title: New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency.
abstract: There are now nine inherited diseases that have been identified in the pathway of mitochondrial fatty acid oxidation, including LCAD, MCAD, SCAD, and HMG-CoA lyase deficiencies, two forms each of CPT and MAD deficiencies and an incompletely characterized disorder of primary carnitine deficiency. The varied range of clinical manifestations in this new group of diseases should attract the attention not only of general pediatricians (coma, hypoglycemia) but also of pediatric subspecialists in neurology (myopathy), cardiology (cardiomyopathy), and gastroenterology (fatty liver), as well as genetics and metabolism. The presenting features of the genetic defects in fatty acid oxidation fit well with the concept that fatty acid oxidation plays a major role in energy production during prolonged fasting and in working cardiac and skeletal muscle. Life-threatening episodes of coma and hypoglycemia induced by fasting are a common presenting feature in most of the fatty acid oxidation disorders (MCAD, LCAD, and HMG-CoA lyase deficiencies, the infantile form of CPT deficiency, the mild form of MAD deficiency, and in some cases of primary carnitine deficiency). The hypoglycemia in these disorders is most easily explained by the inability of affected patients to use fatty acids as a fuel as a substitute for glucose. It should be stressed, however, that the coma in these disorders may occur from direct toxic effects of fatty acids or fatty acid intermediates before plasma glucose concentrations reach hypoglycemic levels. Severe disturbances of muscle function are a feature in several of the disorders; hypertrophic cardiomyopathy and chronic skeletal muscle weakness occur in both the mild and severe forms of MAD deficiency, in primary carnitine deficiency, and in some patients with LCAD deficiency. In contrast, patients with the adult form of CPT deficiency have normal muscle strength but are prone to episodes of painful rhabdomyolysis induced by prolonged exercise. These manifestations presumably reflect the requirement of working cardiac and skeletal muscle for energy supplied from fatty acid oxidation. In two of the disorders, SCAD deficiency and the severe form of MAD deficiency, chronic CNS toxicity is a dominant feature. The severe effects on the brain in these two disorders may reflect the fact that short-chain fatty acids more readily cross the blood-brain barrier than longer-chain fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine.
authors.forename: C A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D042964:Acyl-CoA Dehydrogenase; D002331:Carnitine / Q000172:deficiency* / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency; D002648:Child; D044943:Fatty Acid Desaturases / Q000172:deficiency; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids; D044943:Fatty Acid Desaturases; D042964:Acyl-CoA Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine