Introduction

Mitochondrial fatty acid oxidation (FAO) is an essential component of energy production and homeostasis in humans. During periods of limited glucose supply, FAO in the liver provides energy for hepatic function and the acetyl-CoA substrate needed for hepatocytes to synthesize and release ketone bodies into circulation. Ketone bodies provide an alternative energy substrate for peripheral tissues when glucose supply is limited. Other tissues such as skeletal and cardiac muscle rely on FAO for energy production. The oxidation of fatty acids can provide up to 80% of the energy requirements for cardiac and skeletal muscle while sparing glucose for use by the brain and CNS during moderate exercise, fasting, or illness. Disorders in the ability to use fatty acids for energy production manifest during periods of increased energy demands or reduced energy intake.

At least 22 different inherited genetic disorders in the mitochondrial FAO pathway have been described. Most of the disorders have an increasingly broad range of recognized phenotypes from mild to severe. Severe phenotypes typically present in infancy with catastrophic episodes of fasting or illness-induced hypoketotic hypoglycemia. The most common clinical presentation in childhood of FAO disorders generally includes nausea, vomiting, somnolence, and hepatic encephalopathy, similar to what was once known as Reye syndrome, which can progress to coma and death if untreated. Cardiomyopathy can be a life-threatening complication of acute metabolic decompensation in some FAO defects. These defects may also present as sudden unexpected death in infancy; prior to the introduction of expanded newborn screening for these disorders, as many as one-third of the initial episodes were fatal [1]. Alternatively, mild phenotypes of FAO deficiency may not present until adolescence or adulthood and these patients present with exercise intolerance with recurrent episodes of rhabdomyolysis and myoglobinuria. Patients with milder phenotypes who present later in life typically have not reported episodes of hypoketotic hypoglycemia during fasting or illness [1].