOLECULAR-BASIS OF PEDIATRIC LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE-DEFICIENCY ASSOCIATED WITH MATERNAL ACUTE FATTY LIVER OF PREGNANCY

Mitochondrial long chain fatty acid beta-oxidation provides the major source of energy in the heart. Deficiencies of human beta-oxidation en zymes produce sudden, unexplained death in childhood, acute hepatic en cephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydro xyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD( +) oxidoreductase, EC 1.1.1.211] catalyzes the third step in beta-oxid ation, and this activity is present on the C-terminal portion of the a lpha subunit of mitochondrial trifunctional protein. We used single-st randed conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficie ncy in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome) . In all families, the mothers had acute fatty liver and associated se vere complications during pregnancies with the affected infants. The a nalysis in two affected children revealed a G to C mutation at positio n 1528 (G1528C) of the alpha subunit of the trifunctional protein on b oth alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature alpha subunit. The third chil d had this G1528C mutation an one allele and a different mutation (C11 32T) creating a premature termination codon (residue 342) on the secon d allele. Our results demonstrate that mutations in the LCHAD domain o f the trifunctional protein alpha subunit in affected offspring are as sociated with maternal acute fatty liver of pregnancy. This is the ini tial delineation of the molecular basis of isolated LCHAD deficiency.