title: Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy.
abstract: Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.
authors: Department of Neurology, University of Halle-Wittenberg, Halle (Saale), Germany.
authors: Diana
authors: D
authors: Lehmann
authors: Department of Neurology, University of Halle-Wittenberg, Halle (Saale), Germany.
authors: Kathrin
authors: K
authors: Schubert
authors: Department of Neurology, University of Halle-Wittenberg, Halle (Saale), Germany.
authors: Pushpa R
authors: PR
authors: Joshi
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors: Steven A
authors: SA
authors: Hardy
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors: Helen A L
authors: HA
authors: Tuppen
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors: Karen
authors: K
authors: Baty
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors: Emma L
authors: EL
authors: Blakely
authors: Department of Neurology, Rhein-Mosel-Fachklinik, Andernach, Germany.
authors: Christian
authors: C
authors: Bamberg
authors: Department of Neurology, University of Halle-Wittenberg, Halle (Saale), Germany.
authors: Stephan
authors: S
authors: Zierz
authors: Department of Neurology, University of Halle-Wittenberg, Halle (Saale), Germany.
authors: Marcus
authors: M
authors: Deschauer
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
authors: Robert W
authors: RW
authors: Taylor
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D012344:RNA, Transfer, Ala / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012344:RNA, Transfer, Ala; D003576:Electron Transport Complex IV