Journal
NEUROMUSCULAR DISORDERS
Volume 28, Issue 4, Pages 350-360Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2017.11.006
Keywords
CPEO; mtDNA common deletion; mt-tRNA variant (m. 7486G > A); Bioenergetic dysfunction; Translation defect
Categories
Funding
- Feder funds through Operational Competitiveness Program - COMPETE2020 [POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-000012-N2323]
- National Funds by FCT - Portuguese Science and Technology Foundation [UID/NEU/04539/2013]
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) [G0800674]
- Lily Foundation
- UK NIHR Biomedical Research Centre
- [Pest-C/SAU/LA0001/2013e2014]
- [FCT-SFRH/BD/86622/2012]
- MRC [G0800674, MR/L016354/1, G0700718] Funding Source: UKRI
- Medical Research Council [1594323, MR/L016354/1, G0700718, G0800674] Funding Source: researchfish
Ask authors/readers for more resources
Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the common deletion in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNA(Ser)( UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondria] depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The common mtDNA deletion is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNA(Ser)(UCN) variant cannot be fully excluded. (C) 2017 The Authors. Published by Elsevier B.V.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available