tract 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.

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Neuromuscular Disorders
Erasmus MC: University Medical Center Rotterdam

Hellebrekers, D., Blakely, E.L., Hendrickx, A.T., Hardy, S.A., Hopton, S., Falkous, G., … Taylor, R. W. (2019). A novel mitochondrial m.4414T > C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy. Neuromuscular Disorders, 29(9), 693–697. doi:10.1016/j.nmd.2019.08.005