Chronic progressive external ophthalmoplegia: II. A qualitative and quantitative electronmicroscopy study of skeletal muscles

Dias-Tosta, Elza

doi:10.1590/S0004-282X1988000200005

Abstracts

This study quantifies the maior electron microscopic changes in limb muscle biopsies from 31 out of 34 patients with the syndrome of chronic progressive external ophthalmoplegia. Patients were divided into three clinical groups - A) 10 sporadic cases with muscle weakness only; B) 9 familial cases with muscle weakness only; C) 15 cases with muscle weakness and one or more of the following features: pigmentary retinopathy, cerebellar ataxia, pyramidal signs and peripheral neuropathy. Electron microscopic mitochondrial abnormalities were found in all groups (8 patients from group A, 3 from group B, 14 from group C). Quantitative measurements of certain muscle fibre constituents, using a point-counting technique, revealed decreased myofibril volume-fractions and increased volume-fractions of mitochondria, glycogen and lipid in some biopsies from each group. Mitochondrial volume-fractions correlated positively with lipid content, the proportion of type 1 fibres, and the percentage of fibres with increased oxidative enzyme activity. The three groups defined clinically showed no significant differences in terms of the relative proportions of these measured constituents.

Trata-se de estudo quantitativo das principais alterações encontradas em microscopia eletrônica de biópsia de músculos somáticos de 31 entre 34 pacientes com síndrome de oftalmoplegia externa crônica e progressiva (OECP). Os pacientes foram divididos em três grupos clínicos - A) 10 casos esporádicos, com OECP e fraqueza muscular; B) 9 casos com história familiar positiva, OECP e fraqueza muscular; C) 15 casos com OECP, fraqueza muscular e alguns dos seguintes sintomas: retinopatia pigmentar, ataxia cerebelar, sinais piramidais e neuropatia periférica. Foram encontradas alterações em todos os grupos (8 do grupo A, três do grupo B e 14 do grupo C). As avaliações quantitativas de certos constituintes das fibras musculares, usando a técnica de contagem de pontos revelou: diminuição da fração-volumétrica de miofibrilas, aumento das frações-volumétricas de mitocôndria, glicogênio e lipídeos. As frações-volumétricas de mitocôndria correlacionam positivamente com o conteúdo lipídico, com a proporção de fibras do tipo 1 e com a percentagem de fibras com aumento da atividade enzimática oxidativa (definidas em estudo anterior). Os três grupos definidos clinicamente não mostraram diferenças significativas em termos de. proporções relativas dos constituintes analisados.

Elza Dias-Tosta

M.D., Ph.D. - Neurocytology Laboratory, National Hospital for Nervous Diseases, University of London, Queen Square, London, England

SUMMARY

This study quantifies the maior electron microscopic changes in limb muscle biopsies from 31 out of 34 patients with the syndrome of chronic progressive external ophthalmoplegia. Patients were divided into three clinical groups - A) 10 sporadic cases with muscle weakness only; B) 9 familial cases with muscle weakness only; C) 15 cases with muscle weakness and one or more of the following features: pigmentary retinopathy, cerebellar ataxia, pyramidal signs and peripheral neuropathy. Electron microscopic mitochondrial abnormalities were found in all groups (8 patients from group A, 3 from group B, 14 from group C). Quantitative measurements of certain muscle fibre constituents, using a point-counting technique, revealed decreased myofibril volume-fractions and increased volume-fractions of mitochondria, glycogen and lipid in some biopsies from each group. Mitochondrial volume-fractions correlated positively with lipid content, the proportion of type 1 fibres, and the percentage of fibres with increased oxidative enzyme activity. The three groups defined clinically showed no significant differences in terms of the relative proportions of these measured constituents.

RESUMO

Trata-se de estudo quantitativo das principais alterações encontradas em microscopia eletrônica de biópsia de músculos somáticos de 31 entre 34 pacientes com síndrome de oftalmoplegia externa crônica e progressiva (OECP). Os pacientes foram divididos em três grupos clínicos - A) 10 casos esporádicos, com OECP e fraqueza muscular; B) 9 casos com história familiar positiva, OECP e fraqueza muscular; C) 15 casos com OECP, fraqueza muscular e alguns dos seguintes sintomas: retinopatia pigmentar, ataxia cerebelar, sinais piramidais e neuropatia periférica. Foram encontradas alterações em todos os grupos (8 do grupo A, três do grupo B e 14 do grupo C).

As avaliações quantitativas de certos constituintes das fibras musculares, usando a técnica de contagem de pontos revelou: diminuição da fração-volumétrica de miofibrilas, aumento das frações-volumétricas de mitocôndria, glicogênio e lipídeos. As frações-volumétricas de mitocôndria correlacionam positivamente com o conteúdo lipídico, com a proporção de fibras do tipo 1 e com a percentagem de fibras com aumento da atividade enzimática oxidativa (definidas em estudo anterior). Os três grupos definidos clinicamente não mostraram diferenças significativas em termos de. proporções relativas dos constituintes analisados.

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Aknowledgements - Grateful aknowledgement is made to Dr. D.N. Landon and Dr. J.A. Morgan-Hughes for collaboration in this study with their laboratory facilities and helpful discussion. I am grateful to Miss E. Paul for her help with the statistics analysis, to Mr. B. Young and Miss L. Collins for excelent technical assistance. I also thank the physicians of the National Hospital for Nervous Diseases who allowed me to study patients under their care. The author was supported during preparation of this work by the Brazilian Government.

Unidade de Neurologia, Hospital de Base do Distrito Federal - 10000 Brasília DF - Brasil.

1. Afifi AK, Ibrahim MZM, Bergman RA, Haydar NA, Mire J, Bahut N, Kaylani F - Morphologic features of hypermetabolic mitochondrial disease: a light microscopic, histochemical and electronmicroscopic study. J Neurol Sci 15: 271, 1972.
2. Bastiaensen LAK, Joosten EMG, de Rooij JAM, Hommes OR, Stadhouders AM, Jaspar HHJ, Veerkamp JH, Bookelman H, van Hinsbergh VWM - Ophthalmoplegia-plus, a real nosological entity. Acta Neurol Scand 58: 9, 1978.
3. Berenberg RA, Pellock JM, Di Mauro S, Schottand DL, Bonilla E, Eastwood A, Hays A, Vicale CT, Behren M, Chutorian A, Rowland LP - Lumping or splitting? «Ophthalmoplegia-plus» or Kearns-Sayre. syndrome? Ann Neurol 1: 37, 1977.
4. Bosh EP, Gowans JDC, Munsat J - Inflammatory myopathy in oculopharyngeal dystrophy. Muscle Nerve 2: 73, 1979.
5. Casanova G, Jerusalem F - Myopathology of myotonic dystrophy: a morphometric study. Acta Neuropathol (Berlin) 45: 231, 1979.
6. Castaigne P, Lhermitte F, Escourolle R, Chain F, Fardeau M, Hauw JJ, Curet J, Flavigny C - Etude anatomo-clinique d'une observation d' «ophthalmoplegia-plus» avec analyse des lésions musculaires, nerveuses centrales, oculaires, myocardiques et thyroïdiennes. Rev Neurol 133: 369, 1977.
7. Coleman RF, Nienhuis AW, Brown WJ, Munsat TL, Pearson CM - New myopathy with mitochondrial enzyme hyperactivity. JAMA 199 :118, 1967.
8. Cullen MJ, Weightman D. - The ultrastructure of normal human muscle in relations of fibre type. J Neurol Sci 25: 43, 1975.
9. Di Donato S, Cornelio F, Balestrini MR, Bertagnolio B, Peluchetti D - Mitochondria - lipid-glycogen myopathy, hiperlactacidemia and carnitine deficiency. Neurology 28: 1110, 1978.
10. Di Mauro S, Bonilla E, Lee CP, Schotland DL, Scarpa A, Conn H, Chance B. - Luft's disease: further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27: 217, 1976.
11. Di Mauro S, Bonilla E, Zeviani M, Nakagawa M, De Vivo DC - Mitochondrial myopathies. Ann Neurol 17: 521, 1985.
12. Dias-Tosta E. - Chronic progressive external ophthalmoplegia: I. A quantitative histo-chemical study of skeletal muscles. Arq Neuro-Psiquiat (São Paulo) 46: 133, 1988.
13. Eisenberg B, Kuda A, Peter JB - Stereological analysis of mammalian skeletal muscle: 1. Soleus muscle of the adult guinea pig. J Cell Biol 60: 732, 1974.
14. Ernster L, Ikkos D, Luft R. - Enzymic activities of human skeletal muscle mitochondria: a tool in clinical metabolic research. Nature 184: 1851, 1959.
15. Haydar NA, Conn HL, Afifi A, Wakid N, Bailas S, Faway K - Severe hypermetabolism with primary abnormality of skeletal muscle mitochondria. Ann Int Med 74: 548, 1971.
16. Hoppeler H, Lüthi P, Claassen H, Weibel ER, Howald H. - The ultrastructure of the normal human skeletal muscle. Pflügers Arch 344: 217, 1973.
17. Jankowicz E, Berger H, Kurasz S, Winogrodzka W, Elgasz L - Familial progressive external ophthalmoplegia with abnormal muscle mitochondria. Europ Neurol 15: 318, 1977.
18. Jerusalem F, Engel AG, Peterson HA - Human muscle fibre fine structure: morphometric data on controls. Neurology 25: 127, 1975.
19. Jerusalem F, Rakusa M, Engel AG, MacDonald RD - Morphometric analysis of skeletal muscle capillary ultrastructure in inflammatory myopathies. J Neurol Sci 23:391, 1974.
20. Julien J, Vital C, Vallat JM, Vallat M, De Blanc M - Oculopharyngeal muscular dystrophy: a case with abnormal mitochondria and «fingerprint» inclusions. J Neurol Sci 21: 165, 1974.
21. Kamieniecka Z - Myopathies with abnormal mitochondria: a clinical histological and electrophysiological study. Acta Neurol Scand 55: 57, 1976.
22. Kaminiecka Z, Schmalbruch H - Neuromuscular disorders with abnormal muscle mitochondria. Int Rev Cytol 65: 321, 1980.
23. Kark RAP, Rodriguez-Budelli M - The spectrum of ataxic syndromes due to lipoamide dehydrogenase deficiency. Neurology 27: 359, 1977.
24. Kark RAP, Rodriguez-Budelli M - Pyruvate dehydrogenase deficiency in spinocerebellar degeneration. Neurology 29: 126, 1979.
25. Kark RAP, Rodriguez-Budelli M - Clinical correlations of partial deficiency of lipoamide dehydrogenase. Neurology 29: 1006, 1979.
26. Lambert CD, Fairfax AJ - Neurological associations of chronic heart block. J Neurol Neurosurg Psychiat 39: 571, 1976.
27. Leveille AS, Newell FW - Autosonal dominant Kearns-Sayre syndrome. Ophthalmol 87: 99, 1980.
28. Luft R, Ikkos D, Palmieri G, Ernster L, Afzelins B - A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical and morphological study. J Clin Inv 41: 1776, 1962.
29. Martin JJR, Centerick CM, Mercelis RJ - Nuclear inclusions in oculopharyngeal muscular dystrophy. Muscle Nerve 5: 735, 1982.
30. Mitsumoto H, Aprille JR, Wray S, Nemni R, Bradley WG - Chronic progressive external ophthalmoplegia (CPEO): clinical, morphologic and biochemical studies. Neurology 33: 452, 1983.
31. Monens L, Gabreels F, Willems JL - A metabolic myopathy associated with chronic lactic acidemia, growth failure and nerve deafness. J Pediatr 86: 983, 1975.
32. Morgan-Hughes JA - Mitochondrial myopathies. In Mastaglia FL, Walton JN (eds): Skeletal Muscle Pathology. Churchill Livingstone, London, 1982, pg 309.
33. Morgan-Hughes JA, Darveniza P, Kahn SN, Landon DN, Sherrat RM, Land JM, Clark JB - A mitochondrial myopathy characterized by a deficiency in reducible cytochrome b. Brain 100: 617, 1977.
34. Morgan-Hughes JA, Darveniza P, Landon DN, Land JM, Clark JB - A mitochondrial myopathy with a deficiency of respiratory chain NaDH-CoQ reductase activity. J Neurol Sci 43: 27, 1979.
35. Morgan-Hughes JA, Mair WGP - Atypical muscle mitochondria in oculo-skeletal myopathy. Brain 96 :215, 1973.
36. Neville HE, Brooke MH - Muscle biopsy in the diagnosis of oculopharyngeal myopathy. J Neuropathol Exp Neurol 33: 193, 1974.
37. Ogata T, Murata F - Cytological features of three fibre types in human striated muscle. Tohoku J Exp Med 99: 225, 1969.
38. Palmucci L, Bertolotto A, Cavicchioli D, Monga G, Schieffer D - Sporadic oculopharyngeal myopathy with abnormal mitochondria. Acta Neurol Belg 78: 373, 1978.
39. Payne CM, Sterns LZ, Curless RG, Hannapel LK - Ultrastructural fibre typing in normal and diseased human muscle. J Neurol Sci 25: 99, 1975.
40. Pellegrini G, Valli G, Sergi P, Moggio M, Scarlato G - Ophthalmoplegia-plus: a multisystem disorder of unknown etiopathogenesis. Ital J Neurol Sci 2: 85, 1980.
41. Probst A, Tackmann W, Stoeckli HR, Jerusalem F, Ulrich J - Evidence for a chronic axonal atrophy in oculopharyngeal «muscular dystrophy». Acta Neuropathol 57: 209, 1982.
42. Shafiq SA, Gorycki MA, Goldstone L, Milhorat AT - Fine structure of fibre types in normal human muscle. Anat Rec 156: 283, 1966.
43. Schnitzler ER, Robertson WC - Familial Kearns-Sayre syndrome. Neurology 29: 1172, 1979.
44. Tomé FMS, Fardeau M - Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuro-pathologica 49: 85, 1980.
45. van Biervliet JPGM, Bruinvis L, Ketting D, De Bree PK, van der Heiden C, Wadman SK, Willems JL, Bookelman H, van Haelst V, Monnens AH - Hereditary mitochondrial myopathy with lactic acidemia, a De Toni-Fanconi-Debré syndrome and a defective respiratory chain in voluntary striated muscles. Pediatr Res 11: 1088, 1977.
46. Vracko R - Skeletal muscle capillaries in diabetics: a quantitative, analysis. Circulation 41: 271, 1970.
47. Willems JD, Monnens LAH, Trijbels JMF, Veerkamp JH, Meyer AEFH, van Dam K, van Haelst V - Leigh's encephalomyelopathy in a patient with cytochrome C oxidase deficiency in muscle tissue. Pediatrics 60: 850, 1977.

Chronic progressive external ophthalmoplegia: II. A qualitative and quantitative electronmicroscopy study of skeletal muscles

Oftalmoplegia externa crônica progressiva: II. Estudo qualitativo e quantitativo por microscopia eletrônica de músculos esqueléticos

Publication Dates

Publication in this collection
21 June 2011
Date of issue
June 1988

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Afifi AK, Ibrahim MZM, Bergman RA, Haydar NA, Mire J, Bahut N, Kaylani F - Morphologic features of hypermetabolic mitochondrial disease: a light microscopic, histochemical and electronmicroscopic study. J Neurol Sci 15: 271, 1972.

[2] 2. Bastiaensen LAK, Joosten EMG, de Rooij JAM, Hommes OR, Stadhouders AM, Jaspar HHJ, Veerkamp JH, Bookelman H, van Hinsbergh VWM - Ophthalmoplegia-plus, a real nosological entity. Acta Neurol Scand 58: 9, 1978.

[3] 3. Berenberg RA, Pellock JM, Di Mauro S, Schottand DL, Bonilla E, Eastwood A, Hays A, Vicale CT, Behren M, Chutorian A, Rowland LP - Lumping or splitting? «Ophthalmoplegia-plus» or Kearns-Sayre. syndrome? Ann Neurol 1: 37, 1977.

[4] 4. Bosh EP, Gowans JDC, Munsat J - Inflammatory myopathy in oculopharyngeal dystrophy. Muscle Nerve 2: 73, 1979.

[5] 5. Casanova G, Jerusalem F - Myopathology of myotonic dystrophy: a morphometric study. Acta Neuropathol (Berlin) 45: 231, 1979.

[6] 6. Castaigne P, Lhermitte F, Escourolle R, Chain F, Fardeau M, Hauw JJ, Curet J, Flavigny C - Etude anatomo-clinique d'une observation d' «ophthalmoplegia-plus» avec analyse des lésions musculaires, nerveuses centrales, oculaires, myocardiques et thyroïdiennes. Rev Neurol 133: 369, 1977.

[7] 7. Coleman RF, Nienhuis AW, Brown WJ, Munsat TL, Pearson CM - New myopathy with mitochondrial enzyme hyperactivity. JAMA 199 :118, 1967.

[8] 8. Cullen MJ, Weightman D. - The ultrastructure of normal human muscle in relations of fibre type. J Neurol Sci 25: 43, 1975.

[9] 9. Di Donato S, Cornelio F, Balestrini MR, Bertagnolio B, Peluchetti D - Mitochondria - lipid-glycogen myopathy, hiperlactacidemia and carnitine deficiency. Neurology 28: 1110, 1978.

[10] 10. Di Mauro S, Bonilla E, Lee CP, Schotland DL, Scarpa A, Conn H, Chance B. - Luft's disease: further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27: 217, 1976.

[11] 11. Di Mauro S, Bonilla E, Zeviani M, Nakagawa M, De Vivo DC - Mitochondrial myopathies. Ann Neurol 17: 521, 1985.

[12] 12. Dias-Tosta E. - Chronic progressive external ophthalmoplegia: I. A quantitative histo-chemical study of skeletal muscles. Arq Neuro-Psiquiat (São Paulo) 46: 133, 1988.

[13] 13. Eisenberg B, Kuda A, Peter JB - Stereological analysis of mammalian skeletal muscle: 1. Soleus muscle of the adult guinea pig. J Cell Biol 60: 732, 1974.

[14] 14. Ernster L, Ikkos D, Luft R. - Enzymic activities of human skeletal muscle mitochondria: a tool in clinical metabolic research. Nature 184: 1851, 1959.

[15] 15. Haydar NA, Conn HL, Afifi A, Wakid N, Bailas S, Faway K - Severe hypermetabolism with primary abnormality of skeletal muscle mitochondria. Ann Int Med 74: 548, 1971.

[16] 16. Hoppeler H, Lüthi P, Claassen H, Weibel ER, Howald H. - The ultrastructure of the normal human skeletal muscle. Pflügers Arch 344: 217, 1973.

[17] 17. Jankowicz E, Berger H, Kurasz S, Winogrodzka W, Elgasz L - Familial progressive external ophthalmoplegia with abnormal muscle mitochondria. Europ Neurol 15: 318, 1977.

[18] 18. Jerusalem F, Engel AG, Peterson HA - Human muscle fibre fine structure: morphometric data on controls. Neurology 25: 127, 1975.

[19] 19. Jerusalem F, Rakusa M, Engel AG, MacDonald RD - Morphometric analysis of skeletal muscle capillary ultrastructure in inflammatory myopathies. J Neurol Sci 23:391, 1974.

[20] 20. Julien J, Vital C, Vallat JM, Vallat M, De Blanc M - Oculopharyngeal muscular dystrophy: a case with abnormal mitochondria and «fingerprint» inclusions. J Neurol Sci 21: 165, 1974.

[21] 21. Kamieniecka Z - Myopathies with abnormal mitochondria: a clinical histological and electrophysiological study. Acta Neurol Scand 55: 57, 1976.

[22] 22. Kaminiecka Z, Schmalbruch H - Neuromuscular disorders with abnormal muscle mitochondria. Int Rev Cytol 65: 321, 1980.

[23] 23. Kark RAP, Rodriguez-Budelli M - The spectrum of ataxic syndromes due to lipoamide dehydrogenase deficiency. Neurology 27: 359, 1977.

[24] 24. Kark RAP, Rodriguez-Budelli M - Pyruvate dehydrogenase deficiency in spinocerebellar degeneration. Neurology 29: 126, 1979.

[25] 25. Kark RAP, Rodriguez-Budelli M - Clinical correlations of partial deficiency of lipoamide dehydrogenase. Neurology 29: 1006, 1979.

[26] 26. Lambert CD, Fairfax AJ - Neurological associations of chronic heart block. J Neurol Neurosurg Psychiat 39: 571, 1976.

[27] 27. Leveille AS, Newell FW - Autosonal dominant Kearns-Sayre syndrome. Ophthalmol 87: 99, 1980.

[28] 28. Luft R, Ikkos D, Palmieri G, Ernster L, Afzelins B - A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical and morphological study. J Clin Inv 41: 1776, 1962.

[29] 29. Martin JJR, Centerick CM, Mercelis RJ - Nuclear inclusions in oculopharyngeal muscular dystrophy. Muscle Nerve 5: 735, 1982.

[30] 30. Mitsumoto H, Aprille JR, Wray S, Nemni R, Bradley WG - Chronic progressive external ophthalmoplegia (CPEO): clinical, morphologic and biochemical studies. Neurology 33: 452, 1983.

[31] 31. Monens L, Gabreels F, Willems JL - A metabolic myopathy associated with chronic lactic acidemia, growth failure and nerve deafness. J Pediatr 86: 983, 1975.

[32] 32. Morgan-Hughes JA - Mitochondrial myopathies. In Mastaglia FL, Walton JN (eds): Skeletal Muscle Pathology. Churchill Livingstone, London, 1982, pg 309.

[33] 33. Morgan-Hughes JA, Darveniza P, Kahn SN, Landon DN, Sherrat RM, Land JM, Clark JB - A mitochondrial myopathy characterized by a deficiency in reducible cytochrome b. Brain 100: 617, 1977.

[34] 34. Morgan-Hughes JA, Darveniza P, Landon DN, Land JM, Clark JB - A mitochondrial myopathy with a deficiency of respiratory chain NaDH-CoQ reductase activity. J Neurol Sci 43: 27, 1979.

[35] 35. Morgan-Hughes JA, Mair WGP - Atypical muscle mitochondria in oculo-skeletal myopathy. Brain 96 :215, 1973.

[36] 36. Neville HE, Brooke MH - Muscle biopsy in the diagnosis of oculopharyngeal myopathy. J Neuropathol Exp Neurol 33: 193, 1974.

[37] 37. Ogata T, Murata F - Cytological features of three fibre types in human striated muscle. Tohoku J Exp Med 99: 225, 1969.

[38] 38. Palmucci L, Bertolotto A, Cavicchioli D, Monga G, Schieffer D - Sporadic oculopharyngeal myopathy with abnormal mitochondria. Acta Neurol Belg 78: 373, 1978.

[39] 39. Payne CM, Sterns LZ, Curless RG, Hannapel LK - Ultrastructural fibre typing in normal and diseased human muscle. J Neurol Sci 25: 99, 1975.

[40] 40. Pellegrini G, Valli G, Sergi P, Moggio M, Scarlato G - Ophthalmoplegia-plus: a multisystem disorder of unknown etiopathogenesis. Ital J Neurol Sci 2: 85, 1980.

[41] 41. Probst A, Tackmann W, Stoeckli HR, Jerusalem F, Ulrich J - Evidence for a chronic axonal atrophy in oculopharyngeal «muscular dystrophy». Acta Neuropathol 57: 209, 1982.

[42] 42. Shafiq SA, Gorycki MA, Goldstone L, Milhorat AT - Fine structure of fibre types in normal human muscle. Anat Rec 156: 283, 1966.

[43] 43. Schnitzler ER, Robertson WC - Familial Kearns-Sayre syndrome. Neurology 29: 1172, 1979.

[44] 44. Tomé FMS, Fardeau M - Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuro-pathologica 49: 85, 1980.

[45] 45. van Biervliet JPGM, Bruinvis L, Ketting D, De Bree PK, van der Heiden C, Wadman SK, Willems JL, Bookelman H, van Haelst V, Monnens AH - Hereditary mitochondrial myopathy with lactic acidemia, a De Toni-Fanconi-Debré syndrome and a defective respiratory chain in voluntary striated muscles. Pediatr Res 11: 1088, 1977.

[46] 46. Vracko R - Skeletal muscle capillaries in diabetics: a quantitative, analysis. Circulation 41: 271, 1970.

[47] 47. Willems JD, Monnens LAH, Trijbels JMF, Veerkamp JH, Meyer AEFH, van Dam K, van Haelst V - Leigh's encephalomyelopathy in a patient with cytochrome C oxidase deficiency in muscle tissue. Pediatrics 60: 850, 1977.