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

Abstract

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 P-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 Cs to Clo 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 (Cs 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-ketoacylCoA 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. (Pediatr Res 28: 657-662, 1990)

Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency

“…One of those siblings died on the third day of life (Wanders et al, 1990). In the two siblings who had died before their respective index cases the presumptive diagnosis of 3-hydroxydicarboxylic aciduria could be confirmed retrospectively by the demonstration of measurable concentrations of 3-hydroxy fatty acids of chain lengths between 6 and 10 carbon atoms and up to 18 carbon atoms in filter-paper blood samples obtained for neonatal screening and stored for up to 6 years (Von D6beln et al, 1990).…”

“…Of 25 patients reported with presumed or proven long-chain HAD-deficiency, 17 died during an acute attack either before therapy or despite therapy (Dionisi Vici et al, 1990;Hagenfeldt et al, 1990, Pollitt, 1990Rocchiccioli et al, 1990). As a rule, the disease became manifest in the first months of life with symptoms resembling Reye syndrome.…”

“…There were reports on 10 siblings of patients who had died earlier during similar crises with diagnosis of 'sudden infant death syndrome' or Reye syndrome Wanders et at., 1990;Pollitt, 1990). One of those siblings died on the third day of life (Wanders et al, 1990).…”

“…The activity of HAD in fibroblast homogenate was measured as described elsewhere (Wanders et aL, 1990) in a medium containing 50 mmol 2-(N-morpholino)-ethanesulphonic acid (MES), 100 mmol potassium phosphate, 0.1 mmol dithiothreitol, 0.1% (w/v) Triton X-100, 100/~mol NADH (final pH 6.16). Reactions were started by adding the 3-oxoacyl-CoA ester at a final concentration of 25 pmol/L.…”

“…A reduction in activity of the long-chain HAD in fibroblast homogenates has been proved in 6 cases (Wanders et al, 1989;Dionisi Vici et al, 1990;Hale et al, 1990;Rocchiccioli et al, 1990). In one patient a reduction in the activity of short-chain HAD has been found (Hale and Thorpe, 1989).…”