Primary systemic carnitine deficiency is a potentially lethal but very treatable inborn error of fatty acid oxidation, which is due to a defect in the high-affinity carnitine transporter (OCTN2) expressed in the muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in carnitine deficiency, an important cofactor for the transport of fatty acids in the mitochondria. The most affected tissues are skeletal and cardiac muscles, which depend on this fuel. Primary systemic carnitine deficiency is clinically characterized by carnitine-responsive progressive hypokinetic dilated cardiomyopathy; episodes of hypoglycemic, hypoketotic coma; or acute hepatic injuries such as Reye’s syndrome (which may occur after periods of fasting or infections), failure to thrive, and weakness, with very low plasma carnitine concentrations and severe renal leak of carnitine; diminished hepatic uptake of carnitine by passive diffusion impairs ketogenesis.