Fatty acid oxidation disorders deficiencies

Carnitine deficiency is a clinically useful term describing a diversity of biochemical disorders affecting fatty acid oxidation. Carnitine deficiency may be tissue-specific or generalized. 

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. 

Shen JJ, Matern D, Millington DS, et al (2000) Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders. J Inherit Metab Dis 23 27-44... 

Among the fatty acid oxidation disorders, medium-chain acyl-CoA dehydrogenase deficiency (MCAD) is the most common and its frequency is similar to that of phenylketonuria. The disorder can be identified by mutant alleles and some key abnormal metabolites. An A G transition mutation occurs at position 985 of MCAD-cDNA in about 90% of cases. This mutation leads to replacement of lysine with glutamate at position 329 (K329E) of the polypeptide. 

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. 

Sometimes a test for more than one protein is needed and mass spectrometry is the method of choice for that purpose. A good example for this would be the use of tandem mass spectrometry to screen neonates for metabolic disorders such as amino acidemias (e.g., phenylketonuria—PKU), organic acidemias (e.g., propionic acidemia—PPA), and fatty acid oxidation disorders (e.g.. Medium-chain acyl-CoA Dehydrogenase deficiency—MCAD) [9]. Although the price of this capital equipment could be high, costs of using it as a sensor is quite low (usually < U.S. 50.00 to screen for more than 20 metabolic disorders), and many states in the United States provide the service to newborns during the first week of life. 

We conclude that C8-camitine levels measured by MS-MS, are very useful to monitor the metabolic status in patients with MCAD deficiency. This marker will allow determining the best dietary treatment and fasting tolerance for these patients. This will probably be true as long as normal levels of free carnitine are maintained and valproic acid, which can increase C8-camitine levels and is contraindicated in patients with MCAD deficiency, is not given. Our results also highlight the importance of carefully recording the hours of fasting when values of AC are measured in patients with fatty acid oxidation disorders. 

L-camitine is given in many metabohc disorders as a supplement or to correct a carnitine deficiency. The dose of carnitine can vary between 50 and 100 mg/kg/day, and in some organic acidurias, as much as 200-300 mg/kg/24 days may be necessary, hi some of the long-chain fatty acid oxidation disorders, use of carnitine is controversial, and in the view of potential adverse effects (formation of car-diotoxic acylcamitines), supplementation at time of metabolic decompensation should be avoided [18]. 

Djouadi F, et til. Bezafibrate increases veiy-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders. Hum Mol Genet. 2005 14(18) 2695-703. 

Very low plasma total carnitine levels (i.e. <15 pM) with a normal acyl-carnitine pattern could signal any of a number of acquired deficiencies (diet or drug related) or a deficiency of the plasma membrane transporter. Patients with certain metabolic disorders, especially GA-I and fatty acid oxidation disorders such as MCAD and VLCAD, who have never received carnitine supplement can become markedly carnitine deficient, and their acylcarnitine profiles may be interpreted as normal if pathognomonic metabolite levels do not exceed the normal cut-off. Carnitine deficiency or in-... 

Al Odaib and colleagues have described two children who had recurrent episodes of liver disease culminating in liver failure and who underwent liver transplantation [18]. The laboratory data, as well as the hepatic acyl-carnitine profile in one of those patients, were interpreted as suggestive of a fatty acid oxidation disorder. Cultured fibroblasts derived from both patients showed a moderate reduction in the uptake and oxidation of oleic and palmitic acid. It was concluded that an impairment in the uptake of long-chain fatty acids, probably caused by a defective transporter, was the cause of liver disease in these patients [18]. The molecular defect remains undetermined in particular, the relationship between this putative Tiver/fi-broblast LCFA transporter and the widely expressed CD36/LCFA transporter molecule, a genetic deficiency of which is rather common and may be implicated in cardiomyopathy, is unclear [19]. 

In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

In mitochondria, there are four fatty acyl CoA dehydrogenase species, each of which has a specificity for either short-, mediurr-long-, or very-long-chain fatty acids. MCAD deficiency, an autos mal, recessive disorder, is one of the most common inborn errors of metabolism, and the most common inborn error of fatty add oxidation, being found in 1 in 12,000 births in the west, and 1 in 40,000 worldwide. It causes a decrease in fatty acid oxidation and severe hypoglycemia (because the tissues cannot obtain full ener getic benefit from fatty acids and, therefore, must now rely on glu cose). Treatment includes a carbohydrate-rich diet. [Note Infants are particularly affected by MCAD deficiency, because they rely for their nourishment on milk, which contains primarily MCADs. 

Several classes of inborn errors of metabolism in addition to inborn errors of urea synthesis can cause neonatal hyperammonemia. These include organic acidurias, fatty acid oxidation defects, amino acidopathies, and mitochondrial respiratory chain disorders. All of these disorders have a number of features in common. Labor and delivery tend to be normal, and there are no predisposing risk factors. Clinical features present after 24 h of life and are progressive. They are inherited, and thus a family history of previously affected children or neonatal deaths may be present. While most are inherited in an autosomally recessive manner, ornithine tran-scarbamoylase (OTC) deficiency is X linked, and a family history of affected males in the maternal pedigree is not uncommon. 

Gregersen N., Andiesen B.S., Bross P., Bolund L. Kolvraa S. (1994) Disorders of mitochondrial fatty acid oxidation especially medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In Farriaux J.P. Dhondt J.L. eds New Horizons in Neonatal Screening. Elsevier Science BV, pp 247-55. 

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