Abstract 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 2 ) during incremental exercise (dQ/dVO 2 ) provides an indirect surrogate of mitochondrial function. A high dQ/dVO 2 slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO 2 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 2 . In these patients, dQ/dVO 2 was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO 2 was significantly associated with the severity score (B = 0.831, p = 0.008) and triheptanoin treatment (B = −0.547, p = 0.025). dQ/dVO 2 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.

Circulatory response to exercise relative to oxygen uptake assessed in the follow‐up of patients with fatty acid beta‐oxidation disorders