Deficiency of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase: A Cause of Lethal Myopathy and Cardiomyopathy in Early Childhood

Department of Paediatrics, University of Amsterdam, Amsterdamo, North Holland, Netherlands
Pediatric Research (Impact Factor: 2.31). 11/1990; 28(6):657-662. DOI: 10.1203/00006450-199012000-00023


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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    • "Inactivity of this mitochondrial enzyme causes disfunction of long chain fatty acids metabolism (LCHADD) and leads to insufficient energy production and accumulation of toxic intermediates . The clinical manifestations typically appear during infancy or early childhood, are very variable and include, among others, hypoglycemia, cardiomyopathy, coma and sudden death (Wanders et al. 1989; Rocchicciolo et al. 1990). Diversity of symptoms impedes proper diagnosis and treatment, which was a cause of numerous child deaths before molecular diagnostics era. "
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    • "Kearns±Sayre syndrome is a disorder caused by deletion of mtDNA and heteroplasmy with a high percentage of deleted mtDNA in muscle characterized by onset in childhood, pigmentary retinopathy , ataxia and cardiac conduction defects (Leonard & Schapira 2000, Larsson et al. 1990). Three patients with Kearns±Sayre syndrome developed a right bundle branch block, an atrioventricular block type II and an atrioventricular block type III, respectively. Skeletal muscle biopsies showed typical ragged red fibres and deletions of mtDNA of different size, affecting several coding and tRNA genes (Larsson et al. 1990). In s"
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    • "The phenotypic heterogeneity of LCHAD deÐciency is enormous, with some patients presenting immediately after birth with rapidly fatal cardiomyopathy (Rocchiccioli et al 1990 ; Tyni et al 1997). Such patients may have had earlier episodes of hypoketotic hypoglycaemia but this is not always observed. "
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