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Mitochondrial fatty acid oxidation provides the main source of energy for heart and skeletal muscle and, through generation of acetyl-coenzyme A (CoA), for tricarboxylic acid (TCA) cycle function and ketone body production; it also provides energy for other tissues when the supply of glucose is limited. Long-chain fatty acids entering the cell are esterified with carnitine before being transported across the mitochondrial membrane through a series of steps known as the carnitine cycle. The free CoA esters then undergo β-oxidation in the mitochondrial matrix (Fig. 145-1). Disorders that interfere with any of these steps limit energy production in heart and skeletal muscle at rest and reduce the ability of other tissues, including the brain, to tolerate a low-glucose milieu during times of increased energy demand.

Figure 145-1

Transport and metabolism of fatty acids. To cross the mitochondrial membrane, long-chain fatty acids must be covalently attached to carnitine by carnitine palmitoyltransferase I (CPT I) of the mitochondrial outer membrane and transferred by the carnitine-acylcarnitine translocase (CACT) within the inner membrane. Carnitine palmitoyltransferase II (CPT II), also within the inner membrane, releases the fatty acyl-CoA from carnitine into the mitochondrial matrix. Medium- and short-chain fatty acids can freely enter the mitochondria and do not require the carnitine cycle. Fatty acids are oxidized in a cycle that removes 1 acetyl-CoA moiety per turn. Dehydrogenases specific to long-, medium-, and short-chain fatty acids catalyze the first reaction. As described in the text, defects have been found in each of the transporters and enzymes shown. Ketone bodies are formed in the liver from acetyl-CoA. All defects of fatty acid oxidation are inherited as autosomal recessive diseases. AS, acyl-CoA synthetase.

Disorders of long-chain fatty acid oxidation (FAO) include defects in the cellular carnitine transporter, carnitine palmitoyltransferase (CPT) I and II, carnitine-acylcarnitine translocase (CACT), very-long-chain acyl-CoA dehydrogenase (VLCAD), mitochondrial trifunctional protein (TFP), and isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). They can present at any age, largely dependent on the residual activity of the defective enzyme. Complete deficiencies typically manifest in infancy or early childhood; about 25% in the first week of life. Neonates may present with cardiac arrhythmias or sudden death, and occasionally with facial dysmorphism and malformations, including renal cystic dysplasia. Infants and young children may show involvement of liver, heart, or skeletal muscle, with life-threatening fasting- or stress-related hypoketotic hypoglycemia or Reye-like syndrome. Conduction abnormalities, arrhythmias, or dilated or hypertrophic cardiomyopathy and muscle weakness or fasting- and/or exercise-induced rhabdomyolysis are common findings. Onset in adolescence and early adulthood is usually with episodes of recurrent rhabdomyolysis without hypoglycemia. Cardiomyopathy may be present. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency historically presented with hypoketotic hypoglycemia with or without hyperammonemia or sudden death with fasting or illness. Most patients with recurrent Reye syndrome ultimately proved to have MCAD deficiency. Once the disease is identified in a patient (possibly by newborn screening), the outlook is ...

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