Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels

Charles A. Stanley, Daniel Hale, Paul M. Coates, Carole L. Hall, Barbara E. Corkey, William Yang, Richard I. Kelley, Elisa L. Gonzales, John R. Williamson, Lester Baker

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye’s syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate <0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 μmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 Mmole/liter), liver (200-500 nmole/ g), and muscle (500-800 nmole/g); however, treatment with l- carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium- chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA— acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase. The carnitine deficiency in these patients appears to be a secondary consequence of their defect in fatty acid oxidation. It is possible that other patients with “systemic carnitine deficiency,” who fail to respond to carnitine therapy, may also have defects in fatty acid oxidation similar to medium-chain acyl-CoA dehydrogenase deficiency.

Original languageEnglish (US)
Pages (from-to)877-884
Number of pages8
JournalPediatric Research
Volume17
Issue number11
DOIs
StatePublished - Jan 1 1983

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Carnitine
Hypoglycemia
Fatty Acids
Acyl-CoA Dehydrogenase
Electron-Transferring Flavoproteins
Fasting
Isovaleryl-CoA Dehydrogenase
Acyl-CoA Dehydrogenases
Liver
Butyryl-CoA Dehydrogenase
Long-Chain Acyl-CoA Dehydrogenase
Reye Syndrome
Hyperammonemia
Dicarboxylic Acids
Acyl Coenzyme A
Ketosis
3-Hydroxybutyric Acid
Volatile Fatty Acids
Brain Edema
Fatty Liver

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Stanley, Charles A. ; Hale, Daniel ; Coates, Paul M. ; Hall, Carole L. ; Corkey, Barbara E. ; Yang, William ; Kelley, Richard I. ; Gonzales, Elisa L. ; Williamson, John R. ; Baker, Lester. / Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. In: Pediatric Research. 1983 ; Vol. 17, No. 11. pp. 877-884.
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title = "Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels",
abstract = "Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye’s syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate <0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 μmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 Mmole/liter), liver (200-500 nmole/ g), and muscle (500-800 nmole/g); however, treatment with l- carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium- chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA— acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5{\%} normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase. The carnitine deficiency in these patients appears to be a secondary consequence of their defect in fatty acid oxidation. It is possible that other patients with “systemic carnitine deficiency,” who fail to respond to carnitine therapy, may also have defects in fatty acid oxidation similar to medium-chain acyl-CoA dehydrogenase deficiency.",
author = "Stanley, {Charles A.} and Daniel Hale and Coates, {Paul M.} and Hall, {Carole L.} and Corkey, {Barbara E.} and William Yang and Kelley, {Richard I.} and Gonzales, {Elisa L.} and Williamson, {John R.} and Lester Baker",
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Stanley, CA, Hale, D, Coates, PM, Hall, CL, Corkey, BE, Yang, W, Kelley, RI, Gonzales, EL, Williamson, JR & Baker, L 1983, 'Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels', Pediatric Research, vol. 17, no. 11, pp. 877-884. https://doi.org/10.1203/00006450-198311000-00008

Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. / Stanley, Charles A.; Hale, Daniel; Coates, Paul M.; Hall, Carole L.; Corkey, Barbara E.; Yang, William; Kelley, Richard I.; Gonzales, Elisa L.; Williamson, John R.; Baker, Lester.

In: Pediatric Research, Vol. 17, No. 11, 01.01.1983, p. 877-884.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels

AU - Stanley, Charles A.

AU - Hale, Daniel

AU - Coates, Paul M.

AU - Hall, Carole L.

AU - Corkey, Barbara E.

AU - Yang, William

AU - Kelley, Richard I.

AU - Gonzales, Elisa L.

AU - Williamson, John R.

AU - Baker, Lester

PY - 1983/1/1

Y1 - 1983/1/1

N2 - Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye’s syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate <0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 μmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 Mmole/liter), liver (200-500 nmole/ g), and muscle (500-800 nmole/g); however, treatment with l- carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium- chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA— acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase. The carnitine deficiency in these patients appears to be a secondary consequence of their defect in fatty acid oxidation. It is possible that other patients with “systemic carnitine deficiency,” who fail to respond to carnitine therapy, may also have defects in fatty acid oxidation similar to medium-chain acyl-CoA dehydrogenase deficiency.

AB - Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye’s syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate <0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 μmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 Mmole/liter), liver (200-500 nmole/ g), and muscle (500-800 nmole/g); however, treatment with l- carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium- chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA— acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase. The carnitine deficiency in these patients appears to be a secondary consequence of their defect in fatty acid oxidation. It is possible that other patients with “systemic carnitine deficiency,” who fail to respond to carnitine therapy, may also have defects in fatty acid oxidation similar to medium-chain acyl-CoA dehydrogenase deficiency.

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