Journal of Inherited Metabolic Disease

, Volume 18, Issue 4, pp 473–490 | Cite as

Disorders of mitochondrial long-chain fatty acid oxidation

  • R. J. Pollitt


The oxidation of long-chain fatty acids requires a series of enzymes which are located in or on the mitochondrial membranes. These include carnitine palmitoyltransferases I and II, a carnitine-acylcarnitine translocase and, newly discovered, very long-chain acyl-CoA dehydrogenase and the mitochondrial trifunctional protein. These last two chain-shorten acyl-CoA esters to the point where they can be transferred to the more soluble medium- and short-chain-specific enzymes within the mitochondrial matrix. The disorders of long-chain fatty acid oxidation show a rather similar range of clinical and biochemical features, though with different emphasis in the different conditions. Patients with severe defects usually present early with acute attacks of hypoketotic hypoglycaemia and impaired liver function, or with cardiomyopathy or cardiac arrhythmia. In milder variants, skeletal myopathy with intermittent myoglobinuria develops later in life. 3-Hydroxyacyl-CoA dehydrogenase deficiency is unusual in producing peripheral neuropathy and retinitis pigmentosa. Treatment is based on the avoidance of fasting and replacement of normal dietary fat by medium-chain triglyceride, the medium-chain fatty acids entering the mitochondria in a carnitine-independent manner and bypassing the long-chain part of the spiral. Diagnosis must ultimately be based on direct assay of the enzyme involved, but preliminary indicators may come from determination of carnitine and intermediate metabolites in plasma, urinary organic acid profiling, and radioisotopic screening assays with lymphocytes or cultured fibroblasts.


Carnitine Retinitis Retinitis Pigmentosa Carnitine Palmitoyltransferases Urinary Organic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aoyama T, Ushida Y, Kelley RI, et al (1993) A novel disease with deficiency of mitochondrial very long-chain acyl-CoA dehydrogenase.Biochem Biophys Res Commun 191: 1369–1372.Google Scholar
  2. Bakker HD, Scholte HR, Jeneson JAL, Busch HFM, Abeling NGGM, van Gennip AH (1994) Vitamin-responsive complex 1 deficiency in a myopathic patient with increased activity of the terminal respiratory chain and lactic acidosis.J Inher Metab Dis 17: 196–204.Google Scholar
  3. Beinert H (1990) Fatty acid oxidation in soluble systems of mammalian origin: the beginnings. In Tanaka K, Coates PM, eds. Fatty Acid Oxidation. Clinical, Biochemical and Molecular Aspects.Prog Clin Biol Res 321: 123–36.Google Scholar
  4. Bennett MJ, Sherwood WG, Gibson KM, Burlina AB (1993) Secondary inhibition of multiple NAD-requiring dehydrogenases in respiratory chain complex I deficiency: possible metabolic markers for the primary defect.J Inher Metab Dis 16: 560–562.Google Scholar
  5. Bennett MJ, Weinberger MJ, Sherwood WG, Burlina AB (1994) Secondary 3-hydroxydicarboxylic aciduria mimicking long-chainl-3-hydroxyacyl-CoA dehydrogenase deficiency.J Inher Metab Dis 17: 283–286.Google Scholar
  6. Berghoffen J, Kaplan P, Hale DE, Bennett MJ, Berry GT (1993) Marked elevation of urinary 3-hydroxydecanedioic acid in a malnourished infant with glycogen storage disease, mimicking long-chainl-3-hydroxyacyl-CoA dehydrogenase deficiency.J Inher Metab Dis 16: 851–856.Google Scholar
  7. Bertrand C, Largillière, Zabot MT, Mathieu M, Vianey-Saban C (1993) Very long-chain acyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid oxidation in fibroblasts.Biochim Biophys Acta 1180: 327–329.Google Scholar
  8. Bonham JR (1993) The investigation of hypoglycaemia during childhood.Ann Clin Biochem 30: 238–247.Google Scholar
  9. Bonham JR, Pollitt RJ, Downing M, Manning NJ, Olpin SE (1994) Plasma free carnitine: useful when interpreting abnormal organic acid profiles.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract A118.Google Scholar
  10. Bonnefont J-P, Specola NB, Vassault, et al (1991) The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyper-ketotic states.Eur J Pediatr 150: 80–85.Google Scholar
  11. Briones P, Garavaglia B, Ribes A, et al (1995) Clinical and biochemical findings in a Spanish boy with primary carnitine deficiency.J Inher Metab Dis 18: 273–240.Google Scholar
  12. Brivet M, Slama A, Saudubray J-M, Legrand A, Lemonior A (1995) Rapid diagnosis of long chain and medium chain fatty acid oxidation disorders using lymphocytes.Ann Clin Biochem 32: 154–159.Google Scholar
  13. Carpenter K, Pollitt RJ, Middleton B (1992) Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria.Biochem Biophys Res Commun 183: 443–448.Google Scholar
  14. Chalmers RA, English N, Hughes EA, Noble-Jamieson C, Wigglesworth JS (1987) Biochemical studies on cultured skin fibroblasts from a baby with long-chain acyl-CoA dehydrogenase deficiency presenting as sudden neonatal death.J Inher Metab Dis 10 (supplement 2): 260–262.Google Scholar
  15. Chalmers RA, Stanley CA, Hale DE, et al (1994) Carnitine-acylcarnitine translocase deficiency in an infant with a putative long-chain fatty acid β-oxidation defect.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract O6.Google Scholar
  16. Christensen E, Vikre-Jørgensen J (1995) Six years experience with carnitine supplementation in a patient with an inherited defective carnitine transport system.J Inher Metab Dis 18: 233–236.Google Scholar
  17. Corr PB, Creer MH, Yamada KA, Saffitz JE, Sobel BE (1989) Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.J Clin Invest 83: 927–936.Google Scholar
  18. Demaugre F, Bonnefont J-P, Brivet M, et al (1992) Pathophysiological approach to carnitine palmitoyltransferase II deficiencies. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation.Prog Clin Biol Res 375: 301–308.Google Scholar
  19. Duran M, Wanders RJA, de Jager JP, et al (1991) 3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment.Eur J Pediatr 150: 190–195.Google Scholar
  20. Eaton S, Bhuiyan AKMJ, Singh Kler R, Turnbull DM, Bartlett K (1993) Intramitochondrial control of the oxidation of hexadecanoate in skeletal muscle.Biochem J 289: 161–168.Google Scholar
  21. Esser V, Britton CH, Weis BC, Foster DW, McGarry JD (1993) Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function.J Biol Chem 268: 5817–5822.Google Scholar
  22. Garland PB, Shepherd D, Yates DW (1965) Steady state concentrations of CoA, acetyl-CoA and long-chain fatty acyl-CoA in rat liver mitochondria.Biochem J 97: 87–594.Google Scholar
  23. Hagenfeldt L, Venizlos N, von Döbeln U (1995) Clinical and biochemical presentation of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.J Inher Metab Dis 18: 245–248.Google Scholar
  24. Haworth JC, Demaugre F, Booth FA, et al (1992) Atypical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family.J Pediatr 121:553–557.Google Scholar
  25. Hesler CB, Olymbios C, Haldar D (1990) Transverse-plane topography of long-chain acyl-CoA synthetase in the mitochondrial outer membrane.J Biol Chem 265: 6600–6605.Google Scholar
  26. Hoppel CL (1990) Carnitine palmitoyltransferase deficiency. In Tanaka K, Coates PM, eds. Fatty Acid Oxidation. Clinical, Biochemical and Molecular Aspects.Prog Clin Biol Res 321: 435–450.Google Scholar
  27. Hug G, Bove KE, Soukup S and Elpeleg ON, Joseph A, Guttman A (1994) Profound carnitine palmitoyltransferase II deficiency.J Pediatr 122: 159–161.Google Scholar
  28. Ijlst L, Wanders RJA (1993) A simple spectrophotometric assay for long-chain acyl-CoA dehydrogenase activity measurements in human skin fibroblasts.Ann Clin Biochem 30: 293–297.Google Scholar
  29. Ijlst L, Ushikubo S, Kamijo T, et al (1995a) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: high frequency of the G1528C mutation with no apparent correlation with the clinical phenotype.J Inher Metab Dis 18: 241–244.Google Scholar
  30. Ijlst L, Wanders RJA, Ushikubo S, Kamijo T, Hashimoto T (1995b) Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a major disease-causing mutation in the α-subunit of the mitochondrial trifunctional protein.Biochim Biophys Acta 1215: 347–350.Google Scholar
  31. Izai K, Uchida Y, Orii T, Yamamoto S, Hashimoto T (1992) Novel β-oxidation enzymes in rat liver mitochondria. I. Purification and properties of very-long-chain acyl-coenzyme A dehydrogenase.J Biol Chem 267: 1027–1033.Google Scholar
  32. Jackson S, Bartlett K, Land J, et al (1991) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.Pediatr Res 29: 406–411.Google Scholar
  33. Jackson S, Singh-Kler R, Bartlett K, et al (1992) Combined enzyme defect of mitochondrial fatty acid oxidation.J Clin Invest 90: 1219–1225.Google Scholar
  34. Kamijo T, Aoyama T, Komiyama A, Hashimoto T (1994a) Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein.Biochem Biophys Res Commun 199: 818–825.Google Scholar
  35. Kamijo T, Wanders RJA, Saudubray J-M, Aoyama T, Komiyama A, Hashimoto T (1994b) Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients.J Clin Invest 93: 1740–1747.Google Scholar
  36. Korenke GC, Wanders RJA, Krohn H-P, Hanefeld (1994) Intermittent myoglobinuria in a girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract O4.Google Scholar
  37. Land JM, Mistry S, Squier W, Hope P, Orford M, Saggerson ED (1992) Neonatal carnitine palmitoyltransferase deficiency: a case with a muscular presentation. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation.Prog Clin Biol Res 375: 309–315.Google Scholar
  38. Manning NJ, Olpin SE, Pollitt RJ, Webley J (1990) A comparison of [9,10-3H]palmitic and [9,10-3H]myristic acids for the detection of defects of fatty acid oxidation in intact fibroblasts.J Inher Metab Dis 13: 58–68.Google Scholar
  39. Mayatepek E, Wanders RJA, Hoffmann GF (1995) Mitochondropathy presenting with non-ketotic hypoglycaemia as 3-hydroxydicarboxylic aciduria.J Inher Metab Dis 18: 249–252.Google Scholar
  40. Morris AAM, Deshpande S, Ward-Platt MP, et al (1995) Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia.J Inher Metab Dis 18: 28–32.Google Scholar
  41. Nada MA, Wappner RS, Ding JH, Roe CR (1994) Prenatal diagnosis of mitochondrial fatty acid oxidation disorders.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract P117.Google Scholar
  42. Niezen-Koning KE, Ijlst L, van Spronson FJ, et al (1995) A patient with lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency.J Inher Metab Dis 18: 230–232.Google Scholar
  43. Ogilvie I, Poufarzam M, Jackson S, Stockdale C, Bartlett K, Turnbull DM (1994) Very long-chain acyl-CoA dehydrogenase deficiency presenting with exercise-induced myoglobinuria.Neurology 44: 467–473.Google Scholar
  44. Olpin SE, Manning NJ, Carpenter K, Middleton B, Pollitt RJ (1992) Differential diagnosis of hydroxydicarboxylic aciduria based on the release of3H2O from [9,10-3H]myristic and [9,10-3H]palmitic acids by intact cultured fibroblasts.J Inher Metab Dis 15: 883–890.Google Scholar
  45. Pande SV, Murthy MSR (1994) Carnitine-acylcarnitine translocase deficiency: implications for human pathology.Biochim Biophys Acta 1226: 269–276.Google Scholar
  46. Pande SV, Brivet M, Slama A, Demaugre F, Aufrant C, Saudubray J-M (1993) Carnitine-acylcarnitine translocase deficiency with severe hypoglycaemia and auriculo-ventricular block. Translocase assay in permeabilised fibroblasts.J Clin Invest 91: 1247–1252.Google Scholar
  47. Parini R, Garavaglia B, Saudubray J-M, et al (1991) Clinical diagnosis of long-chain acyl-coenzyme A-dehydrogenase deficiency: use of stress and fat-loading tests.J Pediatr 119: 77–80.Google Scholar
  48. Pollitt RJ (1990) Clinical and biochemical presentations in twenty cases of hydroxydicarboxylic aciduria. In Tanaka K, Coates PM, eds. Fatty Acid Oxidation. Clinical, Biochemical and Molecular Aspects.Prog Clin Biol Res 321: 495–502.Google Scholar
  49. Pollitt RJ, Manning NJ, Olpin SE, Young ID (1994) Prenatal diagnosis of a defect in medium-chain fatty acid oxidation.J Inher Metab Dis 17: 279–282.Google Scholar
  50. Poll-The BT, Bonnefont J-P, Ogier H (1988) Familial hypoketotic hypoglycaemia associated with peripheral neuropathy, pigmentary retinopathy and C6-C14 hydroxydicarboxylic aciduria. A new defect in fatty acid oxidation?J Inher Metab Dis 11 (supplement 2): 183–185.Google Scholar
  51. Rabier D, Bardet J, Parvy Ph, et al (1995) Do criteria exist from urinary organic acids to distinguish β-oxidation defects?J Inher Metab Dis 18: 257–260.Google Scholar
  52. Rasmussen TG, Rosendal J, Knudsen J (1993) Interaction of acyl-CoA binding protein (ACBP) on processes for which acyl-CoA is a substrate, product, or inhibitor.Biochem J 292: 907–913.Google Scholar
  53. Rhead WJ (1994) New techniques for fatty acid oxidation screening in skin fibroblasts.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract A105.Google Scholar
  54. Rhead WJ, Kutschke W, Marshall T (1994) Flavin homeostasis and biochemical heterogeneity in patients with riboflavin-responsive myopathies.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract O5.Google Scholar
  55. Roe CR, Millington DS, Norwood DL, et al (1990) 2,4-Dienoyl-coenzyme A reductase deficiency: a possible new disorder of fatty acid oxidation.J Clin Invest 85: 1703–1707.Google Scholar
  56. Seddon HR, Green A, Gray RGF, Leonard JV, Pollitt RJ (1995) Incidence and diagnosis rate of medium-chain acyl-CoA dehydrogenase deficiency.Lancet 345: 135–136.Google Scholar
  57. Slama A, Brivet M, Boutron A, et al (1994) Study of fatty acid oxidation in fibroblasts from patients with carnitine palmitoyltransferase 2 deficiency.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract P120.Google Scholar
  58. Smeitink J, Duran R, Dorland B, Berger R, Bergman D, Poll-The B-T (1994) 3-Hydroxydicarboxylic aciduria after LTC-loading in a patient with cytochromec oxidase deficiency.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract O8.Google Scholar
  59. Stanley CA, DeLeeuw S, Coates PM, et al (1991) Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake.Ann Neurol 30: 709–716.Google Scholar
  60. Stanley CA, Hale DE, Berry GT, De Leeuw S, Boxer J, Bonnefont J-P (1992a) A deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane.N Engl J Med 327: 19–23.Google Scholar
  61. Stanley CA, Sunaryo F, Hale DE, Bonnefont J-P, Demaugre F, Saudubray J-M (1992b) Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase-I deficiency.J Inher Metab Dis 15: 785–789.Google Scholar
  62. Sumegi B, Porpaczy Z, Alkonyi I (1991) Kinetic advantages of the interaction between fatty acid β-oxidation enzymes and complexes of the respiratory chain.Biochim Biophys Acta 1081: 121–128.Google Scholar
  63. Taroni F, Verderio E, Fiorucci S, et al (1992) Molecular characterisation of inherited carnitine palmitoyltransferase II deficiency.Proc Natl Acad Sci USA 89: 8429–8433.Google Scholar
  64. Taroni F, Verderio E, Dworzak F, Willems PJ, Cavadini P, Di Donato S (1993) Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients.Nature Genetics 4: 314–320.Google Scholar
  65. Tein I, Demaugre F, Bonnefont J-P, Saudubray J-M (1989) Normal muscle CPT-I and CPT-II activities in hepatic presentation patients with CPT-I deficiency in fibroblasts: tissue-specific isoforms of CPT-I?J Neurol Sci 92: 229–245.Google Scholar
  66. Tein I, De Vivo DC, Ranucci D, DiMauro S (1993) Skin fibroblast carnitine uptake in secondary carnitine deficiency disorders.J Inher Metab Dis 16: 135–146.Google Scholar
  67. Tein I, Christodoulou J, Donner E, McInnes RR (1994) Carnitine palmitoyltransferase II deficiency: a new cause of recurrent pancreatitis.J Pediatr 124: 938–940.Google Scholar
  68. Uchida Y, Izai K, Orii T, Hashimoto T (1992) Novel β-oxidation enzymes in rat liver mitochondria. II. Purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein.J Biol Chem 267: 1034–1041.Google Scholar
  69. Ventura FV, Ruiter JPN, Tavares-Almeida I, Wanders RJA (1994) Pathogenesis of long-chain fatty acid oxidation disorders: inhibition of oxidative phosphorylation by palmitoyl-CoA but not palmitoyl-carnitine.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract P116.Google Scholar
  70. Vianey-Liaud C, Divry P, Gregersen N, Mathieu M (1987) The inborn errors of mitochondrial fatty acid oxidation.J Inher Metab Dis 10 (supplement 1): 159–198.Google Scholar
  71. Vianey-Saban C, Mousson B, Bertrand C, et al (1993) Carnitine palmitoyl transferase I deficiency presenting as a Reye-like syndrome without hypoglycaemia.Eur J Pediatr 152: 334–338.Google Scholar
  72. Vianey-Saban C, Divry P, Zabot MT, Mathieu M (1994) Mitochondrial very long chain acyl-CoA dehydrogenase deficiency: identification of this new inborn error of fatty acid oxidation in 11 patients.Abstracts, SSIEM 32nd Annual Symposium, Edinburgh 1994, Abstract O1.Google Scholar
  73. Wanders RJA, Ijlst L, Poggi F, et al (1992) Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid β-oxidation.Biochem Biophys Res Commun 188: 1139–1145.Google Scholar
  74. Watmough NJ, Bindoff LA, Birch-Machin MA, et al (1990) Impaired mitochondrial oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.J Clin Invest 85: 177–184.Google Scholar
  75. Weis BC, Esser V, Foster DW, McGarry JD (1994) Rat heart expresses two forms of mitochondrial carnitine palmitoyltransferase I. The minor component is identical to the liver enzyme.J Biol Chem 269: 18712–18715.Google Scholar
  76. Wilcken B, Leung K-C, Hammond J, Kamath R, Leonard JV (1993) Pregnancy and fetal long-chain 3-hydroxyacyl-CoA coenzyme A dehydrogenase deficiency.Lancet 341: 407–408.Google Scholar
  77. Woeltje KF, Esser V, Weis BC, et al (1990) Inter-tissue and inter-species characterisation of the mitochondrial carnitine palmitoyltransferase enzyme system.J Biol Chem 265: 10714–10719.Google Scholar
  78. Yamaguchi S, Indo Y, Coates PM, Hasimoto T, Tanaka K (1993) Identification of very long-chain acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency.Pediatr Res 34: 111–113.Google Scholar

Copyright information

© SSIEM and Kluwer Academic Publishers 1995

Authors and Affiliations

  • R. J. Pollitt
    • 1
  1. 1.Neonatal Screening Laboratory and University Department of PaediatricsThe Children's HospitalSheffieldUK

Personalised recommendations