Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants

• Published in: Clinica chimica acta Vol. 471; pp. 101 - 106
• Main Authors: Dessein, Anne-Frédérique, Fontaine, Monique, Joncquel-Chevalier Curt, Marie, Briand, Gilbert, Sechter, Claire, Mention-Mulliez, Karine, Dobbelaere, Dries, Douillard, Claire, Lacour, Arnaud, Redonnet-Vernhet, Isabelle, Lamireau, Delphine, Barth, Magalie, Minot-Myhié, Marie-Christine, Kuster, Alice, de Lonlay, Pascale, Gregersen, Niels, Acquaviva, Cécile, Vianey-Saban, Christine, Vamecq, Joseph
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2017; Elsevier
• Subjects: ACADS; ACADS pathogenic mutation; ACADS susceptibility variants (c.511C > T and c.625G > A); Acyl-CoA Dehydrogenase - deficiency; Acyl-CoA Dehydrogenase - genetics; Child, Preschool; Female; Genetic Predisposition to Disease - genetics; Genotype; Humans; In situ fluxomic assessment of protein function; Infant; Infant, Newborn; Life Sciences; Male; Metabolic Flux Analysis; Mitochondria - metabolism; Oxidation-Reduction; Palmitic Acid - metabolism; Phenotype; Polymorphism, Single Nucleotide; SCAD deficiency; SCAD functional impairment; Short-chain acyl-CoA dehydrogenase [SCAD]; SCAD deficiency; ACADS susceptibility variants (c.511C>T and c.625G>A); SCAD functional impairment; In situ fluxomic assessment of protein function; ACADS; Short-chain acyl-CoA dehydrogenase [SCAD]; ACADS pathogenic mutation; POPULATION; SCAD GENE; of protein function; ACADS susceptibility variants (c.511C \textgreater T; SCAD functional; DEFICIENCY; impairment; and c.625G \textgreater A; FREQUENCY; ACADS Short-chain acyl-CoA dehydrogenase [SCAD]; COMMON; In situ fluxomic assessment; NEWBORN BLOOD SPOTS
• ISSN: 0009-8981; 1873-3492; 1873-3492
• DOI: 10.1016/j.cca.2017.05.026

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. 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. 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). 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. •ACADS susceptibility variants (c.511C>T, c.625G>A) are considered to be non-pathogenic.•Fluxomic acylcarnitine profiling documents the site(s) for β-oxidation enzyme blockade.•It also detected symptomatic patients with ACADS susceptibility variants.•In these patients, SCAD contribution to mitochondrial palmitate oxidation was impaired.•This finding is consistent with known altered kinetics of encoded proteins.