Schwantje M; Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
van Brussel M; Takken T; Langeveld M; Visser G; Fuchs SA;

Journal of inherited metabolic disease [J Inherit Metab Dis] 2025 Sep; Vol. 48 (5), pp. e70070.

Long-chain fatty acid oxidation disorders are characterized by rhabdomyolysis, often provoked by physical exercise. For the newborn screening (NBS) cohort, it remains uncertain to what extent they will develop the myopathic phenotype. This study assesses physiological responses to exercise, muscle symptoms, and activity levels in 14 adolescent lcFAOD patients (VLCADD (n = 8), LCHADD (n = 4), CPT2D (n = 1) and LCKATD (n = 1); ages 9.9-17.8 years). Analyses of incremental and prolonged cardiopulmonary exercise tests, a symptom-based questionnaire, and the Short Questionnaire to Assess Health-enhancing physical activity were performed. The results revealed a decreased ventilatory anaerobic threshold compared to control data (z-score - 0.5 (0.8) [median (interquartile range (IQR))], p = 0.001) and, on average, a decreased relative peak oxygen uptake (z-score - 1.3 (2.8), p = 0.005) and relative peak work rate (z-score - 0.7 (1.3), p = 0.03). There were no adverse events during and following prolonged exercise under well-fed circumstances (based on symptoms and post-exercise creatine kinase). The symptom-based questionnaire revealed that the presence of provoking factors (e.g., infection, inadequate intake) increased the risk of rhabdomyolysis during/after exercise. Screening (n = 11) and symptomatically (n = 3) diagnosed patients showed normal levels of physical activity (medians: 3.5 h per week) compared to their healthy peers (3.2 h), despite debilitating muscle pain in 46% of the by screening and all of the symptomatically diagnosed patients. In conclusion, patients with seemingly normal exercise patterns reported debilitating muscle symptoms and rhabdomyolysis, especially when additional provoking factors were present. Exercise tests may provide a valuable tool to monitor and guide exercise potential in these new NBS cohorts.