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Mitochondrial fatty acid beta-oxidation plays an important role in energy production, particularly in skeletal and heart muscle, and in hepatic ketone body formation. Disorders of fatty acid oxidation (FAO) are characterized by hypoglycemia, hepatic dysfunction, encephalopathy, skeletal myopathy, and cardiomyopathy. Most FAO disorders have a rather similar presentation and their biochemical diagnosis can, at times, be difficult. Commonly used metabolite screens such as urine organic acids, plasma acylcarnitines, and fatty acids are influenced by dietary factors and the clinical status of the patient. This often leads to incomplete diagnostic information or even false-negative results. Enzyme assays are limited to 1 enzyme per assay, and molecular assays for common mutations are limited by the frequent occurrence of compound heterozygous patients with uncommon, private mutations that must be distinguished from unaffected carriers. Furthermore, neither specific enzyme assays nor molecular genetic testing is available for each of the known defects. The purpose of the in vitro probe assay is to offer screening for several defects of FAO and organic acid metabolism under controlled laboratory conditions using fibroblast cultures.
In vitro confirmation of biochemical diagnoses of the following fatty acid oxidation disorders:
-Short-chain acyl-CoA dehydrogenase (SCAD) deficiency
-Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
-Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
-Trifunctional protein deficiency
-Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
-Carnitine palmitoyl transferase deficiency type II (CPT-II)
-Carnitine-acylcarnitine translocase (CACT) deficiency
In addition, the following organic acid disorders can be confirmed by this assay:
-2-Methylbutyryl-CoA dehydrogenase (SBCAD) deficiency
-Isobutyryl-CoA dehydrogenase (IBD) deficiency
Work is in progress to evaluate the applicability of this assay to the remaining disorders of fatty acid transport and mitochondrial oxidation.
Abnormal results will include a description of the abnormal profile, in comparison to normal and abnormal co-run controls. In addition, the concentration of those acylcarnitine species that abnormally accumulated in the cell medium are provided and compared to the continuously updated reference range based on analysis of normal controls. Interpretations of abnormal acylcarnitine profiles also include information about the results' significance, a correlation to available clinical information, possible differential diagnoses, recommendations for additional biochemical testing and confirmatory studies if indicated, name and phone number of contacts who may provide these studies at the Mayo Clinic or elsewhere, and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.
This assay is not informative if the deficient enzyme is physiologically not expressed in skin fibroblasts.
Sometimes, an abnormal acylcarnitine profile cannot differentiate between 2 disorders. In such instances, independent biochemical (eg, specific enzyme assay) or molecular genetic analyses are required. Recommendations for such testing will be included in the report.
An interpretive report will be provided.
1. Roe CR, Ding J: Chapter 101: Mitochondrial Fatty Acid Oxidation Disorders. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Available at www.ommbid.com. Accessed 04/22/2014
2. Ensenauer R, Vockley J, Willard JM, et al: A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet 2004;75(6):1136-1142
3. Rinaldo P, Matern D, Bennet MJ: Fatty acid oxidation disorders. Ann Rev Physiol 2002;64:477-502
4. Shen JJ, Matern D, Millington DS, et al: Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders. J Inherit Metab Dis 2000;23:27-44
5. Matern D, Huey JC, Gregersen N, et al: In vitro diagnosis of short-chain acyl-CoA dehydrogenase (SCAD) deficiency. J Inherit Metab Dis 2001;24(Suppl.1):66