Summary
Carnitine palmitoyltransferase (CPT) was studied in muscle homogenates of four patients with recurrent attacks of rhabdomyolysis due to muscular CPT deficiency and in those of the clinically asymptomatic father and mother of two patients. In controls CPT II was readily solubilized by the addition of Triton X-100 and 1% Tween 20. In contrast, CPT I was inactivated by Triton X-100 but remained catalytically active and membrane bound in the presence of 1% Tween 20. Total CPT activity was normal in patients and in both parents when measured under optimal assay conditions. After addition of 1% Tween 20 the insoluble CPT activity was also normal in patients and in both parents. The soluble CPT activity, however, was almost completely lost in patients but was only partially decreased in both parents. The data indicate that in patients an enzymatically active CPT II exists which is abnormally sensitive to inhibition by Tween 20, and that CPT I activity is not compensatorily increased in patients. A partial CPT II deficiency can be identified in heterozygotes most sensitively by the separate determination of soluble and insoluble CPT activities in the presence of 1% Tween 20.
Similar content being viewed by others
Abbreviations
- CoA:
-
coenzyme A
- CPT:
-
carnitine palmitoyltransferase
References
Angelini C, Freddo L, Battistella P, Bresolin N, Pierbon-Bormioli S, Armani M, Vergani L (1981) Carnitine palmitoyltransferase deficiency: clinical variability, carrier detection, and autosomal-recessive inheritance. Neurology 31:883–886
Bank WJ, DiMauro S, Bonilla E, Capuzzi DM, Rowland LP (1975) A disorder of muscle lipid metabolism and myoglobinuria: absence of carnitine palmitoyl transferase. N Engl J Med 292:443–449
Brownell AKW, Severson DL, Thompson CD, Fletcher T (1979) Cold induced rhabdomyolysis in carnitine palmitoyl-transferase deficiency. Can J Neurol Sci 6:367–369
Bye AME, Kan AE (1988) Cramps following exercise. Aust Paediatr J 24:258–259
Carey MP, Poulton K, Hawkins C, Murphy RP (1987) Carnitine palmitoyltransferase deficiency with an atypical presentation and ultrastructural mitochondria abnormalities. J Neurol Neurosurg Psychiatr 50:1060–1062
Demaugre F, Bonnefont JP, Cepanec C, Scholte J, Saudubray JM, Leroux LP (1990) Immunoquantitative analysis of human carnitine palmitoyltransferase I and II defects. Pediatr Res 27:497–500
DiMauro S, Eastwood AB (1977) Disorders of glycogen and lipid metabolism, in Griggs RC, Moxley RT (eds) Advances in neurology, vol 17. Raven, New York, pp 123–142
DiMauro S, Melis-DiMauro PM (1973) Muscle carnitine palmitoyltransferase deficiency and myoglobinuria. Science 182:929–930
DiDonato S, Castiglione A, Rimoldi M, Cornelio F, Vendemia F, Cardace G, Bertagnolio B (1981) Heterogeneity of carnitine palmitoyltransferase deficiency. J Neurol Sci 50:207–215
Dupond JL, Mousson B, Guerber F, Humbert P, Maire I, Gibey R (1988) Rhabdomyolyse récidivante et déficit en carnitine palmityltransférase. Preuve de la responsibilité d'un mutant chez 2 frères. Presse Méd 17:2187–2190
Finocchiaro G, Taroni F, Rocchi M, Martin AL, Colombo I, Torri Tarelli G, DiDonato S (1991) cDNA cloning, sequence analysis, and chromosomal localization of the gene for human carnitine palmitoyltransferase. Proc Natl Acad Sci USA 88:661–665
Gieron MA, Korthals JK (1987) Carnitine palmitoyl-transferase deficiency with permanent weakness. Pediatr Neurol 3:51–53
Heier MS, Dietrichson P, Landaas S (1986) Familial combined deficiency of muscle carnitine and carnitine palmitoyl-transferase (CPT). Acta Neurol Scand 74:479–485
Herman J, Nadler HL (1977) Recurrent myoglobinuria and muscle carnitine palmitoyltransferase deficiency. J Pediatr 91:247–250
Hostetler KY, Hoppel CL, Romine JS, Sipe JC, Gross SR, Higginbottom PA (1978) Partial deficiency of carnitine palmitoyltransferase with normal ketone production. N Engl J Med 298:553–557
Hostetler KY, Yazaki PY (1980) Deficiency of carnitine palmitoyltransferase in transformed lymphoblasts from a patient having a deficiency of carnitine palmitoyltransferase in skeletal muscle. Biochem Biophys Res Comm 94:270–277
Ionasescu V, Hug G, Hoppel C (1980) Combined partial deficiency of muscle carnitine palmitoyltransferase and carnitine with autosomal dominant inheritance. J Neurol Neurosurg Psychiatr 43:679–682
Jennekens FGI, Scholte HR, Stinis JT, Luyt-Houwen IEM (1981) Carnitine palmitoyltransferase deficiency: variations in clinical expression, differences between CPT I and II and mode of inheritance. In: Bush HFM, Jennekens FGI, Scholte HR (eds) Mitochondria and musclular diseases. Mefar, Beetsterzwaag, pp 213–218
Kieval RI, Sotrel A, Weinblatt ME (1989) Chronic myopathy with a partial deficiency of the carnitine palmitoyltransferase enzyme. Arch Neurol 46:575–576
Layzer RB, Havel RJ, McIlroy MB (1980) Partial deficiency of-carnitine palmitoyltransferase: physiologic and biochemical consequences. Neurology 30:627–633
Lilienthal JL, Zierler KL, Folk BP, Buka R, Riley MJ (1950) A reference base and system for analysis of muscle constituents. J Biol Chem 182:501–508
Lowry OH, Rosebrough NJ, Farr AL and Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Meola G, Bresolin N, Rimoldi M, Velicogna M, Fortunato F, Scarlato G (1987) Recessive carnitine palmitoyltransferase deficiency: biochemical studies in tissue cultures and platelets. J Neurol 235:74–79
Mongini T, Doriguzzi C, Palmucci L, Chiadò-Piat L, Maniscalo M, Schiffer D (1991) Myoglobinuria and carnitine palmitoyltransferase deficiency in father and son. J Neurol 238:323–324
Moses GC, Henderson AR (1987) Increased serum lactate dehydrogenase isoenzyme 1 and “flipped” LD-1/LD-2 ratio in myopathy associated with partial carnitine palmitoyltransferase deficiency. Clin Chem 33:2111–2113
Murthy MSR, Pande SV (1990) Characterization of a solubilized malonyl-CoA-sensitive carnitine palmitoyltransferase from the mitochondrial outer membrane as a protein distinct from the malonyl-CoA-insensitive carnitine palmitoyltransferase of the inner membrane. Biochem J 268:599–604
Patten BM, Wood JM, Harati YD, Hefferan P, Howell RR (1979) Familial recurrent rhabdomyolysis due to carnitine palmitoyltransferase deficiency. Am J Med 67:167–171
Reuschenbach C, Zierz S (1988) Mutant carnitine palmitoyltransferase deficiency associated with myoadenylate deaminase deficiency in skeletal muscle. J Pediatr 112:600–603
Reza MJ, Kar NC, Pearson CM, Kark RA (1978) Recurrent myoglobinuria due to muscle carnitine palmitoyltransferase deficiency. Ann Intern Med 88:610–615
Richards EW, Hamm MW Otto DA (1991) The effect of palmitoyl-CoA binding to albumin on the apparent kinetic behaviour of carnitine palmitoyltransferase I. Biochem Biophys Acta 1076:23–28
Ross NS, Hoppel CL (1987) Partial muscle carnitine palmitoyltransferase-A deficiency: rhabdomyolysis associated with transiently decreased muscle carnitine content after ibuprofen therapy. JAMA 257:62–65
Scholte HR, Jennekens FGI, Bouvy JJBJ (1979) Carnitine palmitoyltransferase II deficiency with normal carnitine palmitoyltransferase I in skeletal muscle and leucocytes. J Neurol Sci 40:39–51
Schröder JP, Mau W, Schumacher S, Zierz S (1990) Abnorme Regulation der Carnitin Palmitoyl-Transferase bei eineiigen Zwillingen als Ursache einer Rhabdomyolyse. Dtsch Med Wochenschr 115:337–339
Singh R, Shepherd IM, Derrick JP, Ramsay RR, Sherratt HSA, Turnbull DM (1988) A case of carnitine palmitoyltransferase II deficiency in human skeletal muscle. FEBS Lett 241:126–130
Taroni F, Verderio E, Fiorucci S, Cavadini P, Finocchiaro G, Uziel G, Lamantea E, Gellera C, DiDonato S (1992) Molecular characterization of inherited carnitine palmitoyltransferase II deficiency. Proc Natl Acad Sci USA 89:8429–8433
Trevisan CP, Angelini C, Freddo L, Isaya G, Martinuzzi A (1984) Myoglobinuria and carnitine palmitoyltransferase ( CPT) deficiency: studies with malonyl-CoA suggest absence of only CPT II. Neurology 34:353–356
Trevisan CP, Isaya G, Angelini C (1987) Exercise-induced recurrent myoglobinuria: defective activity of inner carnitine palmitoyltransferase in muscle mitochondria of two patients. Neurology 37:1184–1188
Trevisan CP, Angelini C, Fiorellini LA, Isaya G, Zachello G (1986) Malonyl-CoA abnormal inhibition of residual enzyme activity in carnitine palmitoyltransferase deficiency. Eur Neurol 25:309–316
Trevisan CP, Angelini C, Caneve G, Corrazzo R (1990) Inhibition of carnitine palmitoyltransferase (CPT) and carrier detection of CPT deficiency. J Neurol Sci 98 [Suppl]: 274
Woeltje KF, Esser V, Weis BC, Cox WF, Schroeder JG, Liao ST, Foster DW, McGarry JD (1990) Inter-tissue and interspecies characteristics of the mitochondrial carnitine palmitoyltransferase enzyme system. J Biol Chem 265:10714–10719
Woldegiorgis G, Bremer J, Shrago E (1985) Substrate inhibition of carnitine palmitoyltransferase by palmitoyl-CoA and activation by phospholipids and proteins. Biochim Biophys Acta 837:135–140
Zierz S (1993) Carnitine palmitoyltransferase deficiency. In: Engel AG, Franzini-Armstrong C (eds) Myology, 2nd edn. McGraw-Hill, New York
Zierz S, Engel AG (1985) Regulatory properties of a mutant carnitine palmitoyltransferase in human skeletal muscle. Eur J Biochem 149:207–214
Zierz S, Engel AG (1987) Different sites of inhibition of carnitine palmitoyltransferase by malonyl-CoA, and by acetyl-CoA and CoA, in human skeletal muscle. Biochem J 245:205–209
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zierz, S., Mundegar, R.R. & Jerusalem, F. Biochemical evidence for heterozygosity in muscular carnitine palmitoyltransferase deficiency. Clin Investig 72, 77–83 (1993). https://doi.org/10.1007/BF00231124
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00231124