To be oxidized, the long-chain fatty acids undergo a series of biochemical transformations. First they are activated to corresponding acyl-CoA esters by acyl-CoA synthetase, which is located on the outer mitochondrial membrane. Because the inner mitochondrial membrane is impermeable to acyl-CoA esters, they are transferred into the mitochondria as acylcarnitine esters. This is accomplished by carnitine palmitoyltransferase I (CPT I), also located on the outer mitochondrial membrane. A second carnitine palmitoyltransferase (CPT II), bound to the inner face of the inner mitochondrial membrane, reconverts the acylcarnitines to fatty acyl-CoAs, which undergo beta-oxidation within the mitochondrial matrix. The steps in the transport of long-chain fatty acids into the mitochondrial matrix (the carnitine cycle) are described in detail in the reviews of DiMauro and colleagues (1973), and DiDonato and Taroni. Isoforms of CPT are critically involved in this process at the inner and outer membranes of the mitochondria.
Despite the many biochemical abnormalities that have been identified in the fatty acid metabolic pathways, there are essentially 3 clinical patterns by which these defects are expressed: 1. One constellation of symptoms referred to as the encephalopathic syndrome has its onset in infancy or early childhood. Its very first manifestation may be sudden death (sudden infant death syndrome [SIDS]), or there may be vomiting, lethargy and coma, hepatomegaly, cardiomegaly, muscular weakness, and hypoketotic hypoglycemia, with prominent hyperammonemia, that is, a Reye-like syndrome. Undoubtedly, instances of this syndrome have not been recognized as abnormalities of fatty acid metabolism but have been designated incorrectly as the Reye syndrome or as SIDS. They are discussed in Chap. 36 with other inherited metabolic disorders.
2. A second (myopathic) syndrome appears in late infancy, childhood, or adult life and takes the form of a progressive myopathy, with or without cardiomyopathy. The myopathy may follow episodes of hypoketotic hypoglycemia or may develop de novo.
3. The third syndrome is one that usually begins in the second decade of life and is induced by a sustained period of physical activity or fasting. It is characterized by repeated episodes of rhabdomyolysis with or without myoglobinuria.
4. Summarized in the following text are the main disorders of fatty acid metabolism that affect skeletal muscle; these are rare but interesting diseases.
To date, this is the only form of carnitine deficiency that can be considered primary (see further on for discussion of the secondary types). Its main clinical features are progressive lipid storage myopathy and cardiomyopathy, sometimes associated with the signs of hypoketotic hypoglycemia. There is no dicarboxylic aciduria, in distinction to the secondary beta-oxidation defects, in all of which dicarboxylic aciduria is present. The cardiomyopathy, which is fatal if untreated, responds to oral administration of l-carnitine, 2 to 6 g/d. This disorder is inherited as an autosomal recessive trait. In these families there is frequently a history of sudden unexplained death in siblings, so that early identification of affected children is essential.