Role of carnitine and fatty acid oxidation and its defects in infantile epilepsy.
Defects in fatty acid oxidation are a source of major morbidity and are potentially rapidly fatal. Fatty acid oxidation defects encompass a spectrum of clinical disorders, including recurrent hypoglycemic, hypoketotic encephalopathy or Reye-like syndrome in infancy with secondary seizures and potential developmental delay, progressive lipid storage myopathy, recurrent myoglobinuria, neuropathy, and progressive cardiomyopathy. As all of the known conditions are inherited as autosomal recessive diseases, there is often a family history of sudden infant death syndrome in siblings. Early recognition and prompt initiation of therapy and the institution of preventive measures may be life saving and significantly decrease long-term morbidity, particularly with respect to central nervous system sequelae. Seizures may be the result of cerebral bioenergetic failure associated with acute episodes of hypoglycemic, hypoketotic encephalopathy, or hypoxic-ischemic encephalopathy in the context of cardiac arrhythmias and/or cardiomyopathy. This review provides an overview of the fatty acid oxidation pathway and the central role of carnitine, as well as a discussion of normal fasting adaptation and the critical metabolic adaptations that occur at birth. The increased vulnerability of infants and young children to fasting and defective fatty acid oxidation is discussed in the context of the heightened bioenergetic demands of the developing brain. Clinical and laboratory features of specific genetic defects in fatty acid oxidation, approaches to diagnosis, and current treatment methodologies are described. Indications for carnitine supplementation in childhood epilepsy are also discussed.
Tein
Ingrid
I
Division of Neurology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8. ingrid.tein@sickkids.ca
D042964:Acyl-CoA Dehydrogenase; D000927:Anticonvulsants / Q000009:adverse effects; D002331:Carnitine / Q000008:administration & dosage / Q000172:deficiency* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism; D019411:Clinical Laboratory Techniques; D005215:Fasting / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000150:complications / Q000175:diagnosis* / Q000178:diet therapy; D027701:Organic Cation Transport Proteins; D010084:Oxidation-Reduction; D000074058:Solute Carrier Family 22 Member 5; D013036:Spasms, Infantile / Q000188:drug therapy / Q000209:etiology*; D014635:Valproic Acid / Q000009:adverse effects
D000927:Anticonvulsants; D002352:Carrier Proteins; D005227:Fatty Acids; D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D014635:Valproic Acid; D044943:Fatty Acid Desaturases; D042964:Acyl-CoA Dehydrogenase; D002331:Carnitine