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William C Copeland - One of the best experts on this subject based on the ideXlab platform.
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POLG-related disorders and their neurological manifestations
Nature Reviews Neurology, 2019Co-Authors: Shamima Rahman, William C CopelandAbstract:POLG encodes the catalytic subunit of DNA polymerase γ, the enzyme responsible for replicating the mitochondrial DNA (mtDNA). Mutations in POLG are associated with a clinical continuum of heterogeneous syndromes, ranging from infantile-onset epilepsies and liver failure to late-onset ophthalmoplegia and muscle weakness. POLG mutations are a frequent cause of mitochondrial disease, particularly mitochondrial epilepsy, polyneuropathy, ataxia and progressive external ophthalmoplegia. POLG mutations can lead to depletion of the mtDNA and/or accumulation of multiple mtDNA deletions. To a limited extent, clinical phenotypes correlate with the mtDNA phenotype (depletion or deletions). No effective disease-modifying therapies are currently available for POLG -related disease, and symptomatic therapies are the mainstay of treatment. The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG -related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers–Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG -related disorders, focusing particularly on the neurological manifestations of these conditions. Pathogenic variants in POLG , which encodes the catalytic subunit of DNA polymerase γ, cause a spectrum of overlapping disease phenotypes. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG -related disorders, focusing particularly on the neurological manifestations.
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POLG-related disorders and their neurological manifestations.
Nature reviews. Neurology, 2018Co-Authors: Shamima Rahman, William C CopelandAbstract:The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers–Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions. Pathogenic variants in POLG, which encodes the catalytic subunit of DNA polymerase γ, cause a spectrum of overlapping disease phenotypes. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations.
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Clinical and Molecular Features of POLG-Related Mitochondrial Disease
Cold Spring Harbor perspectives in biology, 2013Co-Authors: Jeffrey D. Stumpf, Russell P. Saneto, William C CopelandAbstract:The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
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Mitochondrial DNA replication and disease: Insights from DNA polymerase γ mutations
Cellular and Molecular Life Sciences, 2011Co-Authors: Jeffrey D. Stumpf, William C CopelandAbstract:DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.
Hélène Ogier - One of the best experts on this subject based on the ideXlab platform.
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A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène Ogier, Anthony BéhinAbstract: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.
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a diagnostic flowchart for POLG related diseases based on signs sensitivity and specificity p3 299
Neurology, 2014Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène OgierAbstract: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.
X Ayrignac - One of the best experts on this subject based on the ideXlab platform.
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The wide POLG-related spectrum: An integrated view
Journal of the neurological sciences, 2016Co-Authors: M Béreau, Mathieu Anheim, A Echaniz-laguna, Armelle Magot, Christophe Verny, M Goideau-sevrain, Magalie Barth, Patrizia Amati-bonneau, Stéphane Allouche, X AyrignacAbstract:Abstract The aims of this study were to describe the spectrum of recessively inherited POLG -related disorders, to report new POLG mutations and to discuss genotype-phenotype correlations in order to propose a strategy for diagnosis. Twenty eight patients diagnosed with two POLG mutations at 12 tertiary European centers of adult neurology were studied. Exhaustive phenotypic data, brain MRI, muscle analysis, mitochondrial DNA and POLG analysis findings were collected. Five distinct phenotypes were observed: Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO), autosomal recessive Progressive External Ophthalmoplegia (arPEO), Spino Cerebellar Ataxia with Epilepsy (SCAE), Mitochondrial Neuro Gastro Intestinal Encephalopathy (MNGIE)-like phenotype and Sensory Ataxic Neuropathy with Ophthalmoparesis but without dysarthria which we propose to name SANO. An increasing gradient of functional severity was appreciated from PEO with the best prognosis, to SANO, SANDO and finally SCAE respectively. Four new missense mutations were found. Regarding genotype/phenotype correlations, P587L mutation was associated with SANO rather than with SANDO (p POLG mutations should be priority searched for in cases of SANDO or SANO. Mitochondrial respiratory chain and mitochondrial DNA studies should be considered in the case of negative POLG analysis or other phenotypes.
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The wide POLG-related spectrum: An integrated view
J Neurol Sci, 2016Co-Authors: M Béreau, Mathieu Anheim, A Echaniz-laguna, Armelle Magot, Christophe Verny, M Goideau-sevrain, Magalie Barth, Patrizia Amati-bonneau, Stéphane Allouche, X AyrignacAbstract:The aims of this study were to describe the spectrum of recessively inherited POLG-related disorders, to report new POLG mutations and to discuss genotype-phenotype correlations in order to propose a strategy for diagnosis. Twenty eight patients diagnosed with two POLG mutations at 12 tertiary European centers of adult neurology were studied. Exhaustive phenotypic data, brain MRI, muscle analysis, mitochondrial DNA and POLG analysis findings were collected. Five distinct phenotypes were observed: Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO), autosomal recessive Progressive External Ophthalmoplegia (arPEO), Spino Cerebellar Ataxia with Epilepsy (SCAE), Mitochondrial Neuro Gastro Intestinal Encephalopathy (MNGIE)-like phenotype and Sensory Ataxic Neuropathy with Ophthalmoparesis but without dysarthria which we propose to name SANO. An increasing gradient of functional severity was appreciated from PEO with the best prognosis, to SANO, SANDO and finally SCAE respectively. Four new missense mutations were found. Regarding genotype/phenotype correlations, P587L mutation was associated with SANO rather than with SANDO (p < 0.005) and W748S mutation was associated with SANDO or SCAE (with more severe disease progression), rather than with SANO or PEO (p < 0.004). Distinguishing between various phenotypes can have important diagnosis and prognosis implications. POLG mutations should be priority searched for in cases of SANDO or SANO. Mitochondrial respiratory chain and mitochondrial DNA studies should be considered in the case of negative POLG analysis or other phenotypes.
Alexandra Durr - One of the best experts on this subject based on the ideXlab platform.
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A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène Ogier, Anthony BéhinAbstract: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.
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a diagnostic flowchart for POLG related diseases based on signs sensitivity and specificity p3 299
Neurology, 2014Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène OgierAbstract: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.
Maya Tchikviladzé - One of the best experts on this subject based on the ideXlab platform.
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A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène Ogier, Anthony BéhinAbstract: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.
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a diagnostic flowchart for POLG related diseases based on signs sensitivity and specificity p3 299
Neurology, 2014Co-Authors: Maya Tchikviladzé, Mylène Gilleron, Thierry Maisonobe, Damien Galanaud, Pascal Laforêt, Alexandra Durr, Bruno Eymard, Fanny Mochel, Hélène OgierAbstract: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.