Neurometabolic Research Laboratory, Division of Neurology, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada.
PLoS One. 2011 Apr 1;6(4):e17534. doi: 10.1371/journal.pone.0017534.
To elucidate the pathophysiology of SCAD deficient patients who have a unique neurological phenotype, among fatty acid oxidation disorders, with early developmental delay, CNS malformations, intractable seizures, myopathy and clinical signs suggesting oxidative stress.
We studied skin fibroblast cultures from patients homozygous for ACADS common variant c.625G>A (n = 10), compound heterozygous for c.625G>A/c.319C>T (n = 3) or homozygous for pathogenic c.319C>T (n = 2) and c.1138C>T (n = 2) mutations compared to fibroblasts from patients with carnitine palmitoyltransferase 2 (CPT2) (n = 5), mitochondrial trifunctional protein (MTP)/long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) (n = 7), and medium-chain acyl-CoA dehydrogenase (MCAD) deficiencies (n = 4) and normal controls (n = 9). All were exposed to 50 µM menadione at 37°C. Additional conditions included exposure to 39°C and/or hypoglycemia. Time to 100% cell death was confirmed with trypan blue dye exclusion. Experiments were repeated with antioxidants (Vitamins C and E or N-acetylcysteine), Bezafibrate or glucose and temperature rescue.
The most significant risk factor for vulnerability to menadione-induced oxidative stress was the presence of a FAO defect. SCADD fibroblasts were the most vulnerable compared to other FAO disorders and controls, and were similarly affected, independent of genotype. Cell death was exacerbated by hyperthermia and/or hypoglycemia. Hyperthermia was a more significant independent risk factor than hypoglycemia. Rescue significantly prolonged survival. Incubation with antioxidants and Bezafibrate significantly increased viability of SCADD fibroblasts.
Vulnerability to oxidative stress likely contributes to neurotoxicity of SCADD regardless of ACADS genotype and is significantly exacerbated by hyperthermia. We recommend rigorous temperature control in SCADD patients during acute illness. Antioxidants and Bezafibrate may also prove instrumental in their management.
阐明脂肪酸氧化障碍中具有独特神经表型的 SCAD 缺陷患者的病理生理学，这些患者具有早期发育迟缓、CNS 畸形、难治性癫痫发作、肌病和提示氧化应激的临床体征。
我们研究了来自纯合子 ACADS 常见变异 c.625G>A（n=10）、复合杂合子 c.625G>A/c.319C>T（n=3）或纯合子 c.319C>T（n=2）和 c.1138C>T（n=2）突变的患者皮肤成纤维细胞培养物，与肉碱棕榈酰基转移酶 2（CPT2）（n=5）、线粒体三功能蛋白（MTP）/长链 L-3-羟酰基辅酶 A 脱氢酶（LCHAD）（n=7）和中链酰基辅酶 A 脱氢酶（MCAD）缺乏症（n=4）和正常对照（n=9）的成纤维细胞进行比较。所有细胞均在 37°C 下暴露于 50µM 维生素 K3。其他条件包括暴露于 39°C 和/或低血糖。通过台盼蓝排斥试验确认达到 100%细胞死亡的时间。用抗氧化剂（维生素 C 和 E 或 N-乙酰半胱氨酸）、贝扎贝特或葡萄糖和温度拯救重复实验。
对维生素 K3 诱导的氧化应激易感性的最大危险因素是存在 FAO 缺陷。与其他 FAO 疾病和对照组相比，SCADD 成纤维细胞最脆弱，且不论基因型如何，均受到类似影响。高温和/或低血糖会加剧细胞死亡。高温是比低血糖更重要的独立危险因素。拯救显著延长了存活时间。抗氧化剂和贝扎贝特孵育显著增加了 SCADD 成纤维细胞的活力。
氧化应激的易感性可能导致 SCADD 的神经毒性，无论 ACADS 基因型如何，高温都会显著加剧这种毒性。我们建议在急性疾病期间对 SCADD 患者进行严格的体温控制。抗氧化剂和贝扎贝特也可能在其治疗中发挥重要作用。
