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Inborn Metabolic Diseases pp 197–209Cite as

Defects of the Respiratory Chain

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Abstract

Respiratory chain deficiencies have long been regarded as neuromuscular diseases only. However, oxidative phosphorylation (i.e. ATP synthesis by the respiratory chain) is not restricted to the neuromuscular system but proceeds in all cells that contain mitochondria (Fig. 15.1). Most non-neuromuscular organs and tissues are, therefore, also dependent upon mitochondrial energy supply. Due to the twofold genetic origin of respiratory enzymes [nuclear DNA and mitochondrial (mtDNA)], a respiratory chain deficiency can theoretically give rise to any symptom in any organ or tissue at any age and with any mode of inheritance.

The diagnosis of a respiratory chain deficiency is difficult to consider initially when only one abnormal symptom is present. In contrast, this diagnosis is easier to consider when two or more seemingly unrelated symptoms are observed. The treatment, mainly dietetic, does not markedly influence the usually unfavorable course of the disease.

Keywords

  • Leigh Syndrome
  • Progressive External Ophthalmoplegia
  • Friedreich Ataxia
  • Sideroblastic Anemia
  • Dominant Optic Atrophy

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. von Kleist-Retzow JC, Cormier-Daire V, Viot G et al (2003) Antenatal manifestations of mitochondrial respiratory chain deficiency. J Pediatr 143:208–212

    CrossRef  CAS  Google Scholar 

  2. Cormier V, Rustin P, Bonnefont JP et al (1991) Hepatic failure in neonatal onset disorders of oxidative phosphorylation. J Pediatr 119:951–954

    CrossRef  PubMed  CAS  Google Scholar 

  3. Rötig A, Cormier V, Blanche S et al (1990) Pearson’s marrow-pancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 86:1601–1608

    PubMed  Google Scholar 

  4. Rustin P, LeBidois J, Chretien D et al (1994) Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies. J Pediatr 124:224–228

    PubMed  CAS  Google Scholar 

  5. Bolhuis PA, Hensels GW, Hulsebos TJM et al (1991) Mapping of the locus for X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria (Barth syndrome) to Xq28. Am J Hum Genet 48:481–485

    PubMed  CAS  Google Scholar 

  6. Cormier-Daire V, Bonnefont JP, Rustin P et al (1994) Deletion-duplication of the mitochondrial DNA presenting as chronic diarrhea with villous atrophy. J Pediatr 124:63–70

    CrossRef  PubMed  CAS  Google Scholar 

  7. Saunier P, Chretien D, Wood C et al (1995) Cytochrome c oxidase deficiency presenting as recurrent neonatal myoglobinuria. Neuromuscul Disord 5:285–289

    CrossRef  PubMed  CAS  Google Scholar 

  8. Rötig A, Bessis JL, Romero N et al (1991) Maternally inherited duplication of the mitochondrial DNA in proximal tubulopathy with diabetes mellitus. Am J Hum Genet 50:364–370

    Google Scholar 

  9. Rötig A, Cormier V, Chatelain P et al (1993) Deletion of the mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy and deafness (DIDMOAD, Wolfram syndrome). J Clin Invest 91:1095–1098

    PubMed  Google Scholar 

  10. Hammans SR, Morgan-Hughes JA (1994) Mitochondrial myopathies: Clinical features, investigation, treatment and genetic counselling. In: Schapira AHV, DiMauro S (eds) Mitochondrial disorders in neurology. Butterworth-Enemann, Stoneham, MA, p 4974

    Google Scholar 

  11. Chabrol B, Mancini J, Chretien D et al (1994) Cytochrome c oxidase defect, fatal hepatic failure and valproate: a case report. Eur J Pediatr 153:133–135

    PubMed  CAS  Google Scholar 

  12. Delettre C, Lenaers G, Griffoin JM et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210

    CrossRef  PubMed  CAS  Google Scholar 

  13. Holt IJ, Harding AE, Petty RKH, Morgan-Hugues JA (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46:428–433

    PubMed  CAS  Google Scholar 

  14. Brandon MC, Lott MT, Nguyen KC et al (2005) MITOMAP: a human mitochondrial genome database-2004 update. Nucleic Acids Res 1:33

    Google Scholar 

  15. Zeviani M, Servidei S, Gellera C et al (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339:309–311

    CrossRef  PubMed  CAS  Google Scholar 

  16. Van Goethem G, Dermaut B, Lofgren A et al (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211–212

    CrossRef  PubMed  CAS  Google Scholar 

  17. Kaukonen J, Juselius JK, Tiranti V et al (2000) A Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782–785

    CrossRef  PubMed  CAS  Google Scholar 

  18. Spelbrink JN, Li FY, Tiranti V et al (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28:223–231

    CrossRef  PubMed  CAS  Google Scholar 

  19. Moraes CT, Shanske S, Trischler HJ et al (1991) mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 48:492–501

    PubMed  CAS  Google Scholar 

  20. Mandel H, Szargel R, Labay V et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337–341

    CrossRef  PubMed  CAS  Google Scholar 

  21. Saada A, Shaag A, Mandel H et al (2001) Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29:342–344

    CrossRef  PubMed  CAS  Google Scholar 

  22. Bione S, D’Adamo P, Maestrini E et al (1996) A novel X-linked gene, G4.5 is responsible for Barth syndrome. Nat Genet 12:385–389

    CrossRef  PubMed  CAS  Google Scholar 

  23. Schuelke M, Smeitink J, Mariman E et al (1999) Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21:260–261

    CrossRef  PubMed  CAS  Google Scholar 

  24. Loeffen J, Smeitink J, Triepels R et al (1998) The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 63:1598–1608

    CrossRef  PubMed  CAS  Google Scholar 

  25. van den Heuvel L, Ruitenbeek W, Smeets R et al (1998) Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 62:262–268

    CrossRef  PubMed  Google Scholar 

  26. Benit P, Chretien D, Kadhom N et al (2001) Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68:1344–1352

    CrossRef  PubMed  CAS  Google Scholar 

  27. Benit P, Beugnot R, Chretien D et al (2003) Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Hum Mutat 21:582–586

    CrossRef  PubMed  CAS  Google Scholar 

  28. Kirby DM, Salemi R, Sugiana C et al (2004) NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest 114:837–845

    CrossRef  PubMed  CAS  Google Scholar 

  29. Bourgeron T, Rustin P, Chretien D et al (1995) Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 11:144–149

    CrossRef  PubMed  CAS  Google Scholar 

  30. Parfait B, Chretien D, Rotig A et al (2000) Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 106(2):236–243

    CrossRef  PubMed  CAS  Google Scholar 

  31. Zhu Z, Yao J, Johns T, Fu K et al (1998) SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20:337–343

    CrossRef  PubMed  CAS  Google Scholar 

  32. Tiranti V, Hoertnagel K, Carrozzo R et al (1998) Mutation of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 63:1609–1621

    CrossRef  PubMed  CAS  Google Scholar 

  33. Valnot I, Osmond S, Gigarel N et al (2000) Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase (COX) deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67:1104–1109

    PubMed  CAS  Google Scholar 

  34. Papadopoulou LC, Sue CM, Davidson MM et al (1999) Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23:333–337

    CrossRef  PubMed  CAS  Google Scholar 

  35. Valnot I, von Kleist-Retzow JC, Barrientos A et al (2000) A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet 9:1245–1249

    CrossRef  PubMed  CAS  Google Scholar 

  36. Antonicka H, Mattman A, Carlson CG et al (2003) Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 72:101–214

    CrossRef  PubMed  CAS  Google Scholar 

  37. Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689–692

    CrossRef  PubMed  CAS  Google Scholar 

  38. Quinzii C, Naini A, Salviati L et al (2006) A mutation in para-hydroxy-benzoatepolyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78:345–349

    CrossRef  PubMed  CAS  Google Scholar 

  39. Ferrari G, Lamantea E, Donati A et al (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gamma A. Brain 128 (Pt 4):723–731

    CrossRef  PubMed  Google Scholar 

  40. Poggi-Travert F, Martin D, Billette de Villeneur T et al (1996) Metabolic intermediates in lactic acidosis: compounds, samples and interpretation. J Inherit Metab Dis 19:478–488

    CrossRef  PubMed  CAS  Google Scholar 

  41. Bonnefont JP, Chretien D, Rustin P et al (1992) 2-ketoglutarate dehydrogenase deficiency: a rare inherited defect of the Krebs cycle. J Pediatr 121:255–258

    CrossRef  PubMed  CAS  Google Scholar 

  42. Saudubray JM, Marsac C, Cathelineau C (1989) Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings. Acta Paediatr Scand 65:717–724

    Google Scholar 

  43. Estabrook RW (1967) Mitochondrial respiratory control and the polarographic measurement of ADP/O ratios. Methods Enzymol 10:41–47

    CrossRef  CAS  Google Scholar 

  44. Rustin P, Chretien D, Girard B et al (1994) Biochemical, molecular investigations in respiratory chain deficiencies. Clin Chim Acta 220:35–51

    CrossRef  Google Scholar 

  45. Bourgeron T, Chretien D, Rötig A et al (1992) Isolation and characterization of mitochondria from human B lymphoblastoid cell lines. Biochem Biophys Res Commun 186:16–23

    CrossRef  PubMed  CAS  Google Scholar 

  46. Rustin P, Chretien D, Bourgeron T et al (1991) Assessment of the mitochondrial respiratory chain. Lancet 338:60

    CrossRef  PubMed  CAS  Google Scholar 

  47. Gérard B, Bourgeron T, Chretien D et al (1992) Uridine preserves the expression of respiratory enzyme deficiencies in cultured fibroblasts. Eur J Pediatr 152:270

    CrossRef  Google Scholar 

  48. Bourgeron T, Chretien D, Rötig A et al (1993) Fate and expression of the deleted mitochondrial DNA differ between heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures. J Biol Chem 268:19369–19376

    PubMed  CAS  Google Scholar 

  49. Koga Y, Akita Y, Nishioka J et al (2005) L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64:710–712

    CrossRef  PubMed  CAS  Google Scholar 

  50. Ogasahara S, Engel AG, Frens D, Mack D (1989) Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci USA 86:2379–2382

    CrossRef  PubMed  CAS  Google Scholar 

  51. Sobreira C, Hirano M, Shanske S et al (1997) Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 48:1238–1243

    PubMed  CAS  Google Scholar 

  52. Boitier E, De goul F, Desguerre I et al (1998) A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency. J Neurol Sci 156:41–46

    CrossRef  PubMed  CAS  Google Scholar 

  53. Di Giovanni S, Mirabella M, Spinazzola A et al (2001) Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 57:515–518

    PubMed  Google Scholar 

  54. Musumeci O, Naini A, Slonim AE et al (2001) Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56:849–855

    PubMed  CAS  Google Scholar 

  55. Rötig A, Appelkvist EL, Geromel V et al (2000) Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 356:391–395

    CrossRef  PubMed  Google Scholar 

  56. Rahman S, Hargreaves I, Clayton P, Heales S (2001) Neonatal presentation of coenzyme Q10 deficiency. J Pediatr 139:456–458

    CrossRef  PubMed  CAS  Google Scholar 

  57. Leshinsky-Silver E, Levine A, Nissenkorn A et al (2003) Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency. Mol Genet Metab 79:288–293

    CrossRef  PubMed  CAS  Google Scholar 

  58. Hausse AO, Aggoun Y, Bonnet D et al (2002) Idebenone and reduced cardiac hypertrophy in Friedreich’s ataxia. Heart 87:346–349

    CrossRef  PubMed  CAS  Google Scholar 

  59. Stacpoole P, Harman EM, Curry SH et al (1983) Treatment of lactic acidosis with dichloroacetate. N Engl J Med 309:390–396

    CrossRef  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Département de Génétique Médicale, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743, Paris Cedex 15, France

    Arnold Munnich

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  1. Arnold Munnich
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Editor information

Editors and Affiliations

  1. Department of Pediatrics, University Hospital Groningen, Burgemeester Weertslaan 31, 8162 DP, Epe, The Netherlands

    John Fernandes

  2. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75043, Paris Cedex 15, France

    Jean-Marie Saudubray

  3. Metabolic Research Group, Christian de Duve Institute of Cellular Pathology, University of Louvain Medical School, Avenue Hippocrate 75-39, 1200, Brussels, Belgium

    Georges van den Berghe

  4. Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester, M27 4HA, UK

    John H. Walter

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© 2006 Springer Medizin Verlag Heidelberg

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Munnich, A. (2006). Defects of the Respiratory Chain. In: Fernandes, J., Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg . https://doi.org/10.1007/978-3-540-28785-8_15

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  • DOI: https://doi.org/10.1007/978-3-540-28785-8_15

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