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

Neuromuscul Disord. 2020 Apr;30(4):346-350. doi: 10.1016/j.nmd.2020.02.020. Epub 2020 Mar 5.

Abstract

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.

Keywords: Mitochondria; Pathogenicity; Progressive external ophthalmoplegia; de novo mutation; tRNA Pro.

Publication types

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

MeSH terms

  • Adult
  • Female
  • Humans
  • Ophthalmoplegia, Chronic Progressive External / genetics*
  • Ophthalmoplegia, Chronic Progressive External / physiopathology*
  • Point Mutation
  • RNA, Mitochondrial / genetics*
  • RNA, Transfer / genetics*

Substances

  • RNA, Mitochondrial
  • RNA, Transfer