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Progressive external ophthalmoplegia due to a recurrent de novo m.15990C>T MT-TP (mt-tRNAPro) gene variant

Lookup NU author(s): Karen Baty, Sila Hopton, Dr Isabell Cordts, Gavin Falkous, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2020 The Authors. Progressive external ophthalmoplegia is typically associated with single or multiple mtDNA deletions but occasionally mtDNA single nucleotide variants within mitochondrial transfer RNAs (mt-tRNAs) are identified. We report a 34-year-old female sporadic patient with progressive external ophthalmoplegia accompanied by exercise intolerance but neither fixed weakness nor multisystemic involvement. Histopathologically, abundant COX-deficient fibres were present in muscle with immunofluorescence analysis confirming the loss of mitochondrial complex I and IV proteins. Molecular genetic analysis identified a rare heteroplasmic m.15990C>T mt-tRNAPro variant reported previously in a single patient with childhood-onset myopathy. The variant in our patient was restricted to muscle. Single muscle fibre analysis identified higher heteroplasmy load in COX-deficient fibres than COX-normal fibres, confirming segregation of high heteroplasmic load with a biochemical defect. Our case highlights the phenotypic variability typically observed with pathogenic mt-tRNA mutations, whilst the identification of a second case with the m.15990C>T mutation not only confirms pathogenicity but shows that de novo mt-tRNA point mutations can arise in multiple, unrelated patients.

Publication metadata

Author(s): Joshi PR, Baty K, Hopton S, Cordts I, Falkous G, Schoser B, Blakely EL, Taylor RW, Deschauer M

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2020

Volume: 30

Issue: 4

Pages: 346-350

Print publication date: 01/04/2020

Online publication date: 15/04/2020

Acceptance date: 27/02/2020

Date deposited: 29/04/2020

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier Ltd


DOI: 10.1016/j.nmd.2020.02.020


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Funder referenceFunder name
“Rare Mitochondrial Disorders of Adults and Children” Diagnostic Service
RWT - Lily Foundation
RWT - Wellcome Centre for Mitochondrial Research(203105/Z/16/Z)
PRJandMDaremembersofthe Germanmito NET, funded by the German Federal Ministry of Education and Research(BMBF)
RWT - Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
RWT - Mitochondrial Disease Patient Cohort(UK) (G0800674)
RWT - Newcastle University Centre for Ageing and Vitality(supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council L016354)
RWT - UK NHS Specialist Commissioners
RWT - UKNIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust