title: A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM CIC9503, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Tchikviladzé
authors.affiliation: 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.
authors.forename: Mylène
authors.initials: M
authors.lastname: Gilleron
authors.affiliation: Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.affiliation: Department of Neuroradiology, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Galanaud
authors.affiliation: AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: 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.
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.affiliation: AP-HP, Maladies héréditaires du métabolisme, GH Robert Debré, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier
authors.affiliation: AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Béhin
authors.affiliation: AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stojkovic
authors.affiliation: Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Degos
authors.affiliation: AP-HP, Centre de référence Epilepsies rares, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourfinkel-An
authors.affiliation: 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.
authors.forename: Frederic
authors.initials: F
authors.lastname: Sedel
authors.affiliation: Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: INSERM, CESP, Social and occupational determinants of health, U1018, Villejuif, France Université Versailles St-Quentin, UMRS 1018, Villejuif, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Elbaz
authors.affiliation: Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Viala
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
authors.affiliation: 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.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: 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.
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002493:Central Nervous System Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004568:Electrodiagnosis; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000737:chemistry; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology; D009154:Mutation / Q000235:genetics; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
keywords: Clinical Neurology; EMG; Genetics; Mitochondrial Disorders