Genetische Defekte der Fettsäurenoxidation und des Ketonstoffwechsels

  • Ute SpiekerkötterEmail author
Living reference work entry

Latest version View entry history

Part of the Springer Reference Medizin book series (SRM)


Den Störungen der mitochondrialen Fettsäurenoxidation und des Ketonstoffwechsels liegen autosomal-rezessiv vererbte Enzym- oder Transporterdefekte zugrunde. Erst in den letzten 25 Jahren wurden viele dieser inzwischen mehr als 20 Defekte erstmals identifiziert. Angeborene Störungen des Riboflavin-Metabolismus gehören mittlerweile auch zu den Störungen der Fettsäurenoxidation.

Weiterführende Literatur

  1. Andresen BS, Dobrowolski SF, O’Reilly L et al (2001) Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet 68:1408–1418CrossRefGoogle Scholar
  2. Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften e.V. (AWMF).
  3. Boer ME den, Wanders RJ, Morris AA et al (2002) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: Clinical presentation and follow-up of 50 patients. Pediatrics 109:99–104Google Scholar
  4. Clayton PT, Eaton S, Aynsley-Green A et al (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108:457–465CrossRefGoogle Scholar
  5. Copeland WC (2012) Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol 47:64–74CrossRefGoogle Scholar
  6. Corr PB, Creer MH, Yamada KA et al (1989) Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 83:927–936CrossRefGoogle Scholar
  7. Dang CV (2012) Links between metabolism and cancer. Genes Dev 26:877–890CrossRefGoogle Scholar
  8. DiMauro S (2011) A history of mitochondrial diseases. J Inherit Metab Dis 34:261–276CrossRefGoogle Scholar
  9. DiMauro S, Rustin P (2009) A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases. Biochim Biophys Acta 1792:1159–1167CrossRefGoogle Scholar
  10. Frederiksen AL et al (2006) Tissue specific distribution of the 3243A→G mtDNA mutation. J Med Genet 43:671–677CrossRefGoogle Scholar
  11. 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 86:124–133CrossRefGoogle Scholar
  12. Gillingham MB, Harding CO, Goldstein A et al (2015) Triheptanoin lowers cardiac workload compared to medium-chain triglyceride in patients with long-chain fatty acid oxidation disorders. J Inherit Metab Dis 38:S195Google Scholar
  13. Graff C, Clayton DA, Larsson NG (1999) Mitochondrial medicine-recent advances. J Intern Med 246:11–23CrossRefGoogle Scholar
  14. Grunert SC (2014) Clinical and genetic heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Rare Dis 9:117CrossRefGoogle Scholar
  15. Haack TB, Haberberger B, Frisch EM et al (2012) Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet 49:277–283CrossRefGoogle Scholar
  16. Hempel M, Haack TB, Prokisch H (2011) Next generation sequencing. Monatsschr Kinderheilk 159:827–833CrossRefGoogle Scholar
  17. Hoffmann L, Haussmann U, Mueller M et al (2011) VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis 35(2):269–277CrossRefGoogle Scholar
  18. Kamp JM van de, Mancini GMS, Pouwels PJW et al (2011) Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264–272Google Scholar
  19. Klepper J, Leiendecker B, Bredahl R et al (2002) Introduction of a ketogenic diet in young infants. J Inherit Metab Dis 25:449–460CrossRefGoogle Scholar
  20. Koga Y, Akita Y, Nishioka J et al (2005) L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64:710–712CrossRefGoogle Scholar
  21. Koopman WJH, Willems PHGM, Smeitink JAM (2012) Monogenic mitochondrial disorders. N Engl J Med 366:1132–1141CrossRefGoogle Scholar
  22. Luft R (1995) The development of mitochondrial medicine. Biochim Biophys Acta 1271:1–6CrossRefGoogle Scholar
  23. Maldegem BT van, Duran M, Wanders RJ et al (2006) Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA 296:943–952Google Scholar
  24. Mayr JA, Freisinger P, Schlachter K et al (2011) Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet 89:806–812CrossRefGoogle Scholar
  25. Olsen RK, Olpin SE, Andresen BS et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054CrossRefGoogle Scholar
  26. Olsen RKJ, Holzerova E, Giancaspero TA et al (2016) Riboflavin-responsive and non-responsive mutations in the FAD synthase gene cause multiple acyl-CoA dehydrogenase and combined respiratory chain deficiency. Am J Hum Genet 98:1130–1145CrossRefGoogle Scholar
  27. Orngreen MC, Madsen KL, Preisler N et al (2014) Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial. Neurology 82:607–613CrossRefGoogle Scholar
  28. Primassin S, Ter Veld F, Mayatepek E et al (2008) Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. Pediatr Res 63:632–637CrossRefGoogle Scholar
  29. Rhead W (2015) Short-chain acyl-CoA dehydrogenase deficiency is not a disease: common ACADS variants and mutations have no clinical significance. J Inherit Metab Dis 38:S186Google Scholar
  30. Rosenberg EH, Almeida LS, Kleefstra T et al (2004) High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 75:97–105CrossRefGoogle Scholar
  31. Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF (2004) The epidemiology of mitochondrial disorders – past, present and future. Biochim Biophys Acta 1659:115–120CrossRefGoogle Scholar
  32. Schiff M, Veauville-Merllie A, Su CH et al (2016) SLC25A32 mutations and riboflavin-responsive exercise intolerance. N Engl J Med 374:795–797CrossRefGoogle Scholar
  33. Schulze A (2004) Angeborene Störungen des Kreatinstoffwechsels (Kreatinmangelsyndrome). In: Hoffmann G, Grau AJ (Hrsg) Stoffwechselerkrankungen in der Neurologie. Thieme, Stuttgart, S 102–128Google Scholar
  34. Schulze A, Hoffmann GF, Bachert P et al (2006) Successful pre-symptomatic diagnosis and treatment from birth in GAMT deficiency. Neurology 67:719–721CrossRefGoogle Scholar
  35. Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126:1905–1912CrossRefGoogle Scholar
  36. Sperl W, Prokisch H, Karall D, Mayr JA, Freisinger P (2011) Mitochondriopathien, ein Update. Monatsschr Kinderheilk 9:848–854CrossRefGoogle Scholar
  37. Spiekerkoetter U, Tenenbaum T, Hensch A, Wendel U (2003) Cardiomyopathy and pericardial effusion in infancy point to a fatty acid β-Oxidation defect after exclusion of an underlying infection. Pediat Cardiol 24:295–297Google Scholar
  38. Spiekerkoetter U, Khuchua Z, Yue Z et al (2004) 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 55:190–196CrossRefGoogle Scholar
  39. Spiekerkoetter U, Lindner M, Santer R et al (2009) Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis 32:498–505CrossRefGoogle Scholar
  40. Spiekerkoetter U, Haussmann U, Mueller M et al (2010) Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr 157:668–673CrossRefGoogle Scholar
  41. Stickler DE, Valenstein E, Neiberger RE et al (2006) Peripheral neuropathy in genetic mitochondrial diseases. Pediatr Neurol 34:127–131CrossRefGoogle Scholar
  42. Taroni F, Verderio E, Dworzak F et al (1993) Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 4:314–320CrossRefGoogle Scholar
  43. Tyni T, Kivela T, Lappi M et al (1998) Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy. Ophthalmology 105:810–824CrossRefGoogle Scholar
  44. Van Hove JL, Grunewald S, Jaeken J et al (2003) D, L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet 361:1433–1435CrossRefGoogle Scholar
  45. Wallace DC, Fan W, Procaccio V (2010) Mitochondrial energetics and therapeutics. Annu Rev Pathol Mech Dis 5:297–348CrossRefGoogle Scholar
  46. Wanders RJ, Ruiter JP, Ijlst L et al (2010) The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis 33(5):479–494CrossRefGoogle Scholar
  47. Wenz T, Williams SL, Bacman SR et al (2010) Emerging therapeutic approaches to mitochondrial diseases. Dev Disabil Res Rev 16:219–229CrossRefGoogle Scholar
  48. Wilcken B (2010) Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis 33:501–506CrossRefGoogle Scholar
  49. Wilcken B, Leung KC, Hammond J et al (1993) Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 341:407–408CrossRefGoogle Scholar
  50. 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 369:37–42CrossRefGoogle Scholar
  51. Wortmann SB, Rodenburg RJ, Jonckheere A et al (2009) Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy. Brain 132:136–146CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Universitätsklinikum Freiburg, Allgemeine Kinder- und JugendmedizinFreiburgDeutschland

Section editors and affiliations

  • Georg. F. Hoffmann
    • 1
  1. 1.Zentrum für Kinder- und JugendmedizinUniversitätsklinikum HeidelbergHeidelbergDeutschland

Personalised recommendations