A novel pathogenic m.4412G>A MT-TM mitochondrial DNA variant associated with childhood-onset seizures, myopathy and bilateral basal ganglia changes

Mitochondrion. 2019 Jul:47:18-23. doi: 10.1016/j.mito.2019.04.007. Epub 2019 Apr 22.

Abstract

Mitochondrial DNA variants in the MT-TM (mt-tRNAMet) gene are rare, typically associated with myopathic phenotypes. We identified a novel MT-TM variant resulting in prolonged seizures with childhood-onset myopathy, retinopathy, short stature and elevated CSF lactate associated with bilateral basal ganglia changes on neuroimaging. Muscle biopsy confirmed multiple respiratory chain deficiencies and focal cytochrome c oxidase (COX) histochemical abnormalities. Next-generation sequencing of the mitochondrial genome revealed a novel m.4412G>A variant at high heteroplasmy levels in muscle that fulfils all accepted criteria for pathogenicity including segregation within single muscle fibres, thus broadening the genotypic and phenotypic landscape of mitochondrial tRNA-related disease.

Keywords: Basal ganglia changes; MTTM; Mitochondrial disease; Myopathy; Seizures; mtDNA variant.

Publication types

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

MeSH terms

  • Basal Ganglia* / metabolism
  • Basal Ganglia* / pathology
  • Child
  • DNA, Mitochondrial* / genetics
  • DNA, Mitochondrial* / metabolism
  • Female
  • Humans
  • Mitochondrial Myopathies* / genetics
  • Mitochondrial Myopathies* / metabolism
  • Mitochondrial Myopathies* / pathology
  • Mitochondrial Myopathies* / physiopathology
  • Point Mutation*
  • RNA, Mitochondrial / genetics*
  • RNA, Mitochondrial / metabolism
  • RNA, Transfer, Met / genetics*
  • RNA, Transfer, Met / metabolism
  • Seizures* / genetics
  • Seizures* / metabolism
  • Seizures* / pathology
  • Seizures* / physiopathology

Substances

  • DNA, Mitochondrial
  • RNA, Mitochondrial
  • RNA, Transfer, Met