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

Neuromuscul Disord. 2019 Sep;29(9):693-697. doi: 10.1016/j.nmd.2019.08.005. Epub 2019 Aug 21.

Abstract

We report a novel mitochondrial m.4414T>C variant in the mt-tRNAMet (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-tRNAMet. 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.

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

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex IV / metabolism
  • Female
  • Humans
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Mutation
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • RNA, Transfer, Met / genetics*
  • Severity of Illness Index

Substances

  • DNA, Mitochondrial
  • RNA, Transfer, Met
  • Electron Transport Complex IV