Abstract
There are at least two isoenzymes of 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (EC 4.1.3.5) located in the mitochondrial matrix and the cytoplasm of hepatocytes, respectively. The mitochondrial enzyme is necessary for the synthesis of ketone bodies, which are important fuels during fasting. We report a child with a deficiency of this isoenzyme. He presented at 16 mo with hypoglycemia. There was no rise in ketone bodies during fasting or after a long chain fat load but there was a small rise after a leucine load. Measurement of β-oxidation flux in fibroblasts was normal. Using antibodies specific for mitochondrial HMG-CoA synthase, no immunoreactive material could be detected on Western blotting. Total HMG-CoA synthase activity in liver homogenate was only slightly lower than in control samples. Presumably, as there was no mitochondrial HMG-CoA synthase enzyme protein, this activity arose from the cytoplasmic or other (e.g. peroxisomal) isoenzymes. With avoidance of fasting, our patient has had no problems since presentation and is developing normally at 4 y of age.
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Abbreviations
- HMG:
-
3-hydroxy-3-methylglutaryl
References
Quant PA, Tubbs PK, Brand MD 1990 Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme. Eur J Biochem 187: 169–174.
Quant PA, Robin D, Robin P, Ferre P, Brand MD, Girard J 1991 Control of hepatic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase during the foetal/neonatal transition, suckling and weaning in the rat. Eur J Biochem 195: 449–454.
Reed WD, Clinkenbeard KD, Lane MD 1975 Molecular and catalytic properties of mitochondrial (ketogenic) 3-hydroxy-3-methylglutaryl coenzyme A synthase of liver. J Biol Chem 250: 3117–3123.
Boukaftane Y, Duncan A, Wang S, Labuda D, Robert M-F, Sarrazin J, Schappert K, Mitchell GA 1994 Human mitochondrial HMG-CoA synthase: liver cDNA and partial genomic cloning, chromosomal mapping to 1p12-p13, and possible role in vertebrate evolution. Genomics 23: 552–559.
Russ AP, Ruzicka V, Maerz V, Appelhans H, Gross W 1992 Amplification and direct sequencing of a cDNA encoding human cytosolic 3-hydroxy-3-methylglutaryl-coenzyme A synthase. Biochim Biophys Acta 1132: 329–331.
Krisans SK, Rusnak N, Keller GA, Edwards PA 1988 Localisation of 3-hydroxy-3-methylglutaryl coenzyme A synthase in rat liver peroxisomes. J Cell Biol 107: 122a
Gibson KM, Breuer J, Nyhan WL 1988 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 143: 180–186.
Thompson GN, Hsu BYL, Pitt J, Treacey E, Stanley CA 1997 Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. N Engl J Med 337: 1203–1207.
Dixon MA, Leonard JV 1992 Intercurrent illness in inborn errors of metabolism. Arch Dis Child 67: 1387–1391.
Morris AAM, Thekekara AG, Wilks Z, Clayton PT, Leonard JV, Aynsley-Green A 1996 Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease. Arch Dis Child 75: 115–119.
Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Saudubray JM 1991 Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 87: 859–864.
Manning N, Olpin S, Pollitt R, Webley J 1990 A comparison of [9,10-3H]palmitic and [9,10-3H]myristic acids for the detection of defects of fatty acid oxidation in intact cultured fibroblasts. J Inherit Metab Dis 13: 58–68.
Lascelles C, Quant PA 1997 Investigation of human hepatic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase in post mortem and biopsy tissue. Clin Chim Acta 260: 85–96.
Tein I, Demaugre F, Bonnefont JP, Saudubray JM 1989 Normal muscle CPT1 and CPT2 activities in hepatic presentation patients with CPT1 deficiency in fibroblasts. Tissue specific isoforms of CPT1?. J Neurol Sci 92: 229–245.
Coates PM, Hale DE, Finocchiaeo G, Tanaka K, Winter SC 1988 Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J Clin Invest 81: 171–175.
Binkiewicz A, Senior B 1973 Decreased ketogenesis in Von Gierke's disease (type I glycogenosis). J Pediatr 83: 973–978.
Morris AAM, Deshpande S, Ward-Platt MP, Whitfield AE, Aynsley-Green A, Leonard JV, Pourfarzam M, Bartlett K 1995 Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency. J Inherit Metab Dis 18: 28–32.
Morris AAM, Taanman J-W, Blake J, Cooper JM, Lake BD, Malone M, Love S, Leonard JV, Clayton PT, Schapira AHV 1998 Liver failure associated with mitochondrial DNA depletion. J Hepatol 28: 556–563.
Quant PA, Tubbs PK, Brand MD 1989 Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase activity and decreases succinyl-CoA content in liver. Biochem J 262: 159–164.
Ashmarina LI, Rusnak N, Miziorko HM, Mitchell GA 1994 3-Hydroxy-3-methylglutaryl-coenzyme A lyase is present in mouse and human peroxisomes. J Biol Chem 269: 31929–31932.
Curi R, Williams JF, Newsholme EA 1989 Formation of ketone bodies by resting lymphocytes. Int J Biochem 21: 1133–1136.
Thompson G, Pitt J, Treacey E, Stanley C VIth International Congress on Inherited Metabolic Disease Milan 1994 Abstract W28.1
Koper JW, Lopes-Cardoso ML, Van Gold LMG . 1981 Preferential use of ketone bodies for the synthesis of myelin cholesterol in vivo. Biochim Biophys Acta 666: 411–417.
Acknowledgements
The authors thank Drs. D. M. Easton and K. Hussain for referring the patient and Drs. S Krywawych and A. W. Johnson for organic acid and acylcarnitine analysis.
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Support was provided by the Sir Halley Stewart Trust and the Sir Samuel Scott of Yews Trust, C.V.L. holds a Krebs Memorial Scholarship.
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Morris, A., Lascelles, C., Olpin, S. et al. Hepatic Mitochondrial 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase Deficiency. Pediatr Res 44, 392–396 (1998). https://doi.org/10.1203/00006450-199809000-00021
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DOI: https://doi.org/10.1203/00006450-199809000-00021
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