Mitochondrial respiratory chain defects are associated with diverse clinical phenotypes in both adults and children, and may be caused by mutations in either nuclear or mitochondrial DNA (mtDNA). We report the molecular genetic investigations of a patient with chronic progressive external ophthalmoplegia (CPEO) and myopathy where muscle biopsies taken 11 years apart revealed a progressive increase in the proportion of cytochrome c oxidase (COX)-deficient fibres. Mitochondrial genetic analysis of the early biopsy had seemingly excluded both mtDNA rearrangements and mtDNA point mutations. Sequencing mtDNA from individual COX-deficient muscle fibres in the second biopsy, however, identified an unreported m.14723T>C substitution within the mitochondrial tRNAGlu (MTTE) gene, which fulfilled all canonical criteria for pathogenicity. The m.14723T>C mutation was absent from several tissues, including muscle, from maternal relatives suggesting a de novo event, whilst quantitative analysis of the first muscle biopsy confirmed a very low level of the mutation (7% mutated mtDNA), highlighting a potential problem whereby pathogenic mtDNA mutations may remain undetected using established screening methodologies.
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