A Diagnostic Flowchart For POLG Related Diseases Based On Signs Sensitivity And Specificity (P3.299)

Objective: The purpose of this study was the evaluation of the specificity and sensitivity of the signs/symptoms considered indicative of a POLG-related disease. Backgroud: The highly diverse presentations associated with mitochondrial diseases make them an important diagnostic challenge to the neurological community. This is the case for POLG-related diseases, which are responsible widespread neurological syndromes. As a consequence the demands for POLG sequencing have steadily increased, especially in adult Neurology. These numerous indications for POLG gene sequencing are costly and often disclose either normal sequence or variants of unknown significance. Design/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/symptoms, 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 mutation (POLG-/- group). Results: High sensitivity but low specificity was observed with single signs such as 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 neuropathy associated with weakness of ocular, pharyngeal, axial and/or limb weakness. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule below 50 years of age. Conclusion. The large series of patients show that phenotypes associated with POLG mutations follow a reproducible pattern which allows establishing a diagnostic flowchart. Disclosure: Dr. Tchikviladze has received personal compensation for activities with Merck Serono, Sanofi-Aventis Pharmaceuticals Inc., Novartis, and Teva Neuroscience. Dr. Gilleron has nothing to disclose. Dr Maisonobe has received personal compensation for activities with LFB as a speaker. Dr. Galanaud has nothing to disclose. Dr. Laforet has received personal compensation for activities with Genzyme Corp. Dr. Durr has received personal compensation for activities with Pfizer, Inc. Dr. Eymard has received personal compensation for activities with the LFB Group and Biomarin. Dr. Mochel has received research support from Inserm, Ipsen, and Ultragenyx Pharmaceutical. Dr. Ogier has nothing to disclose. Dr. Behin has received personal compensation for activities with Genzyme Corporation. Dr. Stojkovic has received personal compensation for activities with LFB. Dr. Degos has received personal compensation for activities with Novartis and Ipsen. Dr. Gourfinkel-An has nothing to disclose. Dr. Sedel has nothing to disclose. Dr. Anheim has nothing to disclose. Dr. Elbaz has received personal compensation for activities with the French National Research Agency (ANR). Dr. Viala has nothing to disclose. Dr. Vidailhet has nothing to disclose. Dr. Brice has received personal compensation for activities with the Wolfson Foundation. Dr. Jardel has nothing to disclose. Dr. Lombes has received personal compensation for activities with the ANR, and the Association Francaise contre les Myopathies and Assocation contre les Maladies Mitochondriales.