Chapter 101a

### Abstract

1. The carnitine shuttle represents a mechanism by which long-chain fatty acids, which are impermeable to the mitochondrial membranes, are transported into the mitochondrial matrix for the purpose β-oxidation and energy production. The shuttle takes activated long-chain fatty acids as their coenzyme A esters, converts them to the corresponding acylcarnitines, which are then translocated through the inner mitochondrial membrane and finally reactivated to long-chain acyl-CoA’s for β-oxidation. The system consists of three components:first,carnitine palmitoyltransferase 1 (CPT1) at the inner side of the outer mitochondrial membrane converts acyl-CoAs to corresponding acylcarnitines;next, carnitine:acylcarnitine translocase or carnitine:acylcarnitine carrier (CACT or CAC),translocates acylcarnitines through the inner mitochondrial membrane; finally,carnitine palmitoyltransferase 2 (CPT2),on the innersurface of the inner mitochondrial membrane convertsacylcarnitines back to acyl-CoAs and releases free carnitinethat is recycled to the cytosolby the actionof CACT.

2. CPT1 activity is unusual amongst the enzymes involved in fatty acid β-oxidation in that tissue-specific isoforms exist. CPT1A is found predominantly in liver and kidney (and of diagnostic note, is also expressed in skin fibroblasts); it is highly allosterically regulated byprandial status. Post-prandial intracellular levels of malonyl-CoA are high and inhibit CPT1A activity thus switching off the transport of fatty acids into the mitochondria when there is a plentiful supply of calories from dietary sources. During periods of fasting, intracellular levels of malonyl-CoA fall and relieve this inhibition thus driving fatty acids into the mitochondria for the purpose of β-oxidation. CPT1B is found in skeletal and cardiac muscle and the kinetics of malonyl-CoA inhibition are such that these tissues can still utilize fatty acids during periods of high demand and not only during states of prolonged fasting.CPT1C is expressed predominantly in brain and its functions are still being evaluated.

3. Autosomal recessively inherited genetic disorders of all three components of the carnitine shuttle have been described. All three disorders present as defects of long-chain fatty acid oxidation. So far CPT1A is the only known defect affecting CPT1 activity (MIM 255120). CPT1A deficiency is primarily a disorder of hepatic fasting intolerance and signs and symptoms are those of failure to generate ketone bodies by the liver in response to reduced caloric intake. Patients may also have renal tubular acidosis. CACT and CPT2 enzymes are expressed in all tissues and signs and symptoms of CACT deficiency (MIM 212138) and CPT2 deficiency (MIM 255110, 600649, 608836 representing neonatal lethal, infantile and adult presentations) are systemic and include cardiac and skeletal muscle involvement in addition to liver disease.

4. All of the genes for thethree forms of CPT1, of CACT and of CPT2 have been cloned in a variety of species. In humans the genes have been mapped as follows: CPT1A 1on 11q13.3, CPT1B on 22q13.33, CPT1C on 19q13.33, CACT on 3p21.31 and CPT2 on 1p32.3.

5. CPT1A deficiency classically presents as a fasting-induced disorder with hepatic failure leading to encephalopathy, hypoglycemia and hypoketosis. There may be an associated moderate hyperammonemia and high levels of plasma transaminases. The acute clinical phenotype is identical to that seen in medium-chain acyl-CoA dehydrogenase ...

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