Histopathological Diagnosis of Mitochondrial Myopathies – Indications and the Utility of Muscle Biopsy

Czech version

Authors: O. Souček ¹; P. Ješina ²; J. Zeman ²; M. Elleder ³; H. Hůlková ³; Z. Lukáš ¹
Authors‘ workplace: Ústav patologie LF MU a FN Brno ¹; Klinika dětského a dorostového lékařství 1. LF UK a VFN v Praze ²; Ústav dědičných a metabolických poruch 1. LF UK a VFN v Praze ³
Published in: Cesk Slov Neurol N 2011; 74/107(4): 428-436
Category: Review Article

Overview

Mitochondrial myopathies make up a complex heterogenous group of diseases characterized by mitochondrial dysfunction. Mitochondrial disorders are caused biochemically, by impairment of the oxidative phosphorylation system formed by five multi-subunit polypeptide complexes (I-V) located within the inner mitochondrial membrane, along with two electron carriers (Q10 and cytochrome c). The electron carriers and complex II are nuclear DNA-encoded, while the remaining complexes are encoded both by nuclear and mitochondrial DNA. Classification of mitochondrial disorders is rendered complicated by clinical and genetic heterogeneity. Morphological examination is based on evaluation of the general pattern of histopathological changes in a muscle biopsy, of quantitative and qualitative alteration of the mitochondria and, last but not least, on assessment of the presence/absence of ragged red fibres in relation to the cytochrome c oxidase and succinyldehydrogenase reactivity. Combined with immunohistochemistry and in situ hybridisation, this may allow assessment of the type of heredity and/or point to a disorder in a certain complex of the oxidative phosphorylation chain.

Key words:
mitochondrial myopathy – muscle biopsy – diagnosis – classification

Sources

1. DiMauro S. Mitochondrial diseases. Biochim Biophys Acta 2004, 1658(2–3): 80–88.

2. DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005, 15(4): 276–286.

3. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283(1): 1482–1488.

4. Zeviani M. Mitochondrial disorders. Brain 2004; 127 (10): 2153–2172.

5. Munnich A, Rustin P. Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 2001; 106(1): 4–17.

6. Dubowitz V, Sewry CA. Muscle biopsy. A Practical Approach. London: Saunders Elsevier 2007.

7. Bednařík J et al. Nemoci kosterního svalstva. Praha: Triton 2001.

8. Taylor RW, Schaefer AM, Barron MJ, McFarland R, Turnbull DM. The diagnosis of mitochondrial muscle disease. Neuromuscul Disord 2004, 14(4): 237–245.

9. Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Ann Neurol 1991; 29(6): 610–615.

10. Haller RG, Henriksson KG, Jorfeldt L, Hultman E, Wibom R, Sahlin K et al. Deficiency of skeletal muscle succinate dehydrogenase and aconitase: pathofysiology of exercise in a novel human muscle oxidative defect. J Clin Invest 1991; 88(4): 1197–1206.

11. Hall RE, Henriksson KG, Lewis SF, Haller RG, Kennaway NG. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency: abnormalities of several iron-sulfur proteins. J Clin Invest 1993; 92(6): 2660–2666.

12. Lindal S, Lund I, Torbergsen T, Aasly J, Mellgren SI, Borud O et al. Mitochondrial diseases and myopathies: a series of muscle biopsy specimens with ultrasctructural changes in the mitochondria. Ultrastruct Pathol 1992; 16(3): 263–275.

13. Kyriacou K, Hadjisavvas A, Zenios A, Papacharalambous R, Kyriakides T. Morphological methods in the diagnosis of mitochondrial encephalomyopathies: the role of electron microscopy. Ultrastruct Pathol 2005; 29(3–4): 169–174.

14. Carpenter S, Karpáti G. Pathology of skeletal muscle. 2nd ed. New York: Oxford University Press 2001.

15. Bourgeois JM, Tarnopolsky MA. Pathology of skeletal muscle in mitochondrial disorders. Mitochondrion 2004; 4(5–6): 441–452.

16. Rifai Z, Welle S, Kamp C, Thornton CAl. Ragged red fibers in normal aging and inflammatory myopathy. Ann Neurol 1995; 37(1): 24–29.

17. Nelson RL, Prayson RA. Mitochondrial abnormalities and inclusion body myositis: a histopathologic and ultrastructural study of 36 patients. J Surg Pathol 1997; 2: 63–68.

18. Askanas V, Engel WK. Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer’s and Parkinson’s disease brains. Acta Neuropathol 2008; 116(6): 583–595.

19. Yerroum M, Pham-Dang C, Authier FJ, Monnet I, Gherardi R, Chariot P. Cytochrome c oxidase deficiency in the muscle of patients with zidovudine myopathy is segmental and affects both mitochondrial DNA- and nuclear DNA-encoded subunits. Acta Neuropathol 2000; 100(1): 82–86.

20. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol 1984; 16(4): 481–488.

21. Andreu AL, Hanna MG, Reichmann H, Bruno C, Penn AS, Tanji K et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999; 341(14): 1037–1044.

22. Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CM, Jay C et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999; 45(6): 820–823.

23. Horváth R, Schoser BGH, Müller-Höcker J, Völpel M, Jaksch M, Lochmüller Hl. Mutations in mt-DNA encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy. Neuromuscul Disord 2005; 15(12): 851–857.

24. Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH et al. The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 2007; 130(8): 2037–2044.

25. Carta A, Carelli V, D‘Adda T, Ross-Cisneros FN, Sadun AA. Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber‘s hereditary optic neuropathy. Br J Ophthalmol 2005; 89(7): 825–827.

26. Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 1998; 20(4): 337–343.

27. Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 1998; 63(6): 1609–1621.

28. McFarland R, Clark KM, Morris AA, Taylor RW, Macphail S, Lightowlers RN et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 2002, 30(2): 145–146.

29. Taylor RW, Giordano C, Davidson MM, d‘Amati G, Bain H, Hayes CM et al. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypetrophic cardiomyopathy. J Am Coll Cardiol 2003; 41(10): 1786–1796.

30. Bresolin N, Zeviani M, Bonilla E, Miller RH, Leech RW, Shanske S et al. Fatal infantile cytochrome c oxidase deficiency: decrease of immunologically detectable enzyme in muscle. Neurology 1985; 35(6): 802–812.

31. Tritschler HJ, Bonilla E, Lombes A, Andreetta F, Servidei S, Schneyder B et al. Differential diagnosis of fatal and benign cytochrome c oxidase-deficient myopathies of infancy: an immunohistochemical approach. Neurology 1991; 41(1): 300–305.

32. DiMauro S, Lombes A, Nakase H, Mita S, Fabrizi GM, Tritschler HJ et al. Cytochrome c oxidase deficiency. Pediatr Res 1990; 28(5): 536–541.

33. Cacić M, Wilichowski E, Mejaski-Bosnjak V, Fumić K, Lujić L, Marusić Della Marina B et al. Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome. J Child Neurol 2001; 16(8): 616–619.

34. De Paepe B, Smet J, Lammens M, Seneca S, Martin JJ, De Bleecker J et al. Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects. J Clin Pathol 2009; 62(2): 172–176.