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•A patient with pathogenic variants in ACAD9 presented as a critically ill infant with lactic acidosis and cardiomyopathy unresponsive to riboflavin.•Treatment with high doses of bezafibrate and nicotinamide riboside resulted in temporary stabilization, but long-term follow-up showed fatal progression of cardiomyopathy.•Pharmacokinetics analysis shows a large increase of nicotinamide metabolites, but despite the high dose bezafibrate levels only reached the active concentration at peak levels.•Proteomics analysis in blood cells showed a pattern indicative of ACAD9 deficiency.
Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.