Ute Spiekerkoetter

..The degree of reduction in thiolase antigen also correlated with the severity of clinical presentation. Although TFP deficiency is highly heterogeneous, there is genotype-phenotype correlation...

..On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects...

..However, later-onset exercise-induced myopathic symptoms remain characteristic clinical features of long-chain fatty acid oxidation defects. Disease prevalence has increased with newborn screening...

..In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies...

..In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects...

..Severe cardiac mitochondrial proliferation in TFP deficiency suggests pathophysiologically relevant energy deficiency in this condition...

..In asymptomatic mild VLCADD, a fat-reduced diet may not be necessary, whereas in later infancy and adolescence, strenuous physical exercise may require additional energy from medium-chain fat...

..Whether this is due to lack of a substrate, inhibitory effects on other gluconeogenic enzymes or impaired transcription of gluconeogenic enzymes needs to be resolved in the future...

..With increasing pathophysiological knowledge, new treatment options have been identified and are being clinically evaluated. These include the use of bezafibrates in myopathic long-chain defects...

..Our data suggest that carnitine supplementation in long-chain beta-oxidation defects may not be required, and blood carnitine concentrations do not reflect tissue carnitine homeostasis...

..The predominant cardiac manifestation of severe TFP deficiency reflects its essential role in myocardial energetics, not its tissue-specific expression...

..In this paper we have used the VLCAD knockout mouse as a model to study changes in blood carnitine and acylcarnitine profiles under stress...

..Therefore, this disorder must be considered in the differential diagnosis of progressive peripheral neuropathy with or without episodic myoglobinuria...

..Both alpha- and beta-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in alpha- or beta-mutation-derived disease and explaining the biochemical and clinical similarities...

..Further diagnostic evaluation, including enzyme and molecular analyses, is essential to identify very long-chain acyl-coenzyme A dehydrogenase deficiency correctly...

..An MCT diet does not prevent hepatic damage during catabolism and metabolic derangement...

..Dietary fat plays a crucial role in disease pathogenesis and fat restriction is a common treatment measure. We here investigate the hepatic and muscular effects of a fat-enriched and a fat-restricted diet...

..The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency...

..However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations...

..In contrast, continuous MCT treatment produces a higher skeletal muscle content of long-chain acylcarnitines after exercise and increases hepatic lipid storage in VLCAD KO mice...

..Studies in greater patient numbers are needed to correlate residual activities >10% with the genotype and the outcome...

..This is the first study demonstrating that acylcarnitines and acyl-CoA directly correlate and concomitantly increase after exercise in VLCAD-deficient muscle...

..Therefore, we developed a new liquid chromatography tandem mass spectrometry (LC-MS/MS) method to rapidly determine both MCAD- and/or VLCAD-activity in human lymphocytes in order to confirm diagnosis...

..To determine whether asymptomatic persons with biochemical evidence of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency identified through expanded newborn screening with tandem mass spectometry have confirmed disease...

..An increased C14:1-carnitine level can also occur in heterozygous individuals. Elevated C14:1-carnitine level on neonatal screening warrants further diagnostic workup even if a repeat sample demonstrates normal acylcarnitine levels...

..To evaluate newborn screening (NBS) for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), we further characterized newborns with elevation of one or all C14-carnitine derivatives on NBS from a total of 90 338 newborns...

....

..In the muscle, there is evidence of a muscle fibre type adaptation with a predominance of glycolytic muscle fibres. Dietary modification as represented by an MCT-diet does not improve these strategies long-term...

..These results suggest a critical reconsideration of a long-term MCT-modified diet in human VLCADD. In contrast, MCT in situations of increased energy demand appears to be a safer treatment alternative...

....

..The octanoyl-CoA oxidation rate, therefore, allows a risk assessment at birth and the identification of new ACADM genotypes associated with asymptomatic disease variants...

..TFP and LCHAD deficiencies remain life-threatening disorders. This is in clear contrast to other defects of long-chain fatty acid oxidation after identification by newborn screening...

..The concentration and the predictive value of the carnitine precursor γ-butyrobetaine in blood during carnitine deficiency are unknown...

..The applied MS strategy, based on two different MS platforms (LC/MS/MS and FTMS), allowed the rapid identification analysis of the drug metabolites from human extracts and could be used for pharmaceutical research and drug development...

..TFP deficiency is another disorder that has become manifest due to isodisomy of chromosome 2. This information will impact genetic counseling for these families, reducing greatly the 25% risk normally used for recessive disorders...

..In most countries, hereditary tyrosinemia type 1 is not included in routine newborn screening...