Clin Biochem, Vol. 24, pp. 319-329, 1991 Printed in Canada. All right~ reserved.

0009-9120/91 $3.00 + .00 Copyright © 1991 The Canadian Society of Clinical Chemists.

Inborn Errors of Fatty Acid Oxidation in Man WILLIAM J. RHEAD Division of Medical Genetics, Department of Pediatrics, University of Iowa, College of Medicine, Iowa City, IA 52242, USA Inborn errors of fatty acid oxidation have only been recently identified. The clinical and biochemical presentations of these disorders are presented, as are analytic, biochemical and enzymatic approaches to their diagnosis. Recent clinical, biochemical and molecular information is summarized in detail. The identification and characterization of riboflavin-responsive ~-oxidation disorders is discussed. Approaches for clinical and biochemical screening a r e also described for these disorders.

KEY WORDS: mitochondria; flbroblasts; fatty acids; organic acids; 13-oxidation; acyl-CoA dehydrogenase; carnitine palmityl-transferase; carnitine; riboflavin; L-3-hydroxyacyl-CoA dehydrogenase; electron-transfer flavoprotein; electron-transfer flavoprotein:ubiquinone oxidoreductase. Introduction

lthough f3-oxidation is a fundamental biochemical process (1), inborn errors of mitoA chondrial fatty acid ~3-oxidation have only been identified in the last 15 years. Fatty acid oxidation enzymes, whose deficiencies result in disease, include those mediating cellular carnitine uptake (primary systemic carnitine deficiency; 2,3), "muscular" and "hepatic" carnitine palmityltransferases (CPT; 4,5), short-chain (SCAD; 6), medium-chain (MCAD; 7), and long-chain acyl-CoA dehydrogenases (LCAD; 8), L-3-hydroxyacyl-CoA dehydrogenase (HAD; 9), electron transfer flavoprotein (ETF) and electron transfer flavoprotein-dehydrogenase (ETF-DH; electron transfer flavoprotein:ubiquinone oxidoreductase; 10,11). Their considerable clinical, metabolic and biochemical variation renders their diagnosis difficult, and their clinical presentation and biochemical findings may be indistinguishable. There are several additional reviews on f3-oxidation and its disorders (1,12,13). Fatty acid oxidation in mammals is a complicated process largely localized to the mitochondrion, but also requiring the involvement of

Correspondence: William J. Rhead, M.D., Ph.D., Division of Medical Genetics, Department of Pediatrics, University of Iowa, College of Medicine, Iowa City, IA 52242, USA. Manuscript received September 18, 1990; revised December 8, 1990; accepted March 19, 1991. CLINICAL BIOCHEMISTRY, VOLUME 24, AUGUST 1991

several cytoplasmic systems (1). L-carnitine is synthesized in liver and kidney to meet endogenous requirements; secondary alterations in circulating carnitine as well as acylcarnitine to free carnitine ratios occur in many disorders of 13-oxidation (12,14). Long-chain fatty acids are activated to their acyl-CoA esters by a microsomal fatty acylCoA synthetase (1). Long-chain fatty acyl-carnitines are then transported through the mitochondrial membranes by the carnitine palmityltransferases and are again transesterified in the mitochondrial matrix to long-chain fatty acylCoAs. Short chain acetyl-carnitine transferase also serves to export acetyl moities from the mitochondrion to the cytoplasmic compartment. Whereas long-chain fatty acids are incapable of entering the mitochondrion as free acids, short- and mediumchain fatty acids enter the mitochondria directly, where they are converted to their respective acylCoA esters by acyl-CoA synthetases (1). Once present in the mitochondrial matrix in this activated form, the acyl-CoA esters undergo ~-oxidation. Under normal physiologic conditions, straight-chain fatty acyl-CoAs follow a known reaction sequence through the f3-oxidation spiral involving enzymes with defined chain length specificities (Figure 1). f3-Oxidation of acyl-CoA involves four steps catalyzed sequentially by the acyl-CoA dehydrogenases, the enoyl-CoA hydratases, L-3-hydroxyacyl-CoA dehydrogenases and 3-ketoacyl-CoA thiolases (1,12). Electrons derived from acyl-CoA dehydrogenase reactions are transferred by ETF and ETF-DH sequentially to coenzyme Q; reoxidization of the reduced dehydrogenases restores their catalytic activity. ETF is a heterodimer containing one FAD per dimer, while ETF-DH is a monomer protein containing a single FAD and iron sulfur center (10,13). Depending on fatty acid chain length, the first step in 13-oxidation is catalyzed by three distinct acyl-CoA dehydrogenases with different chain length specificities (15,16). SCAD catalyzes the dehydrogenation of only 4 and 6 carbon acyl-CoAs, while MCAD desaturates substrates from 4 to 14 carbons in length. LCAD is most active with acyl-CoA substrates from 12 to 18 carbons in length. While their substrate specificities vary somewhat between species, SCAD generally has the narrowest chain-length specificity and MCAD the widest, 319

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Inborn errors of fatty acid oxidation in man.

Inborn errors of fatty acid oxidation have only been recently identified. The clinical and biochemical presentations of these disorders are presented,...
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