Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Abstract

ABSTRACT. We describe the clinical features and biochemical findings of two patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Both children presented with an acute metabolic crisis. Both had hypoglycemia and excreted even-chain unsubstituted dicarboxylic and 3-hydroxy-dicarboxylic acids in the urine. Measurement of the enzymes of fatty acid oxidation in cultured skin fibroblasts showed low activity of long-chain 3-hydroxyacyl-CoA dehydrogenase, but normal activity of short-chain 3-hydroxyacyl-CoA dehydrogenase. The defect was further characterized by immunoprecipitating the short-chain enzyme using monospecific antibodies. It is probably inherited as an autosomal recessive trait, inasmuch as intermediate enzyme activity was found in the fibroblasts from the parents of one child. (Pediatr Res 29: 406-411,1991) Abbreviations NR, normal range ETF, electron transfer flavoprotein CTP, carnitine palmitoyltransferase oxoacyl-CoA thiolases. ETF and ETF:ubiquinone oxidoreductase transfer electrons from the acyl-CoA dehydrogenases to the respiratory chain. All these enzymes are required for the complete oxidation of long-chain fatty acids. Defects of several enzymes of @-oxidation have been described in detail, and these include abnormalities of short-chain (3), medium-chain (4), and longchain (5) acyl-CoA dehydrogenases, ETF, and ETF dehydrogenase (6).The 3-hydroxyacyl-CoA dehydrogenases catalyze the reversible dehydrogenation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA. In mitochondria, there appear to be two enzymes that have different substrate specificities (7). The membrane-associated higher molecular weight enzyme has greater activity to the longchain substrates, whereas the enzyme with maximum activity for the short-chain substrates appears to be in the mitochondrial matrix. There have only been two previous reports of defects of the long-chain 3-hydroxyacyl-CoA dehydrogenase (8-10). We describe the clinical and biochemical features of two children who had severe hypoglycemia, metabolic acidosis, and lipid storage due to a defect of long-chain 3-hydroxyacyl-CoA dehydrogenase. CASE REPORTFatty acids are an essential metabolic fuel, particularly at times of stress or prolonged fasting. They are predominantly metabolized in the mitochondria, and defects of mitochondrial fatty acid oxidation are increasingly recognized as an important group of inborn errors of metabolism that can cause sudden infant death syndrome ("cot death"), Reye's syndrome, hypoketotic hypoglycemic coma, and muscle weakness (1).Mitochondria1 p-oxidation requires activation of fatty acids by long-chain acyl-CoA synthetase to form the fatty acyl-CoA ester. The acyl groups are then transferred into the mitochondrial matrix by the concerted action of CPT I, carnitineacylcarnitine translocase, and CPT 11. Acyl-CoA esters then undergo 0-oxidation by a repeated sequence of flavoprotein-linked dehydrogenation, hydration, NAD'-linked dehydrogenation, and thiolysis to generate acetyl-CoA (2). There are two or three enzymes with overlappin...

Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

“…The patients both demonstrated TFP deficiency, with markedly reduced activities of both 3-hydroxyacyl-CoA activity versus long-chain (C16) substrate and longchain 3-ketoacyl-CoA thiolase. The 14-24% residual activity with the 3-keto-palmitoyl-CoA substrate is partially due to matrix SCHAD (5,26), which has an overlapping substrate specificity with TFP.…”

β-Oxidation Enzymes in Fibroblasts from Patients with 3-Hydroxydicarboxylic Aciduria

“…First, the assays were performed in total homogenates of fibroblasts, and activities from the genetically separate peroxisomal p-oxidation enzymes may have been included. Recent immunoprecipitation studies by Jackson et al (18) suggest that the high level of residual activity is almost completely caused by shortchain 3-hydroxyacyl-CoA dehydrogenase, which also reacts with the C16 substrate. Recent gel filtration experiments (16) support this notion.…”

Combined enzyme defect of mitochondrial fatty acid oxidation.

“…Thus, there were thought to be three acyl-CoA dehydrogenases (short-chain, mediumchain, and long-chain), two enoyl-CoA hydratases (shortchain and long-chain), two 3-hydroxyacyl-CoA dehydrogenases (short-chain and long-chain), and two 3-oxoacyl-CoA thiolases (acetoacetyl-CoA specific and a general 3-oxoacylCoA thiolase) (2). Defects of several enzymes of fl-oxidation have been described including abnormalities of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases (3), electron transfer flavoprotein, electron transfer flavoprotein dehydrogenase (4), and long-chain 3-hydroxyacyl-CoA dehydrogenase (5).…”