Fatty acid oxidation defects

Fatty acid oxidation defects often produce recurrent disturbances of brain function [4, 8]. Drowsiness, stupor and coma occur during acute metabolic crises and mimic the Reye s syndrome phenotype. The neurological symptoms have been attributed to hypoglycemia, hypoke-tonemia and the deleterious effects of potentially toxic... 

Nada MA, Vianey-Saban C, Roe CR, et al (1996) Prenatal diagnosis of mitochondrial fatty acid oxidation defects. Prenat Diagn 16 117-124... 

Ventura FV, Costa CG, Struys EA, et al (1999) Quantitative acylcarnitine profiling in fibroblasts using U-C-13 palmitic acid an improved tool for the diagnosis of fatty acid oxidation defects. Clin Chim Acta281 l-17... 

Browning MF, Larson C, Strauss A, Marsden DL (2005) Normal acylcarnitine levels during confirmation of abnormal newborn screening in long-chain fatty acid oxidation defects. J Inherit Metab Dis 28 545-550... 

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. 

Acute liver failure/metabolic crisis Galactosaemia Neonatal haemochromatosis Tyrosinaemia Urea cycle disorders Fatty acid oxidation defects... 

Lactic acidosis occurs in two clinical settings (1) type A (hypoxic), associated with decreased tissue oxygenation, such as shock, hypovolemia, and left ventricular failure and (2) type B (metabolic), associated with disease (e.g., diabetes melUtus, neoplasia, liver disease), drugs and/or toxins (e.g., ethanol, methanol, and salicylates), or inborn errors of metabolism (e.g., methylmalonic aciduria, propionic acidemia, and fatty acid oxidation defects). Lactic acidosis is not uncommon and occurs in approximately 1% of hospital admissions. It has a mortality rate greater than 60%, which approaches 100% if hypotension is also present. Type A is much more common. 

Gregersen N, Andresen BS, Corydon MJ, Corydon TJ, Olsen RK, Bolund L, Bross P. Mutation analysis in mitochondrial fatty acid oxidation defects Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat. 2001 Sep 18(3) 169-89. Review. PubMed citation... 

The release of H20 from [9,10- H]myristate and/or [9,10- I palmitate has been used extensively for detecting medium- and long-chain fatty add oxidation defects, both in cultured fibroblasts and in fresh lymphocytes. Over the past 10 years we have used both substrates to screen routinely for fatty acid oxidation defects in over 1,200 patients and have identified 113 individuals with specific fatty acid oxidation disorders (Table 1). More recently we have examined the use of a third substrate, [9,10- oleate, to improve discrimination of long-chain defects. ... 

Comparison of the absolute and relative activities obtained with fliese two substrates can often pinpoint the nature of the fatty acid oxidation defect. Medium chain acyl-CoA dehydrogenase deficiency (MCAD) is characterised by a much decreased oxidation of myristate and a high palmitate/myristate (P/M) ratio, mean percentage activity relative to simultaneous controls being 11.5 5.1 (n = 18) with a corresponding P/M ratio of 4.6 1.7 (Fig. 1). 

Table 1. Fatty acid oxidation defects detected using HjO release assays, 1988-1998.

Figure 5. The data show how patients with confirmed or suspected defects of the mitochondrial respiratory chain can be separated from patients with confirmed long chain fatty acid oxidation defects (data from Figure 4 plus 8 cases of LCHAD). In each case the release of H O from [9,10- H)myristate, [9,10- H]palmitate and [9,10- H]oleate was determined in parallel with at least 3 unaffected cell lines (not all control data plotted). All determinations were in duplicate and the activities for the individual cell lines are expressed as a proportion of the assay mean.

Manning, N.J., Olpin, S.E., Pollitt, R.J. Webley, J. (1990)/ Inherited Metah. Dis. 13, 58-68. Comparison of [9,10- H]palmitic acid and [9,10- H]myristic acids for the detection of fatty acid oxidation defects in intact cultured fibroblasts. 

RAPID DIAGNOSIS OF ORGANIC ACIDEMIAS AND FATTY-ACID OXIDATION DEFECTS BY QUANTITATIVE ELECTROSPRAY TANDEM-MS ACYL-CARNITINE ANALYSIS IN PLASMA... 

Rapid Diagnosis of Oigamc Acidemias and Fatty-Acid Oxidation Defects... 

In this study, the analysis of plasma samples from patients suffering from fatty acid oxidation defects or organic acidemias (n = 103) showed abnormal acyl-camitine profiles in all cases when the samples were taken under stress (e.g. hypoglycemic episodes). In clinically stable episodes an essentially normal acyl-camitine profile was obtained for only one patient with a mild form of SCAD deficiency and for a patient with a mild form of multiple acyl-CoA dehydrogenase deficiency (data not shown). For all other defects abnormal profiles were observed under a wide variety of clinical conditions illustrating the high sensitivity of the method. In table 2, the upper reference limit, defined as the... 

In The Ross metabolic formula system nutrition support protocols. 373-390. Mitochondrial fatty acid oxidation defects. (Acosta PB Yannicelli S. eds.) 3rd ed. 

Coates, P.M. Tanaka, K. (1992). J Lipid Res 33 1099-1110. Molecular basis of mitochondrial fatty acid oxidation defects. 

Defects of fatty acid oxidation interfere with the production of ketones as a resnlt of impaired beta-oxidation. Hypoglycaitia results from excessive use of glucose by peripheral tissues and the inability to synthesize ketone bodies which can be used as alternative fuels [12]. Patients with fatty acid oxidation defects often have significant hypoketotic hypoglycemia, although it is important to note that there may be mild ketone production and, in rare circumstances, significant... 

In the heart, fatty acid oxidation defects can cause cardiomyopathy. The cardiomyopathy is usually associated with a degree of hypertrophy. Cardiomyopathy is typical for severe fatty acid oxidation defects of long-chain fatty acids. Cardiomyopathy in those with carnitine transporter defect is typically dilated in nature without hypertrophy. Severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes) occur in fatty acid oxidation defects. They are frequent in severe fatty acid oxidation defects of long-chain fatty acids and particularly prominent in camitine-acylcamitine translocase deficiency but can also occur in MCAD deficiency during decompensation. Atrioventricular block can occur but is rare. 

The diagnosis of fatty acid oxidation defects can be made by recognition of typical metabolites, by functional assays, by specific enzyme activity assays, and by molecular analysis. A primary test... 

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