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Current issues regarding treatment of mitochondrial fatty acid oxidation disorders

  • Fatty Acid Oxidation
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Treatment recommendations in mitochondrial fatty acid oxidation (FAO) defects are diverse. With implementation of newborn screening and identification of asymptomatic patients, it is necessary to define whom to treat and how strictly. We here discuss critical questions that are currently under debate. For some asymptomatic long-chain defects, long-chain fat restriction plays a minor role, and a normal diet may be introduced. For patients presenting only with myopathic symptoms, e.g., during exercise, treatment may be adapted to energy demand. As a consequence, patients with exercise-induced myopathy may be able to return to normal activity when provided with medium-chain triglycerides (MCT) prior to exercise. There is no need to limit participation in sports. Progression of retinopathy in disorders of the mitochondrial trifunctional protein complex is closely associated with hydroxyacylcarnitine accumulation. A strict low-fat diet with MCT supplementation is recommended to slow or prevent progression of chorioretinopathy. Additional docosahexanoic acid does not prevent the decline in retinal function but does promote nonspecific improvement in visual acuity and is recommended. There is no evidence that L-carnitine supplementation is beneficial. Thus, supplementation with L-carnitine in a newborn identified by screening with either a medium-chain or long-chain defect is not supported. With respect to the use of the odd-chain medium-chain triglyceride triheptanoin in myopathic phenotypes, randomized trials are needed to establish whether triheptanoin is more effective than even-chain MCT. With increasing pathophysiological knowledge, new treatment options have been identified and are being clinically evaluated. These include the use of bezafibrates in myopathic long-chain defects.

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Abbreviations

CPT2:

carnitine palmitoyl-CoA transferase 2

CPT2D:

carnitine palmitoyl-CoA transferase 2 deficiency

DHA:

docosahexanoic acid

FAO:

fatty acid oxidation

FAOD:

fatty acid oxidation defects

LCHAD:

long-chain 3-hydroxy-acyl-CoA dehydrogenase

LCHADD:

long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency

LCT:

long-chain trigylcerides

MCAD:

medium-chain acyl-CoA dehydrogenase

MCADD:

medium-chain acyl-CoA dehydrogenase deficiency

MCT:

medium-chain triglycerides

mTFP:

mitochondrial trifunctional protein

PPAR:

peroxisome-proliferator-activated receptor

VLCAD:

very-long-chain acyl-CoA dehydrogenase

VLCADD:

very-long-chain acyl-CoA dehydrogenase deficiency

References

  • Agostoni C, Massetto N, Biasucci G et al (2000) Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. J Pediatr 137:504–509

    Article  CAS  PubMed  Google Scholar 

  • Bonnefont JP, Bastin J, Behin A, Djouadi F (2009) Bezafibrate for an inborn mitochondrial beta-oxidation defect. N Engl J Med 360:838–840

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Cox KB, Liu J, Tian L, Barnes S, Yang Q, Wood PA (2009) Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase or very long-chain acyl-CoA dehydrogenase deficiency. Lab Invest 89:1348–1354

    Article  CAS  PubMed  Google Scholar 

  • Djouadi F, Bonnefont JP, Thuillier L et al (2003) Correction of fatty acid oxidation in carnitine palmitoyl transferase 2-deficient cultured skin fibroblasts by bezafibrate. Pediatr Res 54:446–451

    Article  CAS  PubMed  Google Scholar 

  • Djouadi F, Aubey F, Schlemmer D et al (2005) Peroxisome proliferator activated receptor delta (PPAR{delta}) agonist but not PPAR{alpha} corrects carnitine palmitoyl transferase 2 deficiency in human muscle cells. J Clin Endocrinol Metab 90:1791–1797

    Article  CAS  PubMed  Google Scholar 

  • Fahnehjelm KT, Holmstrom G, Ying L et al (2008) Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a cross-sectional study with long-term follow-up. Acta Ophthalmol 86:329–337

    Article  PubMed  Google Scholar 

  • Gillingham MB, Connor WE, Matern D et al (2003) Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Genet Metab 79:114–123

    Article  CAS  PubMed  Google Scholar 

  • Gillingham MB, Weleber RG, Neuringer M et al (2005) Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab 86:124–133

    Article  CAS  PubMed  Google Scholar 

  • Gillingham MB, Scott B, Elliott D, Harding CO (2006) Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab 89:58–63

    Article  CAS  PubMed  Google Scholar 

  • Gobin-Limballe S, Djouadi F, Aubey F et al (2007) Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet 81:1133–1143

    Article  CAS  PubMed  Google Scholar 

  • Herrema H, Derks TG, van Dijk TH et al (2008) Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. Hepatology 47:1894–1904

    Article  CAS  PubMed  Google Scholar 

  • Hoffman DR, Uauy R (1992) Essentiality of dietary omega 3 fatty acids for premature infants: plasma and red blood cell fatty acid composition. Lipids 27:886–895

    Article  CAS  PubMed  Google Scholar 

  • Huidenkoper HH, Schneider J, Westphal T, Vaz PM, Duran M, Wijburg FA (2006) Prolonged moderate-intensity excercise without and with L-carnitine supplementation in patients with MCAD deficiency. J Inherit Metab Dis 29:631–636

    Article  Google Scholar 

  • Innis SM, Adamkin DH, Hall RT et al (2002) Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula. J Pediatr 140:547–554

    Article  CAS  PubMed  Google Scholar 

  • Jeukendrup AE, Saris WH, Wagenmakers AJ (1998) Fat metabolism during exercise: a review–part II: regulation of metabolism and the effects of training. Int J Sports Med 19:293–302

    Article  CAS  PubMed  Google Scholar 

  • Lee PJ, Harrison EL, Jones MG, Jones S, Leonard JV, Chalmers RA (2005) L-carnitine and exercise tolerance in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: a pilot study. J Inherit Metab Dis 28:141–152

    Article  CAS  PubMed  Google Scholar 

  • Lund AM, Joensen F, Hougaard DM et al (2007) Carnitine transporter and holocarboxylase synthetase deficiencies in The Faroe Islands. J Inherit Metab Dis 30:341–349

    Article  CAS  PubMed  Google Scholar 

  • Maier EM, Pongratz J, Muntau AC et al (2009) Validation of MCADD newborn screening. Clin Genet 76:179–187

    Article  CAS  PubMed  Google Scholar 

  • Nasser M, Javaheri H, Fedorowicz Z, Noorani Z. (2009) Carnitine supplementation for inborn errors of metabolism. Cochrane database Syst Rev. 15: CD006659

  • Primassin S, Ter Veld F, Mayatepek E, Spiekerkoetter U (2008) Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. Pediatr Res 63:632–637

    Article  CAS  PubMed  Google Scholar 

  • Roe CR, Sweetman L, Roe DS, David F, Brunengraber H (2002) Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest 110:259–269

    CAS  PubMed  Google Scholar 

  • Roe CR, Yang BZ, Brunengraber H, Roe DS, Wallace M, Garritson BK (2008) Carnitine palmitoyltransferase II deficiency: successful anaplerotoc diet therapy. Neurology 71:260–264

    Article  CAS  PubMed  Google Scholar 

  • SanGiovanni JP, Berkey CS, Dwyer JT, Colditz GA (2000) Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review. Early Hum Dev 57:165–188

    Article  CAS  PubMed  Google Scholar 

  • Schuler AM, Wood PA (2002) Mouse models for disorders of mitochondrial fatty acid beta-oxidation. ILAR J 43:57–65

    CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Sun B, Zytkovicz T, Wanders R, Strauss AW, Wendel U (2003a) MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr 43:335–342

    Google Scholar 

  • Spiekerkoetter U, Sun B, Zytkovicz T, Wanders R, Strauss AW, Wendel U (2003b) MS/MS-based newborn and family screening detects asymptomatic patients with very long-chain acyl-CoA dehydrogenase deficiency. J Pediatr 143:335–342

    Article  PubMed  Google Scholar 

  • Spiekerkoetter U, Tenenbaum T, Heusch A, Wendel U (2003c) Cardiomyopathy and pericardial effusion in infancy point to a fatty acid b-oxidation defect after exclusion of an underlying infection. Pediatr Cardiol 24:295–297

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW (2004a) General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 55:190–196

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Khuchua Z, Yue Z, Strauss AW (2004b) The early-onset phenotype of mitochondrial trifunctional protein deficiency: a lethal disorder with multiple tissue involvement. J Inherit Metab Dis 27:294–296

    Article  CAS  Google Scholar 

  • Spiekerkoetter U, Tokunaga C, Wendel U et al (2005) Tissue carnitine homeostasis in very-long-chain acyl-CoA dehydrogenase-deficient mice. Pediatr Res 57:760–764

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Mueller M, Cloppenburg E et al (2008) Intrauterine cardiomyopathy and cardiac mitochondrial proliferation in mitochondrial trifunctional protein (TFP) deficiency. Mol Genet Metab 94:428–430

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Lindner M, Santer R et al (2009a) Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis 32:488–497

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Lindner M, Santer R et al (2009b) Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis 32:498–505

    Article  CAS  PubMed  Google Scholar 

  • Tenenbaum A, Motro M, Fisman EZ (2005) Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc Diabetol 4:14–19

    Article  PubMed  Google Scholar 

  • Walter JH (2003) L-carnitine in inborn errors of metabolism: what is the evidence? J Inherit Metab Dis 26(2–3):181–188

    Google Scholar 

  • Wanders RJA, Vreken P, Den Boer MEJ et al (1999) Disorders of mitochondrial fatty acyl-CoA β-oxidation. J Inherit Metab Dis 22:442–487

    Article  CAS  PubMed  Google Scholar 

  • Wilcken B, Haas M, Joy P et al (2007) Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet 369:37–42

    Article  CAS  PubMed  Google Scholar 

  • Winter SC (2003) Treatment of carnitine deficiency. J Inherit Metab Dis 26:171–180

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of General Pediatrics, University Children’s Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany

    Ute Spiekerkoetter

  2. Faculté Necker-Enfants Malades, CNRS FRE, 3210, Paris, France

    Jean Bastin

  3. Oregon Health & Science University, Portland, OR, USA

    Melanie Gillingham

  4. Willink Biochemical Genetics Unit, Genetic Medicine, St Mary’s Hospital, Manchester, UK

    Andrew Morris

  5. Department of Pediatrics, University of Amsterdam, Amsterdam, The Netherlands

    Frits Wijburg

  6. Children’s Hospital at Westmead and University of Sydney, Sydney, Australia

    Bridget Wilcken

Authors
  1. Ute Spiekerkoetter
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  2. Jean Bastin
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  3. Melanie Gillingham
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  4. Andrew Morris
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  5. Frits Wijburg
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  6. Bridget Wilcken
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Corresponding author

Correspondence to Ute Spiekerkoetter.

Additional information

Communicated by: Johannes Zschocke

Competing interest: None declared.

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Spiekerkoetter, U., Bastin, J., Gillingham, M. et al. Current issues regarding treatment of mitochondrial fatty acid oxidation disorders. J Inherit Metab Dis 33, 555–561 (2010). https://doi.org/10.1007/s10545-010-9188-1

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  • DOI: https://doi.org/10.1007/s10545-010-9188-1

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