Skip to main content
Log in

Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening

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

Abstract

The different long-chain fatty acid oxidation defects present with similar heterogeneous clinical phenotypes of different severity. Organs mainly affected comprise the heart, liver, and skeletal muscles. All symptoms are reversible with sufficient energy supply. In some long-chain fatty acid oxidation defects, disease-specific symptoms occur. Only in disorders of the mitochondrial trifunctional protein (TFP) complex, including long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHAD) deficiency, neuropathy and retinopathy develop that are progressive and irreversible despite current treatment measures. In most long-chain fatty acid oxidation defects, no clear genotype–phenotype correlation exists due to molecular heterogeneity. However, some isolated mutations have been identified to be associated with only mild phenotypes, e.g., the V243A mutation in very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. LCHAD deficiency is due to the prevalent homozygous 1528G>C mutation and presents with heterogeneous clinical phenotypes, suggesting the importance of other environmental and genetic factors. For some disorders, it was shown that residual enzyme activity measured in fibroblasts or lymphocytes correlated with severity of clinical phenotype. Implementation of newborn screening has significantly reduced morbidity and mortality of long-chain fatty acid oxidation defects. However, the severest forms of TFP deficiency are still highly associated with neonatal death. Newborn screening also identifies a great number of mildly affected patients who may never develop clinical symptoms throughout life. However, later-onset exercise-induced myopathic symptoms remain characteristic clinical features of long-chain fatty acid oxidation defects. Disease prevalence has increased with newborn screening.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACAD9:

Acyl-CoA dehydrogenase 9

CACT:

Carnitine acylcarnitine translocase

CPT1:

Carnitine palmitoyl-CoA transferase 1

CPT2:

Carnitine palmitoyl-CoA transferase 2

GAII:

Glutaric aciduria type II (= electron transfer defect = MAD deficiency)

LCAD:

Long-chain acyl-CoA dehydrogenase

LCHAD:

Long-chain 3-hydroxyacyl-CoA dehydrogenase

LCHADD:

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

LKAT:

Long-chain 3-ketoacyl-CoA thiolase

MAD:

Multiple acyl-CoA dehydrogenase

MCAD:

Medium-chain acyl-CoA dehydrogenase

mTFP:

Mitochondrial trifunctional protein

OCTN2:

Organic cation carnitine transporter 2

VLCAD:

Very-long-chain acyl-CoA dehydrogenase

VLCADD:

Very-long-chain acyl-CoA dehydrogenase deficiency

References

  • Andresen BS, Olpin S, Poorthuis BJ et al (1999) Clear correlation of genotype with disease phenotype in very long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet 64:479–494

    Article  CAS  PubMed  Google Scholar 

  • Arnold GL, Van Hove J, Freedenberg D et al (2009) A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab 96:85–90

    Article  CAS  PubMed  Google Scholar 

  • Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J (2004) Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 25:495–520

    Article  CAS  PubMed  Google Scholar 

  • den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA (2002) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 109:99–104

    Article  Google Scholar 

  • den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA (2003) Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J Pediatr 142:684–689

    Article  Google Scholar 

  • Ensenauer R, He M, Willard JM et al (2005) Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. J Biol Chem 280:32309–32316

    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 

  • Goetzman ES, Wang Y, He M, Mohsen AW, Ninness BK, Vockley J (2007) Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab 91:138–147

    Article  CAS  PubMed  Google Scholar 

  • Gregersen N, Andresen BS, Corydon MJ et al (2001) Mutation analysis in mitochondrial fatty acid oxidation defects: exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat 18:169–189

    Article  CAS  PubMed  Google Scholar 

  • Ibdah JA (2006) Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J Gastroenterol 12:7397–7404, Review

    CAS  PubMed  Google Scholar 

  • Illsinger S, Lücke T, Peter M (2008) Carnitine-palmitoyltransferase 2 deficiency: novel mutations and relevance of newborn screening. Am J Med Genet 146A:2925–2928

    Article  CAS  PubMed  Google Scholar 

  • Laforêt P, Acquaviva-Bourdain C, Rigal O et al (2009) Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord 19:324–329

    Article  PubMed  Google Scholar 

  • Liebig M, Schymik I, Mueller M et al (2006) Neonatal screening for very long-chain acyl-coA dehydrogenase deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics 118:1065–1069

    Article  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 

  • Mütze S, Ahillen I, Rudnik-Schoeneborn S et al (2007) Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome. J Perinat Med; 35:76–78

    Article  PubMed  Google Scholar 

  • Oey NA, Ruiter JP, Ijlst L et al (2006) Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain. Biochem Biophys Res Commun 21(346):33–37

    Article  Google Scholar 

  • Olsen RK, Olpin SE, Andresen BS et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054

    Article  PubMed  Google Scholar 

  • Sander J, Sander S, Steuerwald U et al (2005) Neonatal screening for defects of the mitochondrial trifunctional protein. Mol Genet Metab 85:108–114

    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, Sykut-Cegielska (2007) Prognosis and treatment of LCHAD deficiency. 39th EMG workshop results, pp 16–19. Publication of workshop results, printed by Milupa GmbH, Bahnstrasse 14-30, 61381 Friedrichsdorf, Germany. ISBN 987-3-9811868-0-2. www.Milupa-Metabolics.com

  • Spiekerkoetter U, Huener G, Baykal T et al (2003a) Silent and symptomatic primary carnitine deficiency within the same family due to identical mutations in the organic cation/carnitine transporter OCTN2. J Inherit Metab Dis 26:613–615

    Article  CAS  PubMed  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 beta-oxidation defect after exclusion of an underlying infection. Pediatr Cardiol 24:295–297

    Article  CAS  PubMed  Google Scholar 

  • Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW (2003d) Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum Mutat 21:598–607

    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, Bennett MJ, Ben-Zeev B, Strauss AW, Tein I (2004c) Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein. Muscle Nerve 29:66–72

    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 (2009) 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 

  • Tein I, Demaugre F, Bonnefont JP, Saudubray JM (1989) Normal muscle CPT1 and CPT2 activities in hepatic presentation patients with CPT1 deficiency in fibroblasts. Tissue specific isoforms of CPT1? J Neurol Sci 92:229–245

    Article  CAS  PubMed  Google Scholar 

  • ter Veld F, Mueller M, Kramer S et al (2009) A novel tandem mass spectrometry method for rapid confirmation of medium-and very long-chain acyl-CoA dehydrogenase deficiency in newborns. PLoS One 4(7):e6449

    Article  PubMed  Google Scholar 

  • Tyni T, Kivelä T, Lappi M, Summanen P, Nikoskelainen E, Pihko H (1998) Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy. Ophthalmology 105:810–824

    Article  CAS  PubMed  Google Scholar 

  • Vockley J (2008) Glutaric aciduria type 2 and newborn screening: commentary. Mol Genet Metab 93:5–6

    Article  CAS  PubMed  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 

  • Zhang J, Zhang W, Zou D et al (2002) Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family. Biochem Biophys Res Commun 297:1033–1042

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ute Spiekerkoetter.

Additional information

Communicated by: Verena Peters

Competing interest: None declared.

Presented at the Fulda-Symposium “Fatty acid oxidation: clinical, biochemical and molecular aspects”, 12–14 November 2008

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spiekerkoetter, U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis 33, 527–532 (2010). https://doi.org/10.1007/s10545-010-9090-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-010-9090-x

Keywords

Navigation