Myopathy in very-long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with the fatal cardiac phenotype

Scholte, H. R.; Coster, R.N.A. Van; JONGE, P.C.; Poorthuis, B. J. H. M.; Jeneson, Jeroen A. L.; Andresen, Brage S.; Gregersen, Niels; Klerk, J. B. C. de; Busch, H. F. M.

doi:10.1016/s0960-8966(99)00032-2

Cited by 24 publications

(17 citation statements)

References 29 publications

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“…The tissue-specific acylcarnitine production that we observed in mice was associated with heterogeneous, tissue-specific phenotypes, as described in humans with VLCADD (2). Adult-onset VLCADD presents with skeletal myopathy and rhabdomyolysis that are frequently preceded and induced by intense physical exercise (2,18,19), whereas in infants, reduced tolerance to fasting may allow more stress to the liver, inducing hepatic accumulation of acylcarnitines and hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Tissue Carnitine Homeostasis in Very-Long-Chain Acyl-CoA Dehydrogenase–Deficient Mice

et al. 2005

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Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is the most common long-chain fatty acid oxidation defect and presents with heterogeneous clinical manifestations. Accumulation of long-chain acylcarnitines and deficiency of free carnitine have often been proposed to play an important role in disease pathogenesis. The VLCAD-deficient mouse exhibits similar clinical and biochemical phenotypes to those observed in humans and, therefore, represents an excellent model to study VLCAD deficiency. We measured carnitine and acylcarnitine profiles in liver, skeletal muscle (SkM), bile, and blood from VLCAD knock-out mice and controls under nonstressed and various stress conditions. Carnitine and acylcarnitines were extracted from body fluids with methanol and from tissues with acetonitrile, respectively, and were analyzed as their butyl esters using electrospray ionization tandem mass spectrometry. Fasting combined with a cold challenge for 8 h significantly induced liver long-chain acylcarnitine and free carnitine production. Acylcarnitines in SkM predominantly accumulated during exercise with a concomitant decrease of free carnitine. Changes in blood free carnitine did not correlate with carnitine homeostasis in liver and SkM. Our results demonstrate different tissue-specific long-chain acylcarnitine profiles in response to various stressors, which may be of importance with respect to the heterogeneous clinical manifestations of VLCAD deficiency in humans. Furthermore, we conclude that carnitine biosynthesis in the liver seems sufficiently active to maintain liver carnitine levels during increased demand. Our data suggest that carnitine supplementation in long-chain ␤-oxidation defects may not be required, and blood carnitine concentrations do not reflect tissue carnitine homeostasis. Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is the most common mitochondrial ␤-oxidation defect of long-chain fatty acids, with an incidence of~1:50,000 to 1:100,000 births (1). In humans, three distinct clinical phenotypes of different severities occur: a life-threatening, early-onset presentation with cardiomyopathy and hepatopathy; a hepatic phenotype with recurrent hypoketotic hypoglycemia and onset in infancy; and a milder, myopathic form with episodic muscle weakness, myalgia, and rhabdomyolysis presenting in adolescence or adulthood (2). Treatment interventions such as avoidance of fasting, reduced long-chain fat intake, and supplementation with medium-chain triglycerides may avoid metabolic decompensation, and long-term rehabilitation can be achieved (3,4).Characteristically, long-chain acyl-CoAs accumulate in mitochondria. To leave the mitochondria, they are converted into acylcarnitine esters, which can be assayed in blood (5). As a result of an increased production of acylcarnitines, blood free carnitine concentrations may decrease (5), a condition termed secondary carnitine deficiency. Nevertheless, supplementation of exogenous carnitine to restore intracellular carnitine pools has been controversia...

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Section: Discussionmentioning

confidence: 99%

Tissue Carnitine Homeostasis in Very-Long-Chain Acyl-CoA Dehydrogenase–Deficient Mice

et al. 2005

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“…6 Myoglobinuria triggered by exercise, fasting, or infection is typical of adult-onset presentations, although it may also occur in infantile forms 8,20 and is particularly common in carnitine palmitoyltransferase II (CPT II) 20 and very long-chain acyl CoA dehydrogenase (VLCAD) deficiencies. 18,23 By contrast, weakness due to progressive sensory-motor neuropathy has not been associated with fatty acid oxidation defects other than in a few patients with isolated LCHAD deficiency, 3 another disorder of the TFP complex. Progressive peripheral neuropathy is a significant feature of myopathic TFP deficiency and the combination of both progressive neuropathy and episodic myoglobinuria is present in more than 50% of patients with TFP ␤-subunit mutations (7 of 13 families from our cohort) 25 and in about one-third of reported patients with TFP deficiency due to ␣-subunit mutations.…”

Section: Discussionmentioning

confidence: 99%

Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein

et al. 2003

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Mitochondrial trifunctional protein (TFP) deficiency is a rare disorder of the fatty acid beta-oxidation cycle with heterogeneous phenotypes and occurs secondary to either alpha- or beta-subunit mutations. We characterized the neuromyopathic phenotype of TFP deficiency through adolescence or adulthood in 11 patients, 8 with beta-subunit mutations and 3 with alpha-subunit mutations. Two independent clinical features occurred: infantile-onset progressive peripheral neuropathy and episodic exercise-, illness- or fasting-induced rhabdomyolysis accompanied by respiratory failure (in five patients). The combination of episodic rhabdomyolysis and peripheral neuropathy occurred in 10 of the 11 patients. The neuromyopathic phenotype is common in TFP deficiency (11 of 27 families from our cohort). Therefore, this disorder must be considered in the differential diagnosis of progressive peripheral neuropathy with or without episodic myoglobinuria.

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“…Adolescents or adults with muscle weakness and pain without cardiac and hepatic involvement [Smelt et al, 1998;Scholte et al, 1999]. Cells from such patients were not included in the study performed by Vianey-Saban et al [1998], but it seems probable that the deficiency in this group of patients is the mildest found in VLCAD deficiency, because of the lack of involvement of heart and liver.…”

Section: Pathogenesis In Fatty Acid Oxidation Disordersmentioning

confidence: 99%

Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

et al. 2001

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Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders.

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Myopathy in very-long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with the fatal cardiac phenotype

Cited by 24 publications

References 29 publications

Tissue Carnitine Homeostasis in Very-Long-Chain Acyl-CoA Dehydrogenase–Deficient Mice

Tissue Carnitine Homeostasis in Very-Long-Chain Acyl-CoA Dehydrogenase–Deficient Mice

Peripheral neuropathy, episodic myoglobinuria, and respiratory failure in deficiency of the mitochondrial trifunctional protein

Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship

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