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European Journal of Pediatrics

, Volume 152, Issue 8, pp 665–670 | Cite as

Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria

  • H. Ibel
  • W. Endres
  • H. -B. Hadorn
  • T. Deufel
  • I. Paetzke
  • M. Duran
  • N. G. Kennaway
  • K. M. Gibson
Metabolic Diseases

Abstract

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.

Key words

3-Methylglutaconic aciduria 3-Methylglutaconyl-CoA hydratase Cardiac hypertrophy Complex I Cytochrome c oxidase 

Abbreviations

HMG

3-hydroxy-3-methylglutaric

HMG-CoA

3-hydroxy-3-methylglutaryl-CoA

3-MCR-CoA

3-methylcrotonyl-CoA

3-MGC

3-methylglutaconic

3-MGC-CoA

3-methylglutaconyl-CoA

3-MG

3-methylglutaric

M-5-P

mevalonate-5-pyrophosphate

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References

  1. 1.
    Bakkeren JAJM, Sengers RCA, Ruitenbeek W, trijbels JMF (1992) 3-Methylglutaconic aciduria in a patient with a disturbed mitochondrial energy metabolism. Eur J Pediatr 151:313Google Scholar
  2. 2.
    Bertini E, Vici CD, Burlina AB, Mazziotta MMR, Bartuli A, Ricci E, Manfredi G, Mirabella M, Silvestri G, Servidei S, DiMauro S (1992) Infantile mitochondrial myopathy and cardiomyopathy with variable intrafamilial phenotype. Neurology 42 [Suppl] 3:267Google Scholar
  3. 3.
    Bookelman H, Trijbels JMF, Sengers RCA, Janssen AJM (1978) Measurement of cytochromes in human skeletal muscle mitochondria, isolated from fresh and frozen stored muscle specimens. Biochem Med 19:366–373Google Scholar
  4. 4.
    Brown MS, Dana SE, Goldstein JL (1973) Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts by lipoproteins. Proc Nat Acad Sci USA 70:2162–2166Google Scholar
  5. 5.
    Chitayat D, Chemke J, Gibson KM, Mammer OA, Kronick JB, McGill JJ, Rosenblatt B, Sweetman L, Scriver CR (1992) 3-Methylglutaconic aciduria: a marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a ‘new’ type (‘type 4’). J Inherited Metab Dis 15:204–212Google Scholar
  6. 6.
    De Groot CJ, Beaufort-Krol GCM, Scholte HR, Luyt-Houwen IEM, Arts WF, Blom W (1987) An X-linked [cardio]myopathy and granulocytopenia, with a low succinate cytochrome-C-reductase and cytochrome-C-oxidase activity in skeletal muscle. Proceedings of the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, New Castle, Great BritainGoogle Scholar
  7. 7.
    DiMauro S, Zeviani M, Rizzuto R, Lombes A, Nakase H, Bonilla E, Miranda A, Schon E (1988) Molecular defects in cytochrome oxidase in mitochondrial diseases. J Bioenerg Biomembr 20:353–364Google Scholar
  8. 8.
    Duran M, Beemer FA, Tibosch AS, Bruinvis L, Ketting D, Wadman SK (1982) Inherited 3-methylglutaconic aciduria in two brothers — another defect of leucine metabolism. J Pediatr 101:551–554Google Scholar
  9. 9.
    Engel AG, Rebouche CJ (1984) Carnitine metabolism and inborn errors. J Inherited Metab Dis 7 [Suppl] 1:38–43Google Scholar
  10. 10.
    Fischer JC, Ruitenbeek W, Berden JA, et al (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36Google Scholar
  11. 11.
    Fischer JC, Ruitenbeek W, Stadhouders AM, Trijbels JMF, et al (1985) Investigation of mitochondrial metabolism in small human skeletal muscle biopsy specimens. Improvement of preparation procedure. Clin Chim Acta 145:89–100Google Scholar
  12. 12.
    Fischer JC, Ruitenbeek W, Trijbels JMF, et al (1986) Estimation of NADH oxidation in human skeletal muscle mitochondria. Clin Chim Acta 155:263–274Google Scholar
  13. 13.
    Gibson KM, Hoffmann G, Nyhan WL, Sweetman L, Brandt IK, Wappner RS, Bader PI (1987) Mevalonic aciduria: family studies in mevalonate kinase deficiency, an inborn error of cholesterol biosynthesis. J Inherited Metab Dis 10 [Suppl] 2:282–285Google Scholar
  14. 14.
    Gibson KM, Hoffmann G, Nyhan WL, Sweetman L, Berger R, le Coultre R, Smit GPA (1988) Mevalonate kinase deficiency in a child with cerebellar ataxia, hypotonia, and mevalonic aciduria. Eur J Pediatr 148:250–252Google Scholar
  15. 15.
    Gibson KM, Breuer J, Kaiser K, Nyhan WL, McCoy EE, Ferreira P, Greene CL, Blitzer MG, Shapira E, Reverte F, Conde C, Bagnell P, Cole DEC (1988) 3-Hydroxy-3-methylglutaryl coenzyme A lyase deficiency: report on five new patients. J Inherited Metab Dis 11:76–87Google Scholar
  16. 16.
    Gibson KM, Sherwood WG, Hoffmann GF, Stumpf DA, Dianzani I, Schutgens RBH, Barth PG, Weismann U, Bachmann C, Schrynemackers-Pitance P, Verloes A, Narisawa K, Mino M, Ohya N, Kelley RI (1991) Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria. J Pediatr 118:885–890Google Scholar
  17. 17.
    Gilbert EF (1985) Carnitine deficiency. Pathology 17:161–169Google Scholar
  18. 18.
    Gitzelmann R, Steinmann B, Niederwieser A, Fanconi S, Suormala T, Baumgartner R (1987) Isolated (biotin-resistant) 3-methylcrotonyl-CoA carboxylase deficiency presenting at age 20 months with sopor, hypoglycemia and ketoacidosis. J Inherited Metab Dis 10 [Suppl] 2:290–292Google Scholar
  19. 19.
    Kelley RI, Cheatham JP, Morton DH, Clark BJ, Nigro MA, Powell BR, Sherwood GW, Sladky JT, Swisher WP (1991) X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr 119:738–747Google Scholar
  20. 20.
    Kennaway NG, Wagner ML, Capaldi RA, Takamiya S, Yanamura W, Ruitenbeek W, Sengers RCA, Trijbels JMF (1987) Combined deficiencies of complexes III and IV of the respiratory chain, involving both nuclear and mitochondrial gene products, in skeletal muscle of a patient with lactic acidosis. J Inherited Metab Dis 10 [Suppl] 2:247–251Google Scholar
  21. 21.
    Kennaway NG, Carrero-Valenzuela RD, Ewart G, Balan VK, Lightowlers R, Zhang Y-Z, Powell BR, Capaldi RA, Buist NRM (1990) Isoforms of mammalian cytochrome c oxidase: correlation with human cytochrome c oxidase deficiency. Pediatr Res 28:529–535Google Scholar
  22. 22.
    Kohlschütter A, Hausdorf G (1986) Primary (genetic) cardiomyopathies in infancy. A survey of possible disorders and guidelines for diagnosis. Eur J Pediatr 145:454–459Google Scholar
  23. 23.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  24. 24.
    Moreadith RW, Batshaw ML, Ohnishi T, Kerr D, Knox B, Jackson D, Hruban R, Olson J, Reynafarje B, Lehninger AL (1984) Deficiency of the iron-sulfur clusters of mitochondrial reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis. J Clin Invest 74:685–697Google Scholar
  25. 25.
    Müller-Höcker J, Johannes A, Droste M, Kadenbach B, Pongratz D, Hübner G (1986) Fatal mitochondrial cardiomyopathy in Kearns-Sayre syndrome with deficiency of cytochrome-c-oxidase in cardiac and skeletal muscle. Virchows Arch [B] 52:353–367Google Scholar
  26. 26.
    Müller-Höcker J, Ibel H, Paetzke I, Deufel T, Endres W, Kadenbach B, Gokel JM, Hübner G (1991) Fatal infantile mitochondrial cardiomyopathy and myopathy with heterogeneous tissue expression of combined respiratory chain deficiencies. Virchows Arch [A] 419:355–362Google Scholar
  27. 27.
    Narisawa K, Gibson KM, Sweetman L, Nyhan WL, Duran M, Wadman SK (1986) Deficiency of 3-methylglutaconyl coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria. J Clin Invest 77:1148–1152Google Scholar
  28. 28.
    Nishizawa M, Tanaka K, Shinozawa K, Kuwabara T, Atsumi T, Miyatake T, Ohama E (1987) A mitochondrial encephalomyopathy with cardiomyopathy: a case revealing a defect of complex I in the respiratory chain. J Neurol Sci 78:189–201Google Scholar
  29. 29.
    Papadimitriou A, Neustein HB, DiMauro S, Stanton R, Bresolin N (1984) Histiocytoid cardiomyopathy of infancy: deficiency of reducible cytochrome b in heart mitochondria. Pediatr Res 18:1023–1028Google Scholar
  30. 30.
    Sengers RCA, Trijbels JMF, Bakkeren JAJM, Ruitenbeek W, Fischer JC, Janssen AJM, Stadhouders AM, Laak HJ ter (1984) Deficiency of cytochromes b and aa3 in muscle from a floppy infant with cytochrome oxidase deficiency. Eur J Pediatr 141:178–180Google Scholar
  31. 31.
    Sovik O, Sweetman L, Gibson KM, Nyhan WL (1984) Genetic complementation analysis of 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency in cultured fibroblasts. Am J Hum Genet 36:791–801Google Scholar
  32. 32.
    Sweetman L (1989) Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 791–819Google Scholar
  33. 33.
    Tanaka M, Nishikimi M, Suzuki H, Ozawa T, Nishizawa M, Tanaka K, Miyatake T (1986) Deficiency of subunits in heart mitochondrial NADH-ubiquinone oxidoreductase of a patient with mitochondrial encephalomyopathy and cardiomyopathy. Biochem Biophys Res Commun 140:88–93Google Scholar
  34. 34.
    Tulinius MH, Eriksson BO, Hjalmarson O, Holme E, Oldfors A (1989) Mitochondrial myopathy and cardiomyopathy in siblings. Pediatr Neurol 5:182–188Google Scholar
  35. 35.
    Wallace DC (1992) Diseases of the mitochondrial DNA. Ann Rev Biochem 61:1175–1212Google Scholar
  36. 36.
    Wharton DC, Tzagoloff A (1967) Cytochrome oxidase from beef heart mitochondria. Methods Enzymol 10:245–250Google Scholar
  37. 37.
    Wieland O, Deufel T, Paetzke-Brunner I (1985) Free and esterified carnitine colorimetric method. In: Bergmeyer HU (ed) Methods of enzymatic analysis, vol. 8. VCH Verlagsgesellschaft mbH, Weinheim, 1985, pp 481–488Google Scholar
  38. 38.
    Wysocki SJ, Haehnel R (1986) 3-Hydroxy-e-methylglutaryl coenzyme A lyase deficiency: A review. J Inherited Metab Dis 9:225–233Google Scholar
  39. 39.
    Zeviani M, Van Dyke DH, Servidei S, Bauserman SC, Bonilla E, Beaumont ET, Sharda J, VanderLaan K, DiMauro S (1986) Myopathy and fatal cardiopathy due to cytochrome c oxidase deficiency. Arch Neurol 43:1198–1202Google Scholar
  40. 40.
    Zheng X, Shoffner JM, Lott MT, Voljavec AS, Krawiecki NS, Winn K, Wallace DC (1989) Evidence in a lethal infantile mitochondrial disease for a nuclear mutation affecting respiratory complexes I and IV. Neurology 39:1203–1209Google Scholar
  41. 41.
    Zheng X, Shoffner JM, Voljavec AS, Wallace DC (1990) Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies. Biochim Biophys Acta 1019:1–10Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • H. Ibel
    • 1
  • W. Endres
    • 1
  • H. -B. Hadorn
    • 1
  • T. Deufel
    • 1
  • I. Paetzke
    • 2
  • M. Duran
    • 3
  • N. G. Kennaway
    • 4
  • K. M. Gibson
    • 5
  1. 1.University Children's HospitalMünchen 2Germany
  2. 2.Municipal Hospital München-SchwabingMünchen 40Germany
  3. 3.University Children's HospitalUtrechtThe Netherlands
  4. 4.Department of Molecular and Medical GeneticsThe Oregon Health Sciences UniversityPortlandUSA
  5. 5.Metabolic Disease CenterBaylor University Medical Center and Baylor Research InstituteDallasUSA

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