Anne-Frédérique Dessein1, Monique Fontaine2, Marie Joncquel-Chevalier Curt2, Gilbert Briand2, Claire Sechter3, Karine Mention-Mulliez4, Dries Dobbelaere4, Claire Douillard3, Arnaud Lacour5, Isabelle Redonnet-Vernhet6, Delphine Lamireau6, Magalie Barth7, Marie-Christine Minot-Myhié8, Alice Kuster9, Pascale de Lonlay10, Niels Gregersen11, Cécile Acquaviva12, Christine Vianey-Saban12, Joseph Vamecq13. 1. Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU Lille, France. 2. Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU Lille, France; Univ. Lille, EA 7364 - RADEME - Maladies RAres du Développement et du Métabolisme: du phénotype au génotype et à la Fonction, Lille, France. 3. Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre Hospital, CHRU Lille, France. 4. Univ. Lille, EA 7364 - RADEME - Maladies RAres du Développement et du Métabolisme: du phénotype au génotype et à la Fonction, Lille, France; Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre Hospital, CHRU Lille, France. 5. Medical Reference Center for Adult Neuromuscular Diseases, Roger Salengro Hospital, CHRU Lille, France. 6. Paediatric Intensive Care Unit (DL) and Department of Biochemistry, Laboratory of Inborn Errors of Metabolism and Neonatal Screening (IR-V), Hôpital Pellegrin, CHU Bordeaux, France. 7. Metabolic Diseases and Genetics, CHU Angers, France. 8. Cabinet de neurologie & CHU Rennes, France. 9. Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, France. 10. Reference Center for Inherited Metabolic Diseases, Hôpital Necker, Institut Imagine, Faculté Paris Descartes & Hôpital Necker-Enfants Malades, Paris, France. 11. Research Unit for Molecular Medicine, Institute of Clinical Medicine, Aarhus University, Denmark. 12. Department of Inborn Errors of Metabolism and Neonatal Screening, Center of Biology and Pathology, CHU Lyon, Bron, France. 13. Department of Biochemistry and Molecular Biology, Laboratory of Hormonology, Metabolism-Nutrition & Oncology (HMNO), Center of Biology and Pathology (CBP) Pierre-Marie Degand, CHRU Lille, France; Univ. Lille, EA 7364 - RADEME - Maladies RAres du Développement et du Métabolisme: du phénotype au génotype et à la Fonction, Lille, France; Inserm, Lille, France. Electronic address: joseph.vamecq@inserm.fr.
Abstract
BACKGROUND: Despite ACADS (acyl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C>T and c.625G>A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid β-oxidation still remains, however, unclear. METHODS: De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-2H3,15-2H2-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted β-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a β-oxidation disorder. RESULTS: Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G>A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G>A, 2 compound heterozygous for c.625G>A/c.511C>T). CONCLUSION: Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal β-oxidation consistent with known altered kinetics of these variants.
BACKGROUND: Despite ACADS (acyl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C>T and c.625G>A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid β-oxidation still remains, however, unclear. METHODS: De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-2H3,15-2H2-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted β-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a β-oxidation disorder. RESULTS:Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G>A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G>A, 2 compound heterozygous for c.625G>A/c.511C>T). CONCLUSION: Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal β-oxidation consistent with known altered kinetics of these variants.