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Mitochondrial fatty acid oxidation provides the main source of energy for heart and skeletal muscle and, by generating acetyl-CoA for ketone-body production, provides energy for other tissues when the supply of glucose is limited. Fatty acids entering the cell are esterified with carnitine before being transported across the mitochondrial membrane and being beta-oxidized in the mitochondrial matrix as CoA esters (Fig. 150-1). Disorders that decrease β-oxidation by blocking cellular carnitine uptake or by impairing entry of fatty acids into mitochondria or β-oxidation limit energy production by heart and skeletal muscle at rest and lessen the ability of other tissues, including the brain, to cope with a low-glucose milieu.

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Figure 150-1.
Graphic Jump Location

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

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Most patients with such disorders present before the age of 2 years, about 25% of them in the first week of life. Neonates may present with cardiac arrhythmias or sudden death, occasionally with facial dysmorphism and malformations, including renal cystic dysplasia. Symptoms in infancy and early childhood may relate to the liver or to cardiac or skeletal muscle, and thus include 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.

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Diagnosis may be difficult even when the presentation is characteristic. Probably the most important single diagnostic test is analyzing acylcarnitine esters in serum or plasma by tandem mass spectroscopy (MS-MS), which identifies characteristic esters in many disorders, even when patients are symptom-free. Other tests that may be useful include analysis of urine organic acids and free and total carnitine in serum and urine, loading tests with medium- and long-chain fats, and enzyme assays in leukocytes or fibroblasts.

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Treatment of acute encephalopathy associated with hypoketotic hypoglycemia is with 10% glucose and l-carnitine, given intravenously. Long-term therapy involves replenishing carnitine stores with l-carnitine and preventing hypoglycemia. This may be accomplished by providing a snack before bedtime, but continuous intragastric feeding may be required. Except for MCAD deficiency and the disorders that respond dramatically to carnitine (eg, carnitine uptake defect), the long-term ...

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