Imbard Apolline, de Calbiac Hortense, Le Guillou Edouard, Laforêt Pascal, Schiff Manuel, Brassier Anaïs, Thevenet Elise, Pontoizeau Clément, Lefrère Bertrand, Ottolenghi Chris, Lebigot Elise, Gaignard Pauline, Gobin Stéphanie, Acquaviva-Bourdain Cécile, Benoist Jean-François, Tuchmann-Durand Caroline, Legendre Antoine, de Lonlay Pascale
Service de Biochimie, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Université Paris-Saclay, CEA, Département Médicaments et Technologies pour la Santé, Gif-sur-Yvette, France.
J Inherit Metab Dis. 2025 Jan;48(1):e12819. doi: 10.1002/jimd.12819. Epub 2024 Dec 9.
Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO) during incremental exercise (dQ/dVO) provides an indirect surrogate of mitochondrial function. A high dQ/dVO slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (n = 10), CPT2 (n = 6), VLCAD (n = 7), or MADD (n = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO. In these patients, dQ/dVO was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO was significantly associated with the severity score (B = 0.831, p = 0.008) and triheptanoin treatment (B = -0.547, p = 0.025). dQ/dVO and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.
患有脂肪酸氧化障碍（FAODs）的患者会因ATP代谢受损以及积累的线粒体脂肪酸氧化（FAO）底物或中间体的毒性而出现肌肉症状，尤其是在分解代谢状态下。一个主要问题是缺乏评估代谢平衡的特异性和灵敏的生物标志物。递增运动期间的心输出量（Q）与耗氧量（VO）之间的关系（dQ/dVO）可间接反映线粒体功能。较高的dQ/dVO斜率表明运动期间骨骼肌的氧化磷酸化受损。我们的研究旨在评估dQ/dVO作为FAODs严重程度的潜在标志物。我们回顾性收集了6岁以上FAOD患者的临床、实验室参数和治疗数据，包括疾病严重程度评分、血浆酰基肉碱以及通过胸段生物电阻抗测量Q值的心肺运动试验。如有条件，还在全血和成肌细胞中测量了FAO通量。我们纳入了2015年至2022年随访的27例FAOD患者，其中分别有10例长链3-羟酰基辅酶A脱氢酶（LCHAD）缺乏、6例肉碱棕榈酰转移酶2（CPT2）缺乏、7例极长链酰基辅酶A脱氢酶（VLCAD）缺乏或4例多种酰基辅酶A脱氢酶缺乏症（MADD）。CPT2缺乏且疾病严重程度评分高的患者具有最高的C18:1-、C16-、C18-酰基肉碱水平和dQ/dVO。在这些患者中，dQ/dVO与C18:1、C16和C18酰基肉碱呈正相关。在多元线性回归模型中，dQ/dVO与疾病严重程度评分（B = 0.831，p = 0.008）和三庚酸甘油酯治疗（B = -0.547，p = 0.025）显著相关。dQ/dVO和血浆长链酰基肉碱可能有助于监测CPT2缺乏症（CPT2D），因为这些参数与我们的临床严重程度评分相关，并且可以反映线粒体功能的改变。
