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.
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.
Clin Chim Acta. 2017 Aug;471:101-106. doi: 10.1016/j.cca.2017.05.026. Epub 2017 May 19.
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-H,15-H-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.
尽管 ACADS（酰基辅酶 A 脱氢酶，短链）基因易感变异（c.511C>T 和 c.625G>A）被认为是非致病性的，但已知编码蛋白的动力学发生了改变。然而，它们是否会影响整体脂肪酸β氧化仍不清楚。
用氘化棕榈酸（16-H，15-H-棕榈酸）孵育全血样本的从头生物合成酰基肉碱可作为通量组学探索，以区分正常和中断的β氧化、异常的酰基肉碱谱和不同链长的酰基肉碱的比值表明酶阻断的部位。在 301 名对照受试者中，测定氘丁酰肉碱与氘化 C2 到 C14 酰基肉碱总和的比值作为参考值，用于明确指出在临床和/或生物学怀疑存在β氧化障碍的患者中存在特定功能的 SCAD 损害。
在 39 名患者中发现了功能 SCAD 损害。27 名接受后续基因研究的患者均为 ACADS 突变阳性。27 名患者中有 26 名检测到 c.625G>A 变异。27 名患者中有 23 名仅存在 ACADS 改变的易感性变异（c.625G>A 为 18 个纯合子和 3 个杂合子，c.625G>A/c.511C>T 为 2 个复合杂合子）。
我们目前对 SCAD 的通量组学评估表明，ACADS 易感性变异与异常的β氧化之间存在关联，这与这些变异的已知改变动力学一致。
