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Semin Liver Dis 2001; 21(4): 489-500
DOI: 10.1055/s-2001-19037
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Fatty Acid Transport and Mitochondrial Oxidation Disorders

Piero Rinaldo
  • Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
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Publication History

Publication Date:
17 December 2001 (online)

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ABSTRACT

Inborn errors of fatty acid transport and mitochondrial oxidation (FATMO) represent a group of metabolic disorders that has brought forward many interesting developments in recent years, particularly the discovery of several new defects and the recognition of an ever-increasing spectrum of clinical phenotypes. The impact of newborn and postmortem screening in preventing morbidity and mortality is now recognized beyond specialized academic centers and has emerged as a staple of general pediatric practice. This review focuses on the biochemical basis and clinical manifestations of these disorders, particularly maternal complications of pregnancy, the increasingly complex process of laboratory evaluation, and a synopsis of two recently discovered defects: long-chain fatty acid transport/binding defect and medium- and short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency. Although our understanding of these new disorders is still incomplete, they nevertheless appear to have a more than casual relationship with acute liver failure in pediatric patients.

KEYWORD

Liver failure - maternal complications of pregnancy - newborn screening - sudden death

REFERENCES

  • 1 Distel R J, Robinson G S, Spiegelman B M. Fatty acid regulation of gene expression.  J Biol Chem . 1992;  267 5937-5941
    PubMedGoogle Scholar
  • 2 Eaton S, Bartlett K, Pourfarzam M. Mammalian mitochondrial β-oxidation.  Biochem J . 1996;  320 345-357
    CrossrefPubMedGoogle Scholar
  • 3 Berk P D, Stump D D. Mechanisms of cellular uptake of long chain free fatty acids.  Mol Cell Biochem . 1999;  192 17-31
    CrossrefPubMedGoogle Scholar
  • 4 Stahl A, Gimeno R E, Tartaglia L A. Fatty acid transport proteins: a current view of a growing family.  Trends Endocr Metab . 2001;  12 266-273
    PubMedGoogle Scholar
  • 5 Bremer J. The role of carnitine in cell metabolism. In: De Simone C, Famularo G, eds. Carnitine Today Austin, TX: RG Landes Company, 1997: 1-37
    Google Scholar
  • 6 Ramsay R R, Gandour R D, van der Leij R F. Molecular enzymology of carnitine transfer and transport.  Biochim Biophys Acta . 2001;  1546 21-43
    CrossrefPubMedGoogle Scholar
  • 7 McGarry J D, Brown N F. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.  Eur J Biochem . 1997;  244 1-14
    CrossrefPubMedGoogle Scholar
  • 8 McGarry J D, Foster D W. Regulation of hepatic fatty acid oxidation and ketone body production.  Ann Rev Biochem . 1980;  49 395-420
    CrossrefPubMedGoogle Scholar
  • 9 Mitchell G A, Fukao T. Inborn errors of ketone body metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease, 8th ed New York: McGraw-Hill 2001: 2327-2356
    Google Scholar
  • 10 Saudubray J M, Mitchell G, Bonnefont J. Approach to the patient with a fatty acid oxidation disorder.  Prog Clin Biol Res . 1992;  375 271-288
    PubMedGoogle Scholar
  • 11 Rinaldo P, Raymond K, Al Odaib A. Fatty acid oxidation disorders: clinical and biochemical features.  Curr Opin Pediatr . 1998;  10 615-621
    PubMedGoogle Scholar
  • 12 Bennett M J, Rinaldo P, Strauss A W. Inborn errors of mitochondrial fatty acid oxidation.  Crit Rev Clin Lab Sci . 2000;  37 1-44
    PubMedGoogle Scholar
  • 13 Rinaldo P, Matern D. Disorders of fatty acid transport and mitochondrial oxidation: challenges and dilemmas of metabolic evaluation.  Genet Med . 2000;  2 338-344
    PubMedGoogle Scholar
  • 14 Treem W R. Inborn defects in mitochondrial fatty acid oxidation. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 2nd ed Philadelphia: Lippincott, Williams & Wilkins 2001: 735-785
    Google Scholar
  • 15 Stanley C A, Hale D E, Coates P M. Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels.  Pediatr Res . 1983;  17 877-884
    PubMedGoogle Scholar
  • 16 Autret-Leca E, Jonville-Bera A P, Llau M E. Incidence of Reye's syndrome in France: a hospital-based survey.  J Clin Epidemiol . 2001;  54 857-862
    CrossrefPubMedGoogle Scholar
  • 17 Boles R G, Buck E A, Blitzer M G. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem liver of 418 cases of sudden unexpected death in the first year of life.  J Pediatr . 1998;  132 924-933
    PubMedGoogle Scholar
  • 18 Chace D H, DiPerna J C, Mitchell B L. Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death.  Clin Chem . 2001;  47 1166-1182
    PubMedGoogle Scholar
  • 19 Rinaldo P. Mitochondrial fatty acid oxidation disorders and cyclic vomiting syndrome.  Dig Dis Sci . 1999;  44(suppl) 97-102
    PubMedGoogle Scholar
  • 20 Al Odaib A, Shneider B L, Bennett M J. A defect in the transport of long-chain fatty acids associated with acute liver failure.  N Engl J Med . 1998;  339 1752-1757
    CrossrefPubMedGoogle Scholar
  • 21 Ibdah J A, Bennett M J, Rinaldo P. A fetal fatty acid oxidation disorder causes maternal liver disease of pregnancy.  N Engl J Med . 1999;  340 1723-1731
    CrossrefPubMedGoogle Scholar
  • 22 Knox T A, Olans L B. Liver disease in pregnancy.  N Engl J Med . 1996;  335 569-576
    CrossrefPubMedGoogle Scholar
  • 23 Rinaldo P, Studinski A, Matern D. Prenatal diagnosis of disorders of fatty acid transport and mitochondrial oxidation.  Prenat Diagn . 2001;  21 52-54
    CrossrefPubMedGoogle Scholar
  • 24 Sattar N, Gaw A, Packard C J. Potential pathogenic roles of aberrant lipoprotein and fatty acid metabolism in pre-eclampsia.  Br J Obstet Gynaecol . 1996;  103 614-620
    PubMedGoogle Scholar
  • 25 Sattar N, Bendomir A, Berry C. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis.  Obstet Gynecol . 1997;  89 403-408
    CrossrefPubMedGoogle Scholar
  • 26 Shambaugh 3rd E G. Ketone body metabolism in the mother and fetus.  Fed Proc . 1985;  44 2347-2351
    PubMedGoogle Scholar
  • 27 Herrera E, Amusquivar E. Lipid metabolism in the fetus and the newborn.  Diabetes Metab Res Rev . 2000;  16 202-210
    CrossrefPubMedGoogle Scholar
  • 28 Shekawat P S, Bennett M J, Rakheja D. Fatty acid oxidation (FAO) in normal human placenta: Developmental expression and activity of enzymes of mitochondrial β-oxidation [Abstract].  Pediatr Res . 2001;  49 55
    PubMedGoogle Scholar
  • 29 Rinaldo P, Matern D, Bennett M J. Fatty acid oxidation disorders.  Ann Rev Physiol (in press).
    PubMedGoogle Scholar
  • 30 Strauss A W, Bennett M J, Rinaldo P. Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications.  Semin Perinatol . 1999;  23 100-112
    PubMedGoogle Scholar
  • 31 Rinaldo P. Laboratory diagnosis of inborn errors of metabolism. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 2nd ed Philadelphia: Lippincott, Williams & Wilkins 2001: 171-184
    Google Scholar
  • 32 Patel J S, Leonard J V. Ketonuria and medium-chain acyl-CoA dehydrogenase deficiency.  J Inherit Metab Dis . 1995;  18 98-99
    CrossrefPubMedGoogle Scholar
  • 33 Lagerstedt S A, Hinrichs D R, Batt S M. Quantitative determination of plasma C8-C26 total fatty acids for the biochemical diagnosis of nutritional and metabolic disorders.  Mol Genet Metab . 2001;  73 38-45
    CrossrefPubMedGoogle Scholar
  • 34 Jones P M, Quinn R, Fennessey P. An improved method for measuring serum or plasma free 3-hydroxy-fatty acids using stable isotope dilution gas chromatography-mass spectrometry and its utility for the study of disorders of mitochondrial fatty acid β-oxidation.  Clin Chem . 2000;  46 149-155
    PubMedGoogle Scholar
  • 35 Bonnefont J P, Specola N B, Vassault A. The fasting test in paediatrics: application to the diagnosis of pathological hypo and hyperketotic states.  Eur J Pediatr . 1990;  150 80-85
    PubMedGoogle Scholar
  • 36 Olpin S E, Manning N J, Pollitt R J. The use of [9,10-3H]myristate, [9,10-3H]palmitate and [9,10-3H]oleate for the detection and diagnosis of medium and long-chain fatty acid oxidation disorders in intact cultured fibroblasts.  Adv Exper Med Biol . 1999;  466 321-325
    PubMedGoogle Scholar
  • 37 Hale D E, Cornell J E, Bennett M J. Stability of long-chain and short-chain 3-hydroxyacyl-CoA dehydrogenase activity in postmortem liver.  Clin Chem . 1997;  43 273-278
    PubMedGoogle Scholar
  • 38 Shen J-J, Matern D, Millington D S. Acylcarnitines produced in vitro by cultured fibroblasts of patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and other disorders of fatty acid oxidation.  J Inherit Metab Dis . 2000;  23 27-44
    CrossrefPubMedGoogle Scholar
  • 39 Moon A, Rhead W J. Complementation analysis of fatty acid oxidation disorders.  J Clin Invest . 1987;  79 59-64
    PubMedGoogle Scholar
  • 40 Brivet M, Slama A, Ogier H. Diagnosis of carnitine acylcarnitine translocase deficiency by complementation analysis.  J Inherit Metab Dis . 1994;  17 271-274
    CrossrefPubMedGoogle Scholar
  • 41 Chace D H, Hillman S L, Van Hove L J. Rapid diagnosis of MCAD deficiency: quantitatively analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry.  Clin Chem . 1997;  43 2106-2113
    PubMedGoogle Scholar
  • 42 Wood J, Seashore M R, Magera M J. Retrospective diagnosis of very long chain acyl-CoA dehydrogenase deficiency from an infant's newborn screening card.  Pediatrics . 2001;  108 e19
    CrossrefPubMedGoogle Scholar
  • 43 Charrow J, Goodman S I, McCabe E RG. Tandem mass spectrometry in newborn screening.  Genet Med . 2000;  2 267-269
    PubMedGoogle Scholar
  • 44 Matern D, Rinaldo P. Medium chain acyl-coenzyme A (MCAD) deficiency. In: GeneClinics: Medical Genetics Knowledge Base [database online] University of Washington, Seattle. 2000; http://www.geneclinics.org/profiles/mcad.
    Google Scholar
  • 45 Raymond K, Bale A E, Barnes C A, Rinaldo P. Sudden adult death and medium-chain acyl-CoA dehydrogenase deficiency.  Genet Med . 1999;  1 293-294
    PubMedGoogle Scholar
  • 46 Iafolla A K, Thompson Jr J R, Roe C R. Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children.  J Pediatr . 1994;  124 409-415
    PubMedGoogle Scholar
  • 47 Rinaldo P, Yoon H R, Yu C. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders.  Semin Perinatol . 1999;  23 204-210
    CrossrefPubMedGoogle Scholar
  • 48 Bennett M J, Rinaldo P. The metabolic autopsy comes of age.  Clin Chem . 2001;  47 1145-1146
    PubMedGoogle Scholar
  • 49 Rinaldo P, Al Odaib A, Bennett M J. Complementation analysis of six patients with a defect of long-chain fatty acid transport in fibroblasts [Abstract].  J Inherit Metab Dis . 1999;  22(suppl) 15
    PubMedGoogle Scholar
  • 50 Vockley J, Rinaldo P, Bennett M J. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways.  Mol Genet Metab . 2000;  71 10-18
    CrossrefPubMedGoogle Scholar
  • 51 Tanaka T, Nakata T, Oka T. Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations.  J Lipid Res . 2001;  42 751-759
    PubMedGoogle Scholar
  • 52 Noyes B E, Bradshaw R A. L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. Purification and properties.  J Biol Chem . 1973;  248 3052-3059
    PubMedGoogle Scholar
  • 53 Kobayashi A, Jiang L L, Hashimoto T. Two mitochondrial 3-hydroxyacyl-CoA dehydrogenases in bovine liver.  J Biochem . 1996;  119 775-782
    PubMedGoogle Scholar
  • 54 Osumi T, Hashimoto T. Occurrence of two 3-hydroxyacyl-CoA dehydrogenases in rat liver.  Biochim Biophys Acta . 1979;  574 248-267
    PubMedGoogle Scholar
  • 55 Vredendaal P C M J, van den Berg E T I, Malingre H EM. Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence.  Biochem Biophys Res Commun . 1996;  223 718-723
    CrossrefPubMedGoogle Scholar
  • 56 Tein I, De Vivo C D, Hale D E. Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause of recurrent myoglobinuria and encephalopathy.  Ann Neurol . 1991;  30 415-419
    CrossrefPubMedGoogle Scholar
  • 57 Bennett M J, Weinberger M J, Kobori J A. Mitochondrial short-chain L-3-hydroxybutyryl-CoA dehydrogenase deficiency: a new defect of fatty acid oxidation.  Pediatr Res . 1996;  39 185-188
    PubMedGoogle Scholar
  • 58 Bennett M J, Spotswood S D, Ross K F. Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical, and pathological studies on three subjects with this recently identified disorder of mitochondrial beta-oxidation.  Pediatr Dev Pathol . 1999;  2 337-345
    PubMedGoogle Scholar
  • 59 O'Brien L K, Bennett M J, Rinaldo P. A mouse model for medium and short chain L-3-hydroxyacyl-CoA dehydrogenase deficiency [Abstract].  Pediatr Res . 2001;  49 181
    PubMedGoogle Scholar
  • 60 Clayton P T, Eaton S, Aynsley-Green A. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.  J Clin Invest . 2001;  108 457-465
    CrossrefPubMedGoogle Scholar
  • 61 O'Brien L K, Rinaldo P, Sims H F. Fulminant hepatic failure associated with mutations in the medium and short chain L-3-hydroxyacyl-CoA dehydrogenase gene [Abstract].  J Inherit Metab Dis . 2000;  23(suppl) 127
    PubMedGoogle Scholar
  • 62 Dipple K M, McCabe E RB. Phenotypes of patients with ``simple'' Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics.  Am J Hum Genet . 2000;  66 1729-1735
    Google Scholar
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