Deficiency of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase: A Cause of Lethal Myopathy and Cardiomyopathy in Early Childhood
ABSTRACT A child presented in early childhood with episodes of coma and hypoglycemia and a rapidly evolutive myopathy and cardiomyopathy leading to death at 9 mo of age. Ketosis was decreased (blood β-hydroxybutyrate: 0.07 mmol/L) despite normal plasma levels of fatty acids (0.81 mmol/L). The patient's urine contained excessive amounts of the C6 to C10 dicarboxylic acids present in almost all defects of fatty acid mitochondrial oxidation. More specifically, gas chromatography-mass spectrometry identified an accumulation of medium- and long-chain (C8 to C14) 3-hydroxy-dicarboxylic acids, suggesting a defect of the mitochondrial enzyme that normally dehydrogenates these 3-hydroxyacyl-CoA esters. Biochemical studies in the patient's cultured fibroblasts confirmed the impairment of medium- and long-chain fatty acid oxidation, and allowed the recognition of the deficiency of long-chain 3-hydroxyacyl- CoA dehydrogenase. The activities of long-, medium-, and short-chain acyl-CoA dehydrogenases and 3-ketoacyl- CoA thiolase were normal. These results describe a disorder of fatty acid metabolism that affects the liver, skeletal muscles, and myocardium. It is important to point out that long-chain 3-hydroxyacyl-CoA deficiency shares many clinical similarities with systemic carnitine deficiency, as well as with carnitine-palmityl-CoA transferase and longchain acyl-CoA dehydrogenase deficiencies. The differential diagnosis of this disease relies on the demonstration of long-chain urinary dicarboxylic acids with a hydroxyl group in 3-position and the study of the enzyme activity in cultured fibroblasts.
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ABSTRACT: We present a 9-month-old child presenting with acute cardiomyopathy and fever following a viral illness. He was diagnosed to have acute myocarditis, was proposed for an external hemodynamic assistance but died of ventricular tachycardia. Post-mortem data revealed a very-long-chain acylcoenzyme A dehydrogenase deficiency. Our report raises awareness on the interest for preserving tissue samples and for performing a metabolic screening in acute childhood cardiomyopathy.International Journal of Cardiology 08/1998; 65(3):287-289. · 6.18 Impact Factor
Article: La mitocondria y el corazón[Show abstract] [Hide abstract]
ABSTRACT: The heart is highly dependent for its function on oxidative energy generated in mitochondria, primarily by fatty acid β-oxidation, respiratory electron chain and oxidative phosphorylation. Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophy cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, as well as myocarditis. While a subset of these mitochondrial abnormalities have a defined genetic basis (e.g. mitochondrial DNA changes leading to oxidative phosphorylation dysfunction,fatty acid β-oxidation defects due to specific nuclear DNA mutations), other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized. This review focuses on abnormalities in mitochondrial bioenergetic function and mitochondrial DNA defects associated with cardiovascular diseases, their significance in cardiac pathogenesis as well as on the available diagnostic and therapeutic options. A concise background concerning mitochondrial biogenesis and bioenergetic pathways during cardiac growth,development and aging will also be provided.Revista Espa de Cardiologia 01/2002; 55(12). · 3.34 Impact Factor
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ABSTRACT: In recent years tremendous progress has been made with respect to the enzymology of the mitochondrial fatty acid β-oxidation machinery and defects therein. Firstly, a number of new mitochondrial β-oxidation enzymes have been identified, including very-long-chain acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (MTP). Secondly, the introduction of tandem MS for the analysis of plasma acylcarnitines has greatly facilitated the identification of patients with a defect in fatty acid oxidation (FAO). These two developments explain why the number of defined FAO disorders has increased dramatically, making FAO disorders the most rapidly growing group of inborn errors of metabolism. In this review we describe the current state of knowledge of the enzymes involved in the mitochondrial oxidation of straight-chain, branched-chain and (poly)unsaturated fatty acyl-CoAs as well as disorders of fatty acid oxidation. The laboratory diagnosis of these disorders is described, with particular emphasis on the methods used to identify the underlying enzyme defect and the molecular mutations. In addition, a simple flowchart is presented as a guide to the identification of mitochondrial FAO-disorders. Finally, treatment strategies are discussed briefly.Journal of Inherited Metabolic Disease 01/1999; 22(4):442-487. · 4.14 Impact Factor