Human Disorders of Fatty Acid Oxidation

A method for quantitative acylcamitine profiling in human skin fibroblasts using unlabelled palmitic acid diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency. 

In humans, several genetic disorders of fatty acid catabolism, such as the most common MCAD-deficiency, have been reported but their description falls beyond the scope of this review. Several recent reviews have described many of these diseases and their symptoms in more detail (Longo et al., 2006 Rinaldo et ah, 2002 Wanders and Waterham, 2006 Yang et ah, 2005). For mitochondrial fatty acid oxidation disorders the symptoms often develop at infancy during an episode of increased energy demand such as fasting, exercise or illness. Peroxisomal fatty acid oxidation enzyme deficiencies often involve neuropathy and retinopathy. 

More than 20 other human genetic defects in fatty acid transport or oxidation have been documented, most much less common than the defect in MCAD. One of the most severe disorders results from loss of the long-chain /3-hydroxyacyl-CoA dehydrogenase activity of the tri-functional protein, TFP. Other disorders include defects in the a or /3 subunits that affect all three activities of TFP and cause serious heart disease and abnormal skeletal muscle. ... 

Wanders RJ, Ijlst L, Poggi F, Bonnefont JP, Munnich A, Brivet M, et al. Human trifimctional protein deficiency a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun 1992 188 1139-45. 

N., Nicholls, R. D., Pei, Z., Watkins, P.A., and Vockley, J., 2007. A new genetic disorder in mitochondrial fatty acid p-oxidation ACAD9 deficiency. The American Journal of Human Genetics. 81 87-103. 

Several diseases are known that result in elevations in tissues and fluids of various esters of carnitine and reduce the availability of free carnitine, which is normally synthesized by humans and is necessary for the transport of long-chain fatty acids into mitochondria for oxidation. In several disorders arising from acyl-CoA dehydrogenase deficiencies, the accumulation of the acyl-CoA substrate frequently sequesters coenzyme A and reduces its availability for other unrelated but important and otherwise competent pathways. Carnitine administration can displace and make available much of the coenzyme A that had been isolated, and stimulate the excretion of the accumulating acidic metabolites now esterified to carnitine. Detection of reduced levels of serum or urinary free carnitine and elevations of esterified carnitine is therefore useful for diagnosis of a variety of metabolic disorders, among them congenital inability to synthesize carnitine. In this disorder, carnitine must be supplied by a carnitine-enriched diet as it is, in effect, a vitamin. 

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