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Pathology of Mitochondrial Encephalomyopathies

Published online by Cambridge University Press:  02 December 2014

Harvey B. Sarnat  and
José Marín-García
Harvey B. Sarnat
Affiliation:
University of Calgary Faculty of Medicine and Alberta Children's Hospital, Calgary, Alberta, Canada
José Marín-García
Affiliation:
Molecular Cardiology and Neuromuscular Institute, Highland Park, New Jersey, USA
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Abstract:

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Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

Résumé:

RÉSUMÉ:

La biopsie musculaire est le meilleur tissu pour obtenir confirmation d’une cytopathie mitochondriale. Il existe souvent une corrélation entre les caractéristiques histochimiques et un syndrome spécifique, ce qui facilite le choix d’études biochimiques et génétiques. La présence de ragged-red fibres indique presque toujours un défaut dans les complexes respiratoires I et IV. On observe une augmentation de coloration ponctuée de lipides dans les fibres musculaires dans les syndromes de Kearns-Sayre et PEO, mais non dans les syndromes MELAS et MERRF. Un déficit total en SDH indique qu’il existe un défaut sévère du Complexe II et il existe une corrélation entre une absence totale d’activité COX dans toutes les fibres musculaires et un déficit sévère en Complexe IV ou en coenzyme Q10. La perte elective d’activité COX dans des fibres musculaires éparses, surtout si elle est accompagnée d’une forte coloration SDH dans ces mêmes fibres, est fortement en faveur d’une cytopathie mitochondriale et souvent d’une mutation importante de l’ADN mitochondrial, bien que non spécifique des maladies du Complexe IV. La concentration en glycogène peut être excessive dans les zones de ragged-red fibres. L’examen de l’ultrastructure démontre des changements morphologiques d’une cytopathie mitochondriale dans les axones et dans les cellules endothéliales ainsi que dans les myocytes. Les mitochondries axonales anormales contribuent probablement à l’atrophie musculaire neurogénique, une manifestation secondaire chronique. Des évaluations quantitatives des complexes enzymatiques de la chaîne respiratoire, utilisant la citrate synthase comme contrôle interne, confirment les impressions histochimiques ou peuvent être les seules observations en faveur d’une maladie mitochondriale. Des artefacts biologiques et techniques peuvent fournir des niveaux d’activité enzymatique faussement bas. Des mutations ponctuelles fréquentes de l’ADN mitochondrial peuvent être détecté par des études génétiques. Au niveau du cerveau, on retrouve des altérations histopathologiques caractéristiques dans les maladies mitochondriales. La biopsie cutanée est utile pour l’examen de l’ultrastructure mitochondriale des muscles lisses érecteurs des poils et des axones; les fibroblastes obtenus à partir de la peau peuvent être cultivés. Des changements mitochondriaux peuvent être observés dans plusieurs maladies non mitochondriales et peuvent également être induits par des médicaments et des toxines.

Type
Review Articles
Information
Canadian Journal of Neurological Sciences , Volume 32 , Issue 2 , May 2005 , pp. 152 - 166
Copyright
Copyright © The Canadian Journal of Neurological 2005

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