title: Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency.
abstract: OBJECTIVE
  Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity.
  
  
  METHODS
  We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.
  
  
  RESULTS
  The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05).
  
  
  CONCLUSIONS
  Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Eugene F
authors.initials: EF
authors.lastname: Diekman
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, Spieren voor Spieren Kindercentrum, University Medical Center, Utrecht, The Netherlands.
authors.forename: Ludo
authors.initials: L
authors.lastname: van der Pol
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.affiliation: Department of Paediatric Cardiology, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: A Christiaan
authors.identifier: http://orcid.org/0000-0003-2227-8962
authors.initials: AC
authors.lastname: Blank
authors.affiliation: Department of Cardiology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism*; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000378:metabolism; D015415:Biomarkers; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism*; D000080984:Congenital Bone Marrow Failure Syndromes; D003718:Denmark; D004746:Enoyl-CoA Hydratase / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology*; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology*; D009135:Muscular Diseases / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology*; D015997:Neonatal Screening; D010084:Oxidation-Reduction; D019998:Racemases and Epimerases / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases
references.citation: Circulation. 1999 Mar 16;99(10):1337-43
references.pmid: 10077518
references.citation: Clin Chim Acta. 1998 Jan 12;269(1):43-62
references.pmid: 9498103
references.citation: Am J Hum Genet. 1999 Feb;64(2):479-94
references.pmid: 9973285
references.citation: Mol Genet Metab. 2012 Sep;107(1-2):87-91
references.pmid: 22841441
references.citation: J Inherit Metab Dis. 2010 Oct;33(5):479-94
references.pmid: 20490924
references.citation: Adv Exp Med Biol. 1999;466:321-5
references.pmid: 10709659
references.citation: Science. 2013 Oct 11;342(6155):197-8
references.pmid: 24115426
references.citation: J Inherit Metab Dis. 2010 Oct;33(5):521-6
references.pmid: 20373143
references.citation: Biochim Biophys Acta. 2009 Aug;1791(8):806-15
references.pmid: 19465148
references.citation: J Inherit Metab Dis. 1990;13(1):58-68
references.pmid: 2109149
references.citation: Hum Mol Genet. 2011 May 15;20(10 ):2048-57
references.pmid: 21378393
references.citation: Am J Hum Genet. 1996 May;58(5):971-8
references.pmid: 8651281
references.citation: Biochim Biophys Acta. 2010 Sep;1802(9):728-32
references.pmid: 20538056
references.citation: Mol Genet Metab. 2013 May;109(1):21-7
references.pmid: 23480858
references.citation: Mol Genet Metab. 2009 Mar;96(3):85-90
references.pmid: 19157942
references.citation: J Inherit Metab Dis. 2014 Jan;37(1):137-9
references.pmid: 23807318
references.citation: Clin Chim Acta. 1999 Mar;281(1-2):1-17
references.pmid: 10217622
references.citation: J Inherit Metab Dis. 1999 Jun;22(4):442-87
references.pmid: 10407780
references.citation: J Inherit Metab Dis. 2012 Jul;35(4):603-11
references.pmid: 22552820
references.citation: J Inherit Metab Dis. 2012 Mar;35(2):269-77
references.pmid: 21932095
references.citation: Hum Mol Genet. 2014 Mar 1;23(5):1311-9
references.pmid: 24158852
references.citation: J Pediatr. 2003 Sep;143(3):335-42
references.pmid: 14517516
references.citation: J Inherit Metab Dis. 1997 Jul;20(3):415-9
references.pmid: 9266370
references.citation: Annu Rev Physiol. 2002;64:477-502
references.pmid: 11826276
references.citation: Mol Genet Metab. 2014 Apr;111(4):484-92
references.pmid: 24503138
references.citation: Hum Mutat. 2001 Sep;18(3):169-89
references.pmid: 11524729
references.citation: J Inherit Metab Dis. 2010 Oct;33(5):467-8
references.pmid: 20842433
references.citation: Mol Genet Metab. 2008 Apr;93(4):403-10
references.pmid: 18077198
references.citation: Orphanet J Rare Dis. 2013 Sep 09;8:138
references.pmid: 24016303
references.citation: Circulation. 1999 Nov 30;100(22):2248-53
references.pmid: 10577999
references.citation: Biochem Biophys Res Commun. 1992 Nov 16;188(3):1139-45
references.pmid: 1445348