Skip to main content
SpringerLink
Log in

Muscle mitochondrial DNA in encephalomyopathy and ragged red fibres: a Southern blot analysis and literature review

  • Original Communications
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Summary

Various mitochondrial DNA abnormalities have been described in patients with encephalomyopathies. We performed Southern blot analysis of skeletal muscle mitochondrial DNA in nine adult patients with clinical features and ragged red fibres suggesting mitochondrial dysfunction. Two patients with encephalomyopathy and two with the MERRF syndrome (myoclonus epilepsy with ragged red fibres) had the normal PvuII restriction pattern of muscle mitchondrial DNA. In contrast, mitochondrial DNA deletion was observed in two of six patients with ophthalmoplegia. One suffered from typical Kearns-Sayre syndrome and the other from isolated external ophthalmoplegia. None of these patients had affected relatives. The detection of mitochondrial DNA deletion in external ophthalmoplegia and their site and size support previously reported data.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Anderson S, Bankier AT, Barrel BG, De Bruijn MHL, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJH, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465

    Google Scholar 

  2. Arts WFM, Scholte HR, Bogaard JM, Kerrebijn KE, Luyt-Houwen IEM (1983) NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Lancet II:581–582

    Google Scholar 

  3. Berenberg RA, Pellock JM, DiMauro S, Schotland DL, Bonilla E, Eastwood A, Hays A, Vicale CT, Behrens M, Chutorian A, Rowland LP (1977) Lumping or splitting? Ophthalmoplegiaplus or Kearns-Sayre syndrome? Ann Neurol 1:37–54

    Google Scholar 

  4. Berkovic SF, Carpenter S, Karpati G, Andermann F, Andermann E, Shoubridge E, Arnold D (1987) Cytochrome c oxidase deficiency: a remarkable spectrum of clinical and neuropathologic findings in a single family (abstract). Neurology 37:223

    Google Scholar 

  5. Berkovic SF, Carpenter S, Evans A, Karpati G, Shoubridge E, Andermann F, Meyer E, Tyler JL, Diksic M, Arnold D, Wolfe LS, Andermann E, Hakim AM (1989) Myoclonus epilepsy and ragged red fibers (MERRF). I. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain 112:1231–1260

    Google Scholar 

  6. Bogenhagen D, Clayton DA (1974) The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells: quantitative isolation of mitochondrial deoxyribonucleic acid. J Biol Chem 249:7991–7995

    Google Scholar 

  7. Bresolin N, Moggio M, Bet L, Gallanti A, Prelle A, Nobile-Orazio E, Adobbatti L, Ferrante C, Pellegrini G, Scarlato G (1987) Progressive cytochrome C oxidase deficiency in a case of Kearns-Sayre syndrome: morphological immunological and biochemical studies in muscle biopsies and autopsy tissues. Ann Neurol 21:564–572

    Google Scholar 

  8. Bresolin N, Ponzetto C, Moggio M, Meoloa G, Bet L, Prelle A, Geremia L, Mirata P, Scarlato G (1989) Mitochondrial DNA deletion in one familiar case presenting extrinsic ophthalmoplegia and partial CoX deficiency. Neurology 39 [Suppl 1]:257

    Google Scholar 

  9. Brown WM, George M Jr, Wilson AC (1979) Rapid evolution of animal mitochondrial DNA. Proc Natl Acad Sci USA 76:1967–1971

    Google Scholar 

  10. Byrne E, Dennet X, Trounce I (1985) Mitochondrial myopathy with respiratory failure and myoclonic epilepsy: a case report with biochemical studies. J Neurol Sci 71:273–281

    Google Scholar 

  11. Byrne E, Marzuki S, Sattayasai N, Dennet X, Trounce I (1987) Mitochondrial studies in Kearns-Sayre syndrome: normal respiratory chain function with absence of a mitochondrial translation product. Neurology 37:1530–1534

    Google Scholar 

  12. Carry MR, Ringel SP, Starcevich JM (1986) Mitochondrial morphometrics of histochemically identified human extraocular muscle fibers. Anat Rec 214:8–16

    Google Scholar 

  13. Clayton DA (1984) Transcription of the mammalian mitochondrial genome. Annu Rev Biochem 53:573–594

    Google Scholar 

  14. Deady JP, Morrel AJ, Sutton GA (1989) Recognising aponeurotic ptosis. J Neurol Neurosurg Psychiatry 52:996–998

    Google Scholar 

  15. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, De Vivo DC (1985) Mitochondrial myopathies. Ann Neurol 17:521–538

    Google Scholar 

  16. DiMauro S, Zeviani M, Servidei S, Prelle A, Miranda AF, Bonilla E, Schon EA (1986) Cytochrome oxidase deficiency: clinical and biochemical heterogeneity. Ann NY Acad Sci 488:19–32

    Google Scholar 

  17. DiMauro S, Servidei S, Zeviani M, DiRocco M, DeVivo DC, DiDonato S, Uziel G, Berry K, Hoganson G, Johnsen SD, Johnson PC (1987) Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 22:498–506

    Google Scholar 

  18. DiMauro S, Zeviani M, Servidei S, Bonilla E, Miranda AF, Prelle A, Schon EA (1988) Biochemical and molecular aspects of cytochrome c oxidase deficiency. In: DiDonato S (eds) Advances in neurology: molecular genetics of neurological and neuromuscular disease, vol 48. Raven Press, New York, pp 93–105

    Google Scholar 

  19. Drachmann DA (1975) Ophthalmoplegia plus: a classification of the disorders associated with progressive external ophthalmoplegia. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 22: System disorders and atrophies, part II. Elsevier, New York, pp 203–216

    Google Scholar 

  20. Egger J, Wilson J (1983) Mitochondrial inheritance in a mitochondrially mediated disease. N Engl J Med 309:142–146

    Google Scholar 

  21. Erickson RP (1972) Leber's optic atrophy, a possible example of maternal inheritance. Am J Hum Genet 24:348–349

    Google Scholar 

  22. Fukuhara N, Tokiguchi S, Shirakawa S, Tsubaki T (1980) Myoclonus epilepsy associated with ragged-red fibers (mitochondrial abnormalities): disease entity or syndrome? Light and electron microscopy studies of two cases and review of the literature. J Neurol Sci 47:117–133

    Google Scholar 

  23. Giles RE, Blanc H, Cann HM, Wallace DC (1980) Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 77:6715–6719

    Google Scholar 

  24. Holt IJ, Harding AE, Morgan-Hughes JA (1988) Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717–719

    Google Scholar 

  25. Holt IJ, Harding AE, Cooper JM, Schapira AHV, Toscano A, Clark JB, Morgan-Hughes JA (1989) Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol 26:699–708

    Google Scholar 

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

    Google Scholar 

  27. Johnson MA, Turnbull DM, Dick DJ, Sherratt HSA (1983) A partial deficiency of cytochrome C oxidase in chronic progressive external ophthalmoplegia. J Neurol Sci 60:31–53

    Google Scholar 

  28. Kearns TP, Sayre GP (1958) Retinis pigmentosa, external ophthalmoplegia and complete heart block. Arch Ophthalmol 60:280–289

    Google Scholar 

  29. Lestienne P, Ponsot G (1988) Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. Lancet I:885

    Google Scholar 

  30. Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet I:642–645

    Google Scholar 

  31. Lombes A, Mendell JR, Nakase H, Barohn RJ, Bonilla E, Zeviani M, Yates AJ, Omerza J, Gales TL, Nakahara K, Rizzuto R, Engel WK, DiMauro S (1989) Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann Neurol 26:20–33

    Google Scholar 

  32. Luft R, Ikkos D, Palmieri G (1962) A case of severe hypermetabolism of non thyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical and morphological study. J Clin Invest 41:1776–1804

    Google Scholar 

  33. Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Schon EA, Nakase H, Bonilla E, Werneck LC, Servidei S, Nonaka I, Koga Y, Spiro AJ, Brownell AK, Schmidt B, Schotland DL, Zupanc M, DeVivo DC, Rowland LP (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320:1293–1299

    Google Scholar 

  34. Morgan-Hughes JA (1986) Mitochondrial disease. Trends Neurosci 9:15–19

    Google Scholar 

  35. Morgan-Hughes JA, Hayes DJ, Clark JB, Landon DN, Swash M, Stark RJ, Rudge P (1982) Mitochondrial encephalomyopathies: biochemical studies in two cases revealing defects in the respiratory chain. Brain 105:553–582

    Google Scholar 

  36. Müller Höcker J, Pongratz D, Hübner G (1983) Focal deficiency of cytochrome-c-oxidase in skeletal muscle of patients with progressive external ophthalmoplegia. Virchows Arch [A] 402:61–71

    Google Scholar 

  37. Nelson I, Degoul F, Obermaier-Kusser B, Romero N, Borrone C, Marsac C, Vayssiere JL, Gerbitz K, Fardeau M, Ponsot G, Lestienne P (1989) Mapping of heteroplasmic mitochondrial DNA deletions in Kearns-Sayre syndrome. Nucleic Acids Res 17:8117–8124

    Google Scholar 

  38. Nikoskelainen EK, Hassinen IE, Paljärvi L, Lang H, Kalimo H (1984) Leber's hereditary optic neuroretinopathy, a mitochondrial disease? Lancet II:1474

    Google Scholar 

  39. Olson W, Engel WK, Walsh GO, Einaugler R (1972) Oculocraniosomatic neuromuscular disease with “ragged-red” fibers. Arch Neurol 26:193–211

    Google Scholar 

  40. Ottman R, Hauser WA, Susser M (1985) Genetic and maternal influences on susceptibility to seizures. An analytical review. Am J Epidemiol 122:923–939

    Google Scholar 

  41. Ozawa T, Yoneda M, Tanaka M, Ohno K, Sato W, Suzuki H, Nishikimi M, Yamamoto M, Nonaka I, Horai S (1988) Maternal inheritance of deleted mitochondrial DNA in a family with mitochondrial myopathy. Biochem Biophys Res Commun 154:1240–1247

    Google Scholar 

  42. Parker WD, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26:719–723

    Google Scholar 

  43. Parker WD, Oley CA, Parks JK (1989) A defect in mitochondrial electron transport activity (NADH-Coenzyme Q Oxidoreductase) in Leber's hereditary optic neuropathy. N Engl J Med 320:1331–1333

    Google Scholar 

  44. Pavlakis SG, Phillips PC, DiMauro S, DeVivo DC, Rowland LP (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol 16:481–488

    Google Scholar 

  45. Petty RK, Harding AE, Morgan-Hughes JA (1986) The clinical features of mitochondrial myopathy. Brain 109:915–938

    Google Scholar 

  46. Poulton J, Deadman ME, Gardiner RM (1989) Duplications of mitochondrial DNA in mitochondrial myopathy. Lancet I:236–239

    Google Scholar 

  47. Riggs JE, Schochet SS, Fakadej AV, Papadimitriou A, DiMauro S, Crosby TW, Gutmann L, Moxley RT (1984) Mitochondrial encephalomyopathy with decreased succinate-cytochrome C reductase activity. Neurology 34:48–53

    Google Scholar 

  48. Rivner MH, Shamsnia M, Swift TR, Trefz J, Roesel RA, Carter AL, Yanamura W, Hommes FA (1989) Kearns-Sayre syndrome and complex II deficiency. Neurology 39:693–696

    Google Scholar 

  49. Rosing HS, Hopkins LC, Wallace DC, Epstein CM, Weidenhein K (1985) Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann Neurol 17:228–237

    Google Scholar 

  50. Rötig A, Colonna M, Bonnefont JP, Blanche S, Fischer A, Saudubray JM, Munnich A (1989) Mitochondrial DNA deletion in Pearson's marrow/Pancreas syndrome. Lancet I:902–903

    Google Scholar 

  51. Rowland LP (1983) Molecular genetics, pseudogenetics, and clinical neurology. Neurology 33:1179–1195

    Google Scholar 

  52. Rowland LP, Hausmanowa-Petrusewicz I, Bardurska B, Warburton D, Nibroj-Dobosz I, DiMauro S, Pallai M, Johnson WG (1988) Kearns-Sayre syndrome in twins: lethal dominant mutation or acquired disease? Neurology 38:1399–1402

    Google Scholar 

  53. Saifuddin Noer A, Marzuki S, Trounce I, Byrne E (1988) Mitochondrial DNA deletion in encephalomyopathy. Lancet I:1253

    Google Scholar 

  54. Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson's disease. Lancet I:1269

    Google Scholar 

  55. Schnitzler ER, Robertson WC (1979) Familial Kearns-Sayre syndrome. Neurology 29:1172–1174

    Google Scholar 

  56. Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S (1989) A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science 244:346–348

    Google Scholar 

  57. Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNAlys mutation. Cell 61:931–937

    Google Scholar 

  58. Tome FMS, Fardeau M (1985) Ocular myopathies. Pathol Res Pract 180:19–27

    Google Scholar 

  59. Trounce I, Byrne E, Marzuki S (1989) Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet I:637–639

    Google Scholar 

  60. Vilkki J, Savontaus ML, Nikoskelainen EK (1989) Genetic heterogeneity in Leber hereditary optic neuropathy revealed by mitochondrial DNA polymorphism. Am J Hum Genet 45:206–211

    Google Scholar 

  61. Wallace DC, Zeng X, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM, Hopkins LC (1988) Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological and biochemical characterization of a mitochondrial DNA disease. Cell 55:601–610

    Google Scholar 

  62. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AMS, Elsas LJ, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic atrophy. Science 242:1427–1430

    Google Scholar 

  63. Yoneda M, Tsuji S, Yamauchi T, Inuzuka T, Miyatake T, Horai S, Ozawa T (1989) Mitochondrial DNA mutation in family with Leber's hereditary optic neuropathy. Lancet I:1076–1077

    Google Scholar 

  64. Zeviani M, Peterson P, Servidei S, Bonilla E, DiMauro S (1987) Benign reversible muscle cytochrome c oxidase deficiency. Arch Neurol 43:198–202

    Google Scholar 

  65. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP (1988) Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346

    Google Scholar 

  66. Zeviani M, Servidei S, Gellera C, Bertini E, DiMauro S, DiDonato S (1989) An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-Loop region. Nature 339:309–311

    Google Scholar 

  67. Zupanc ML, Moraes CT, Shanske S, DiMauro S (1989) Deletion of mitochondrial DNA in a patient with features of the Kearns-Sayre and MELAS syndromes. Ann Neurol 26:436

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Département de Neurosciences, Hôpital Henri Mondor, F-94010, Créteil, France

    C. Geny, C. Meyrignac, P. Cesaro, J. D. Degos & R. Gherardi

  2. Département de Pathologie (Neuropathologie), Hôpital Henri Mondor, F-94010, Créteil, France

    R. Gherardi

  3. INSERM U12, Hôpital Necker, F-75015, Paris, France

    V. Cormier & A. Rötig

Authors
  1. C. Geny
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Cormier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Meyrignac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Cesaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. D. Degos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Gherardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Rötig
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Geny, C., Cormier, V., Meyrignac, C. et al. Muscle mitochondrial DNA in encephalomyopathy and ragged red fibres: a Southern blot analysis and literature review. J Neurol 238, 171–176 (1991). https://doi.org/10.1007/BF00319685

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00319685

Key words

Search

Navigation