Volume 78, Issue 6 pp. 871-886

Research Article

New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix–Saguenay

Julie Pilliod PhD,

Julie Pilliod PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Sébastien Moutton MD,

Sébastien Moutton MD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julie Lavie PhD,

Julie Lavie PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Elise Maurat BSc,

Elise Maurat BSc

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Christophe Hubert BSc,

Christophe Hubert BSc

Functional Genomics Center, University of Bordeaux, Bordeaux, France

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Nadège Bellance PhD,

Nadège Bellance PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Mathieu Anheim MD, PhD,

Mathieu Anheim MD, PhD

Neurology Service, Strasbourg University Hospitals, Strasbourg, France

Molecular Cell Biology Genetics Institute, INSERM U964/CNRS UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France

Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch-Graffenstaden, France

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Sylvie Forlani PhD,

Sylvie Forlani PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Fanny Mochel MD, PhD,

Fanny Mochel MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Karine N'Guyen MD, PhD,

Karine N'Guyen MD, PhD

Department of Medical Genetics, Timone Hospital, Marseille, France

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Christel Thauvin-Robinet MD, PhD,

Christel Thauvin-Robinet MD, PhD

Genetics Center, Dijon University Hospital Center, Dijon, France

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Christophe Verny MD,

Christophe Verny MD

Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM U1083, University Hospital Center, Angers, France

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Dan Milea MD,

Dan Milea MD

Ophthalmology Service, Angers University Hospital Center, Angers, France and Singapore National Eye Centre, Singapore Eye Research Institute, Duke–National University of Singapore, Singapore

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Gaëtan Lesca MD, PhD,

Gaëtan Lesca MD, PhD

Genetics Service, Lyon University Hospital Center, Lyon, France

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Michel Koenig MD, PhD,

Michel Koenig MD, PhD

Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University Hospital Center, Montpellier, France

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Diana Rodriguez MD, PhD,

Diana Rodriguez MD, PhD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Robert Debré Hospital, INSERM U1141, Paris, France

Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

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Nada Houcinat BMedSc,

Nada Houcinat BMedSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julien Van-Gils BMedSc,

Julien Van-Gils BMedSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Christelle M. Durand PhD,

Christelle M. Durand PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Agnès Guichet MD,

Agnès Guichet MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Magalie Barth MD,

Magalie Barth MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Dominique Bonneau MD,

Dominique Bonneau MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Philippe Convers MD,

Philippe Convers MD

Nantes Angers le Mans University and Department of Biochemistry and Genetics, University Hospital Center, Angers, France

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Elisabeth Maillart MD,

Elisabeth Maillart MD

Clinical Neurophysiology Service, Saint-Étienne University Hospital Center, Saint-Étienne, France

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Lucie Guyant-Marechal MD,

Lucie Guyant-Marechal MD

Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Didier Hannequin MD, PhD,

Didier Hannequin MD, PhD

Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Guillaume Fromager MD,

Guillaume Fromager MD

Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France

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Alexandra Afenjar MD,

Alexandra Afenjar MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Neurologist, Caen, France

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Sandra Chantot-Bastaraud MD,

Sandra Chantot-Bastaraud MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Neurologist, Caen, France

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Stéphanie Valence MD,

Stéphanie Valence MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

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Perrine Charles MD, PhD,

Perrine Charles MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Patrick Berquin MD, PhD,

Patrick Berquin MD, PhD

Amiens University Hospital Center, Pediatric Neurology Activity Center, Amiens, France

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Caroline Rooryck MD, PhD,

Caroline Rooryck MD, PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julie Bouron BSc,

Julie Bouron BSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Alexis Brice MD,

Alexis Brice MD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Didier Lacombe MD,

Didier Lacombe MD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Rodrigue Rossignol PhD,

Rodrigue Rossignol PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Giovanni Stevanin PhD,

Giovanni Stevanin PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

Laboratory of Neurogenetics, Practical School of Higher Studies, Paris, France

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Giovanni Benard PhD,

Giovanni Benard PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Lydie Burglen MD, PhD,

Lydie Burglen MD, PhD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Robert Debré Hospital, INSERM U1141, Paris, France

Neurologist, Caen, France

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Alexandra Durr MD, PhD,

Alexandra Durr MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Cyril Goizet MD, PhD,

Cyril Goizet MD, PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Isabelle Coupry PhD,

Corresponding Author

Isabelle Coupry PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Address correspondence to Dr Coupry, Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA4576, 2ème étage Ecole de Sages-Femmes, Hôpital Pellegrin, Place Amélie Raba-Léon, 33076 Bordeaux cedex, France. E-mail: [email protected]Search for more papers by this author

Julie Pilliod PhD,

Julie Pilliod PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Sébastien Moutton MD,

Sébastien Moutton MD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julie Lavie PhD,

Julie Lavie PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Elise Maurat BSc,

Elise Maurat BSc

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Christophe Hubert BSc,

Christophe Hubert BSc

Functional Genomics Center, University of Bordeaux, Bordeaux, France

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Nadège Bellance PhD,

Nadège Bellance PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Mathieu Anheim MD, PhD,

Mathieu Anheim MD, PhD

Neurology Service, Strasbourg University Hospitals, Strasbourg, France

Molecular Cell Biology Genetics Institute, INSERM U964/CNRS UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France

Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch-Graffenstaden, France

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Sylvie Forlani PhD,

Sylvie Forlani PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Fanny Mochel MD, PhD,

Fanny Mochel MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Karine N'Guyen MD, PhD,

Karine N'Guyen MD, PhD

Department of Medical Genetics, Timone Hospital, Marseille, France

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Christel Thauvin-Robinet MD, PhD,

Christel Thauvin-Robinet MD, PhD

Genetics Center, Dijon University Hospital Center, Dijon, France

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Christophe Verny MD,

Christophe Verny MD

Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM U1083, University Hospital Center, Angers, France

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Dan Milea MD,

Dan Milea MD

Ophthalmology Service, Angers University Hospital Center, Angers, France and Singapore National Eye Centre, Singapore Eye Research Institute, Duke–National University of Singapore, Singapore

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Gaëtan Lesca MD, PhD,

Gaëtan Lesca MD, PhD

Genetics Service, Lyon University Hospital Center, Lyon, France

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Michel Koenig MD, PhD,

Michel Koenig MD, PhD

Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University Hospital Center, Montpellier, France

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Diana Rodriguez MD, PhD,

Diana Rodriguez MD, PhD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Robert Debré Hospital, INSERM U1141, Paris, France

Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

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Nada Houcinat BMedSc,

Nada Houcinat BMedSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julien Van-Gils BMedSc,

Julien Van-Gils BMedSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Christelle M. Durand PhD,

Christelle M. Durand PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Agnès Guichet MD,

Agnès Guichet MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Magalie Barth MD,

Magalie Barth MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Dominique Bonneau MD,

Dominique Bonneau MD

Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Philippe Convers MD,

Philippe Convers MD

Nantes Angers le Mans University and Department of Biochemistry and Genetics, University Hospital Center, Angers, France

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Elisabeth Maillart MD,

Elisabeth Maillart MD

Clinical Neurophysiology Service, Saint-Étienne University Hospital Center, Saint-Étienne, France

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Lucie Guyant-Marechal MD,

Lucie Guyant-Marechal MD

Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Didier Hannequin MD, PhD,

Didier Hannequin MD, PhD

Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Guillaume Fromager MD,

Guillaume Fromager MD

Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France

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Alexandra Afenjar MD,

Alexandra Afenjar MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Neurologist, Caen, France

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Sandra Chantot-Bastaraud MD,

Sandra Chantot-Bastaraud MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Neurologist, Caen, France

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Stéphanie Valence MD,

Stéphanie Valence MD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

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Perrine Charles MD, PhD,

Perrine Charles MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

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Patrick Berquin MD, PhD,

Patrick Berquin MD, PhD

Amiens University Hospital Center, Pediatric Neurology Activity Center, Amiens, France

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Caroline Rooryck MD, PhD,

Caroline Rooryck MD, PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Julie Bouron BSc,

Julie Bouron BSc

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Alexis Brice MD,

Alexis Brice MD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Didier Lacombe MD,

Didier Lacombe MD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Rodrigue Rossignol PhD,

Rodrigue Rossignol PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Giovanni Stevanin PhD,

Giovanni Stevanin PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

Laboratory of Neurogenetics, Practical School of Higher Studies, Paris, France

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Giovanni Benard PhD,

Giovanni Benard PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

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Lydie Burglen MD, PhD,

Lydie Burglen MD, PhD

Rare Diseases Reference Center “Defects and Congenital Diseases of the Cerebellum,” Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France

Robert Debré Hospital, INSERM U1141, Paris, France

Neurologist, Caen, France

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Alexandra Durr MD, PhD,

Alexandra Durr MD, PhD

Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France

Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities–Pierre and Marie Curie University, Paris, France

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Cyril Goizet MD, PhD,

Cyril Goizet MD, PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France

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Isabelle Coupry PhD,

Corresponding Author

Isabelle Coupry PhD

Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France

First published: 20 August 2015

https://doi.org/10.1002/ana.24509

Citations: 62

This article was published online on 14 November 2015. After online publication errors in Table 1 were corrected. This notice is included in the online and print versions to indicate that both have been corrected on 20 November 2015.

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Abstract

Objective

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment.

Methods

A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene.

Results

We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested.

Interpretation

Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria. Ann Neurol 2015;78:871–886

Supporting Information

References

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Volume78, Issue6

December 2015

Pages 871-886

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ana24509-sup-0001-supptable1.doc95.5 KB	Supporting Information Table 1.
ana24509-sup-0002-supptable2.doc61 KB	Supporting Information Table 2.
ana24509-sup-0003-supptable3.tif8.5 MB	Supporting Information Table 3.
ana24509-sup-0004-supptable4.doc552 KB	Supporting Information Table 4.
ana24509-sup-0005-supptable5.doc65.5 KB	Supporting Information Table 5.

New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix–Saguenay

Abstract

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Citing Literature

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New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix–Saguenay

Abstract

Objective

Methods

Results

Interpretation

Supporting Information

References

Citing Literature

References

Related

Information