A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy.

Debby M E I Hellebrekers, Emma L Blakely, Alexandra T M Hendrickx, Steven A Hardy, Sila Hopton, Gavin Falkous, Irenaeus F M de Coo, Hubert J M Smeets, Nadine M E van der Beek, Robert W Taylor

Neuromuscular disorders : NMD 2019 Sep

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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. Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Debby M E I Hellebrekers, Emma L Blakely, Alexandra T M Hendrickx, Steven A Hardy, Sila Hopton, Gavin Falkous, Irenaeus F M de Coo, Hubert J M Smeets, Nadine M E van der Beek, Robert W Taylor. A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy. Neuromuscular disorders : NMD. 2019 Sep;29(9):693-697