Maya Tchikviladzé1, Mylène Gilleron2, Thierry Maisonobe3, Damien Galanaud4, Pascal Laforêt5, Alexandra Durr6, Bruno Eymard7, Fanny Mochel8, Hélène Ogier9, Anthony Béhin5, Tanya Stojkovic5, Bertrand Degos10, Isabelle Gourfinkel-An11, Frederic Sedel8, Mathieu Anheim10, Alexis Elbaz12, Karine Viala3, Marie Vidailhet13, Alexis Brice6, Claude Jardel14, Anne Lombès15. 1. Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM CIC9503, GHU Pitié-Salpêtrière, Paris, France. 2. INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France UPMC Univ Paris 06, UMR_S975, Paris, France. 3. Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France. 4. Department of Neuroradiology, AP-HP, GHU Pitié-Salpêtrière, Paris, France. 5. AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France. 6. UPMC Univ Paris 06, UMR_S975, Paris, France Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France. 7. UPMC Univ Paris 06, UMR_S975, Paris, France AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France. 8. Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France. 9. AP-HP, Maladies héréditaires du métabolisme, GH Robert Debré, Paris, France. 10. Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France. 11. AP-HP, Centre de référence Epilepsies rares, GH Pitié-Salpêtrière, Paris, France. 12. INSERM, CESP, Social and occupational determinants of health, U1018, Villejuif, France Université Versailles St-Quentin, UMRS 1018, Villejuif, France. 13. Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France. 14. INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France. 15. INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France Université Paris-Descartes-Paris5, Paris, France.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Johannes A Mayr; Tobias B Haack; Peter Freisinger; Daniela Karall; Christine Makowski; Johannes Koch; René G Feichtinger; Franz A Zimmermann; Boris Rolinski; Uwe Ahting; Thomas Meitinger; Holger Prokisch; Wolfgang Sperl Journal: J Inherit Metab Dis Date: 2015-03-17 Impact factor: 4.982