Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance?


Progressive external ophthalmoplegia (PEO) with multiple deletions of mitochondrial DNA (mtDNA) is associated with several mutations in nuclear genes. They include POLG, POLG2, ANT1, C10orf2/Twinkle, and OPA1. However, digenic inheritance in mitochondrial disorders has been documented in a few cases over the years. Here we describe an 80-year-old man with sporadic PEO associated with mtDNA deletions. Sequencing of the POLG revealed a novel heterozygous mutation (c.2831A>G; p.Glu944Gly), predicted in silico as damaging, in the patient who also carried a heterozygous mutation in C10orf2/Twinkle (c.1142T>C; p.Leu381Pro). This case provides a second report of a PEO with different mutations in the POLG and C10orf2/Twinkle genes, supporting the hypothesis that the PEO phenotype can be determined by the co-existence of two abnormalities in separate genes, both involved in the maintenance and stability of mtDNA. Finally, this study expands the spectrum of POLG mutations and highlights the need to sequence the whole set of nuclear genes associated with PEO and multiple mtDNA deletions.

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The research was supported in part by a grant from the Region of Tuscany and the Ministry of Public Health to AF (project entitled “Risk and determinants of dementia in patients with mild cognitive impairment and brain subcortical vascular changes: a study of clinical, neuro-imaging and biological markers”).

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The authors declare no financial or other conflict of interest.

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Correspondence to Antonio Federico.

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Da Pozzo, P., Rubegni, A., Rufa, A. et al. Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance?. Neurol Sci 36, 1713–1715 (2015). https://doi.org/10.1007/s10072-015-2247-5

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  • PEO
  • POLG gene
  • C10orf2/Twinkle gene
  • Digenic disorder