Long oxidation defect

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... 

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. ... 

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.

Olpin, S.E., Manning, N.J., Pollitt, R.J. Clark, S. (1997). J. Inherited Metab. Dis. 20, 415-419. Improved detection of long-chain fatty acid oxidation defects in intact cells using [9,10- H]oleate. Vianey-Saban, C., Divry, C., Brivet, M., Nada, M., Zabot, M.T., Mathieu, M. Roe, C. (1998) Clin. Chim. Acta, 269, 43-62. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency clinical characteristics and diagnostic considerations in 30 patients. 

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. 

Spiekerkoetter U, et al. Treatment recommendations in long-chain fatty add oxidation defects consensus from a workshop. J Inherit Metab Dis. 2009 32(4) 498-505. 

Box 24.1 Principles of Dietary Treatment of Long-Chain Fatty Acid Oxidation Defects... 

Fatty acid oxidation defects cover a wide range of enzyme deficiencies in the metabolism of long-, medium-, and short-chain fats. Patients with LCFAOD and MCAD can present with severe illness or be asymptomatic. Chronic management of LCFAOD involves the restriction of long-chain fat and supplementation of MCT, a readily used source of energy that is not dependent on enzymes used in long-chain... 

As stated earlier, experience with the use of MS/MS for acylglycine analysis is limited, but should be expected to parallel that of previously published GC/MS methods. In many disorders, such as MCAD and MAD deficiencies, there is more than one pathognomonic metabolite. A list of metabolites and their associated disorders is provided in Table E.3. It should be noted that the method does not recognize patients with milder variants of SCAD and MAD deficiencies, and cannot diagnose long-chain fatty acid oxidation defects [8]. 

Urine for organic acid analysis is collected at 0-3 h and 3-6 h after the load. Insufficient ketogenesis (less than twofold increase of the starting value) is observed in long-chain fatty acid oxidation defects and HMGS-defi-ciency. Controls have been shown to accumulate unsaturated C12-C16 acylcarnitines this profile is different from any of the primary defects [18]. Patients with any of the primary defects will accumulate the relevant acylcarnitines and (hydroxy) fatty acids in plasma. Defects distal from CPT2-defi-ciency are additionally characterized by the excretion of dicarboxylic acids in the urines after loading. 

When the suspicion of a long-chain fatty acid oxidation defect is substantial, additional proof can be found by a medium-chain triglyceride (MCT) loading test. This should result in normal ketogenesis, except in patients with MCAD and HMGS deficiency. The value of the latter test is limited. 

Our results also shed light on the long-lived PA3 band detected in transient PM measurements of P3BT (see Fig. 7-19) and can explain changes in the PA spectra observed in several ps transient measurements of films of PPV derivatives at energies around 1.8 eV [9, 25, 60J. In good PPV films the transient PA spectrum shows a PA band of excitons at 1.5 eV whose dynamics match those of the PL and stimulated emission (SE) [9J. However, in measurements of oxidized [25] or C60-doped films 60, there appears a new PA band at about 1.8 eV whose dynamics are not correlated with those of the PL and SE. Based on our A-PADMR results here, we attribute the new PA band at 1.8 eV to polaron pair excitations. These may be created via exciton dissociation at extrinsic defects such as carbo-... 

Inherited defects in the enzymes of (3-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty hver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fetty liver of pr nancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30). 

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