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Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant

Lookup NU author(s): Dr Mariana Rocha, Dr Steven Hardy, Dr Amy VincentORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The Authors. 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-tRNASer(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 mitochondrial 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-tRNASer(UCN) variant cannot be fully excluded.

Publication metadata

Author(s): Bacalhau M, Simoes M, Rocha MC, Hardy SA, Vincent AE, Duraes J, Macario MC, Santos MJ, Rebelo O, Lopes C, Pratas J, Mendes C, Zuzarte M, Rego AC, Girao H, Wong LJC, Taylor RW, Grazina M

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2018

Volume: 28

Issue: 4

Pages: 350-360

Print publication date: 01/04/2018

Online publication date: 23/11/2017

Acceptance date: 15/11/2017

Date deposited: 20/02/2018

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier Ltd


DOI: 10.1016/j.nmd.2017.11.006


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust