Distinct segregation of the pathogenic m.5667G>A mitochondrial tRNAAsn mutation in extraocular and skeletal muscle in chronic progressive external ophthalmoplegia.

Abstract

Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNAAsn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ± 4.6%; skeletal muscle 87.8 %± 5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ± 3%; skeletal muscle 74% ± 4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO.

• Authors: Elena Schlapakow, Viktoriya Peeva, Gábor Zsurka, Monika Jeub, Bettina Wabbels, Cornelia Kornblum, Wolfram S Kunz
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 29 Issue 5 Pg. 358-367 (05 2019) ISSN: 1873-2364 [Electronic] England
• PMID: 30962064 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Electron Transport Chain Complex Proteins
• RNA, Transfer, Asn
• Electron Transport Complex IV

Topics

• Adolescent
• Cytochrome-c Oxidase Deficiency
• Electron Transport Chain Complex Proteins (metabolism)
• Electron Transport Complex IV (metabolism)
• Humans
• Immunohistochemistry
• Male
• Muscle Fibers, Skeletal (metabolism, pathology)
• Muscle, Skeletal
• Oculomotor Muscles (metabolism, pathology)
• Ophthalmoplegia, Chronic Progressive External (genetics, metabolism, pathology)
• Quadriceps Muscle (metabolism, pathology)
• RNA, Transfer, Asn (genetics)