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Research paper
A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity
  1. Maya Tchikviladzé1,2,
  2. Mylène Gilleron3,4,5,
  3. Thierry Maisonobe6,
  4. Damien Galanaud7,
  5. Pascal Laforêt8,
  6. Alexandra Durr5,9,10,11,
  7. Bruno Eymard5,8,10,
  8. Fanny Mochel9,10,12,
  9. Hélène Ogier13,
  10. Anthony Béhin8,
  11. Tanya Stojkovic8,
  12. Bertrand Degos1,
  13. Isabelle Gourfinkel-An14,
  14. Frederic Sedel9,10,12,
  15. Mathieu Anheim1,
  16. Alexis Elbaz15,16,
  17. Karine Viala6,
  18. Marie Vidailhet1,10,11,12,
  19. Alexis Brice5,9,10,11,
  20. Claude Jardel3,4,
  21. Anne Lombès3,4,17
  1. 1Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
  2. 2INSERM CIC9503, GHU Pitié-Salpêtrière, Paris, France
  3. 3INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France
  4. 4Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France
  5. 5UPMC Univ Paris 06, UMR_S975, Paris, France
  6. 6Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
  7. 7Department of Neuroradiology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
  8. 8AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France
  9. 9Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France
  10. 10INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France
  11. 11ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France
  12. 12Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France
  13. 13AP-HP, Maladies héréditaires du métabolisme, GH Robert Debré, Paris, France
  14. 14AP-HP, Centre de référence Epilepsies rares, GH Pitié-Salpêtrière, Paris, France
  15. 15INSERM, CESP, Social and occupational determinants of health, U1018, Villejuif, France
  16. 16Université Versailles St-Quentin, UMRS 1018, Villejuif, France
  17. 17Université Paris-Descartes-Paris5, Paris, France
  1. Correspondence to Dr Anne Lombes, Faculté de médecine, Inserm 1016-Institut Cochin, 24 rue du Fb St Jacques, Paris F-75014, France; anne.lombes{at}


Objective Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations.

Design Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG+/− group) or two POLG alleles (POLG+/+ group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG+/+ and patients without POLG mutation.

Results High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy.

Conclusions Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.

  • Mitochondrial Disorders
  • Genetics
  • Clinical Neurology
  • EMG

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