Disorders of fatty-acid oxidation have been recognized only since the early 1980s, but as a group they represent the most common inborn errors of metabolism. Fat provides a significant source of energy in the form of glucose and ketone bodies during times of metabolic stress (such as febrile illness) or during prolonged fasting. Free fatty acids, released from the adipose tissue, are transported into the mitochondria via the carnitine shuttle system, where they undergo fi-oxidation (Figure 4), the progressive cleavage from an 18-carbon very long-chain fatty acid to the two-carbon aceto-acetyl CoA, the substrate for glucose (via the TCA (Tricarboxylic acid) cycle) and ketones. A deficiency of any of the enzymes in this pathway can cause symptoms of hypoketotic hypoglycemia and hepatic encephalo-pathy, with hyperammonemia (due to secondary inhibition of the urea cycle) and sudden death. Many cases of what would previously have been diagnosed as Reye syndrome are now known to be due to defects of fatty-acid oxidation. Symptoms can occur at any time, from the newborn period to adulthood.
Carnitine has a dual role: in addition to its critical role in the transport of free fatty acids into mitochondria, it conjugates with the fatty acyl CoA intermediates that accumulate proximal to an enzyme block, forming acylcarnitine species that can be excreted by the kidneys. They can also be measured in plasma for diagnostic purposes and in the newborn-screening dried blood spot. Increased use of carnitine owing to an enzyme defect causes a secondary depletion, further impairing fatty-acid oxidation.
Long-chain fatty-acid (carnitine palmityl transferase (CPT) oxidation defects I and II, very long-chain acyl CoA dehydrogenase (VLCAD), TFP (Trifunctional protein), and long-chain 3-hydroxy acyl CoA dehydro-genase (LCHAD)) may present in the newborn period or later in infancy with severe hypoketotic hypoglyce-mia, cardiomyopathy, and hepatic encephalopathy, due to deposition of fat in the heart and liver. Rhab-domyolysis (lysis of muscle cells) is common. Pigmentary degeneration of the retina may be present in LCHAD and is thought to be due to impaired endogenous production of docosahexanoic acid (DHA), which is necessary for normal retinal function. Milder variant forms of CPT II and VLCAD may present in adolescence or adulthood with muscle cramping and rhabdomyolysis, which may be severe enough to cause
Was this article helpful?