The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy.

Abstract

Mitochondrial long chain fatty acid 13-oxidation provides the major source of energy in the heart. Deficiencies of human 13-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in 13-oxidation, and this activity is present on the C-terminal portion of the a subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (et subunit) gene to determine the molecular basis of LCHAD deficiency 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 severe complications during pregnancies with the affected infants. The analysis in two affected children revealed a G to C mutation at position 1528 (G1528C) of the a subunit of the trifunctional protein on both alleles. This is in the LCHAD domain and substitutes glutamine for glutamic acid at position 474 of mature a subunit. The third child had this G1528C mutation on one allele and a different mutation (C1132T) creating a premature termination codon (residue 342) on the second allele. Our results demonstrate that mutations in the LCHAD domain of the trifunctional protein a subunit in affected offspring are associated with maternal acute fatty liver of pregnancy. This is the initial delineation of the molecular basis of isolated LCHAD deficiency.Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NADI oxidoreductase, EC 1.1.1.211] activity catalyzes the third step in the mitochondrial (3-oxidation spiral. (3-Oxidation provides the major source of energy in heart and skeletal muscle and is essential for intermediary metabolism in the liver. The (3-oxidation of long chain fatty acids requires four sequential enzyme activities: the initial fatty acyl-CoA dehydrogenase, a 2,3-enoyl-CoA hydratase, a 3-hydroxyacyl-CoA dehydrogenation step, and a 3-ketoacyl-CoA thiolase. With each cycle through the spiral, the long chain fatty acid substrate is reduced by two carbons, producing acetyl CoA. Because of the range of fatty acid substrate lengths, each of these reactions is catalyzed by two to four separate enzymes encoded by individual nuclear genes and with differing substrate specificities.

Long-chain 3-hydroxyacyl–coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients

“…34-36 The HELLP syndrome, described previously in pregnant mothers of LCHAD-deficient babies, was not diagnosed in any of the mothers in this series. 37,38 Pigmentary retinopathy was a common finding eren among young patients and was conspicuous, with pigment aggregations in what otherwise was a hypopigmented retina. Although pigmentary retinopathy has been detected in a few patients with LCHAD deficiency, we did not find reports of retinopathy in other fatty acid [3-oxidation defects, including defects of long-chain fatty acid oxidation.…”

Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency

“…Subject characteristics and duration on DHA supplementation are presented in Table 1. Nine cases had previously published mutation analyses [11][12][13][14][15][16]. The subjects ranged in age from 1 to 12 years at enrollment.…”

Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia

“…This missense mutation results in the substitution of glutamate to glutamine at amino acid position 510. As this change is located in the catalytically active region, it deteriorates the dehydrogenase activity of the a-subunit protein (Sims et al 1995;Ijlst et al 1996).…”