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Establishing a Reference Interval For Measurement of Flux through the Mitochondrial Fatty Acid Oxidation Pathway in Cultured Skin Fibroblasts

¹ Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA;² Department of Pathology, University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA;³ Department of Pathology, Children’s Medical Center, Dallas, TX

^aaddress correspondence to this author at: Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104; fax 215-590-1998, e-mail narayans@email.chop.edu

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Mitochondrial fatty acid oxidation (FAO) represents a normal metabolic response to increased energy demands during periods of fasting, febrile illness, or muscular exertion. FAO is a complex pathway involving activation of free fatty acids to acyl-CoA species, transport into mitochondria, and cyclic oxidation to break the long-chain fatty acids into acetyl-CoA and a two-carbon chain-shortened acyl-CoA, which is then recycled. Acetyl-CoA is used in the Krebs cycle and in liver as a substrate for ketogenesis (1). Measurement of FAO flux in cultured cells provides valuable information about the integrity of the enzymes and transporters involved in FAO at all stages. Clinical indications for the measurement of FAO flux in skin fibroblasts include fatty acid oxidation enzyme defects, unexplained myopathies, cardiomyopathies, hypoglycemia, liver disease, sudden unexplained infant death, and hypoketotic hypoglycemia. FAO flux is typically measured by monitoring the conversion of radiolabeled fatty acids to carbon dioxide and water. Labeling can be with ¹⁴C with final analysis of the rate of production of ¹⁴CO₂, or with ³H and analysis of production of ³H₂O (2)(3). Palmitic acid (C16) is used to detect long-chain defects, including deficiencies in very long chain acyl-CoA dehydrogenase, long-chain L-3-hydroxy acyl-CoA dehydrogenase, long-chain 3-keto acyl-CoA thiolase, carnitine/acylcarnitine translocase, carnitine pamitoyltransferase 1, and carnitine pamitoyltransferase 2. Myristic acid (C14) is used to detect defects in medium-chain FAO, such as medium-chain acyl-CoA dehydrogenase deficiency. We use tritiated fatty acids labeled in the (9,10) position. The assay will not detect defects in carnitine palmitoyl transferase 1B; short-chain FAO defects, including short-chain acyl-CoA dehydrogenase and short-chain L-3-hydroxy acyl-CoA dehydrogenase; and short-chain-3-keto acyl-CoA thiolase deficiencies.

Historically, patient samples have been compared with batch controls, and a reference interval was not established for this assay. In the present study we have assigned a reference . . . [Full Text of this Article]