Advertisement

Neurological Sciences

, Volume 36, Issue 9, pp 1713–1715 | Cite as

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

  • Paola Da Pozzo
  • Anna Rubegni
  • Alessandra Rufa
  • Elena Cardaioli
  • Ilaria Taglia
  • Gian Nicola Gallus
  • Alessandro Malandrini
  • Antonio Federico
Letter to the Editor

Abstract

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.

Keywords

PEO POLG gene C10orf2/Twinkle gene Digenic disorder 

Notes

Acknowledgments

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”).

Conflict of interest

The authors declare no financial or other conflict of interest.

References

  1. 1.
    Copeland WC, Longley MJ (2014) Mitochondrial genome maintenance in health and disease. DNA Repair (Amst) 19:190–198CrossRefGoogle Scholar
  2. 2.
    Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M et al (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28:223–231CrossRefPubMedGoogle Scholar
  3. 3.
    Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J et al (2010) The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology 74:1619–1626PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Van Goethem G, Löfgren A, Dermaut B, Ceuterick C, Martin JJ, Van Broeckhoven C (2003) Digenic progressive external ophthalmoplegia in sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat 22:175–176CrossRefPubMedGoogle Scholar
  5. 5.
    Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW et al (2003) Mutations of ANT1, Twinkle, and POLG in sporadic progressive external ophthalmoplegia (PEO). Neurology 60:1354–1356CrossRefPubMedGoogle Scholar
  6. 6.
    Vandenberghe W, Van Laere K, Debruyne F, Van Broeckhoven C, Van Goethem G (2009) Neurodegenerative parkinsonism and progressive external ophthalmoplegia with Twinkle mutation. Mov Disord 24:308–309CrossRefPubMedGoogle Scholar
  7. 7.
    Galassi G, Lamantea E, Invernizzi F, Tavani F, Pisano I, Ferrero I et al (2008) Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy. Neuromuscul Disord 18:465–470CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  • Paola Da Pozzo
    • 1
  • Anna Rubegni
    • 2
  • Alessandra Rufa
    • 1
  • Elena Cardaioli
    • 1
  • Ilaria Taglia
    • 1
  • Gian Nicola Gallus
    • 1
  • Alessandro Malandrini
    • 1
  • Antonio Federico
    • 1
  1. 1.Department of Medicine, Surgery and NeuroscienceUniversity of SienaSienaItaly
  2. 2.Molecular Medicine, Neuromuscular and Neurodegenerative UnitIRCCS Stella MarisPisaItaly

Personalised recommendations