A novel mitochondrial m.4414T > C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Debby M. E. I. Hellebrekers*, Emma L. Blakely, Alexandra T. M. Hendrickx, Steven A. Hardy, Sila Hopton, Gavin Falkous, Irenaeus F. M. de Coo, Hubert J. M. Smeets, Nadine M. E. van der Beek, Robert W. Taylor

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Web of Science)


We report a novel mitochondrial m.4414T>C variant in the mt-tRNA(Met) (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T>C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNA(Met). Definitive evidence of pathogenicity is provided by clear segregation of m.4414T>C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy. (C) 2019 The Author(s). Published by Elsevier B.V.

Original languageEnglish
Pages (from-to)693-697
Number of pages5
JournalNeuromuscular Disorders
Issue number9
Publication statusPublished - Sept 2019


  • Mitochondrial disease
  • Chronic progressive external ophthalmoplegia
  • Myopathy
  • mtDNA variant
  • m.4414T>C
  • MTTM

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