Julie Pilliod1, Sébastien Moutton1,2, Julie Lavie1, Elise Maurat1, Christophe Hubert3, Nadège Bellance1, Mathieu Anheim4,5,6, Sylvie Forlani7, Fanny Mochel7,8, Karine N'Guyen9, Christel Thauvin-Robinet10, Christophe Verny11, Dan Milea12, Gaëtan Lesca13, Michel Koenig14, Diana Rodriguez15,16,17, Nada Houcinat2, Julien Van-Gils2, Christelle M Durand1, Agnès Guichet18, Magalie Barth18, Dominique Bonneau18, Philippe Convers19, Elisabeth Maillart20, Lucie Guyant-Marechal21, Didier Hannequin21, Guillaume Fromager22, Alexandra Afenjar15,23, Sandra Chantot-Bastaraud15,23, Stéphanie Valence15,17, Perrine Charles7, Patrick Berquin24, Caroline Rooryck1,2, Julie Bouron2, Alexis Brice7,8, Didier Lacombe1,2, Rodrigue Rossignol1, Giovanni Stevanin7,8,25, Giovanni Benard1, Lydie Burglen15,16,23, Alexandra Durr7,8, Cyril Goizet1,2, Isabelle Coupry1. 1. Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France. 2. Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France. 3. Functional Genomics Center, University of Bordeaux, Bordeaux, France. 4. Neurology Service, Strasbourg University Hospitals, Strasbourg, France. 5. Molecular Cell Biology Genetics Institute, INSERM U964/CNRS UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France. 6. Strasbourg Federation of Translational Medicine, University of Strasbourg, Illkirch-Graffenstaden, France. 7. Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France. 8. Brain and Spinal Cord Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universities-Pierre and Marie Curie University, Paris, France. 9. Department of Medical Genetics, Timone Hospital, Marseille, France. 10. Genetics Center, Dijon University Hospital Center, Dijon, France. 11. Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM U1083, University Hospital Center, Angers, France. 12. Ophthalmology Service, Angers University Hospital Center, Angers, France and Singapore National Eye Centre, Singapore Eye Research Institute, Duke-National University of Singapore, Singapore. 13. Genetics Service, Lyon University Hospital Center, Lyon, France. 14. Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University Hospital Center, Montpellier, France. 15. Rare Diseases Reference Center "Defects and Congenital Diseases of the Cerebellum," Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France. 16. Robert Debré Hospital, INSERM U1141, Paris, France. 17. Genetics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France. 18. Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France. 19. Nantes Angers le Mans University and Department of Biochemistry and Genetics, University Hospital Center, Angers, France. 20. Clinical Neurophysiology Service, Saint-Étienne University Hospital Center, Saint-Étienne, France. 21. Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France. 22. Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France. 23. Neurologist, Caen, France. 24. Amiens University Hospital Center, Pediatric Neurology Activity Center, Amiens, France. 25. Laboratory of Neurogenetics, Practical School of Higher Studies, Paris, France.
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.
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 ataxicpatients 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 ataxiapatients 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.
Authors: Katharina Vill; Wolfgang Müller-Felber; Dieter Gläser; Marius Kuhn; Veronika Teusch; Herbert Schreiber; Joachim Weis; Jörg Klepper; Anja Schirmacher; Astrid Blaschek; Manuela Wiessner; Tim M Strom; Bianca Dräger; Kristina Hofmeister-Kiltz; Moritz Tacke; Lucia Gerstl; Peter Young; Rita Horvath; Jan Senderek Journal: Hum Genet Date: 2018-11-21 Impact factor: 4.132
Authors: Marie Coutelier; Monia B Hammer; Giovanni Stevanin; Marie-Lorraine Monin; Claire-Sophie Davoine; Fanny Mochel; Pierre Labauge; Claire Ewenczyk; Jinhui Ding; J Raphael Gibbs; Didier Hannequin; Judith Melki; Annick Toutain; Vincent Laugel; Sylvie Forlani; Perrine Charles; Emmanuel Broussolle; Stéphane Thobois; Alexandra Afenjar; Mathieu Anheim; Patrick Calvas; Giovanni Castelnovo; Thomas de Broucker; Marie Vidailhet; Antoine Moulignier; Robert T Ghnassia; Chantal Tallaksen; Cyril Mignot; Cyril Goizet; Isabelle Le Ber; Elisabeth Ollagnon-Roman; Jean Pouget; Alexis Brice; Andrew Singleton; Alexandra Durr Journal: JAMA Neurol Date: 2018-05-01 Impact factor: 18.302
Authors: Chiara Criscuolo; C Procaccini; M C Meschini; A Cianflone; R Carbone; S Doccini; D Devos; C Nesti; I Vuillaume; M Pellegrino; A Filla; G De Michele; G Matarese; F M Santorelli Journal: J Neurol Date: 2015-11-03 Impact factor: 4.849
Authors: Adam P Vogel; Natalie Rommel; Andreas Oettinger; Lisa H Stoll; Eva-Maria Kraus; Cynthia Gagnon; Marius Horger; Patrick Krumm; Dagmar Timmann; Elsdon Storey; Ludger Schöls; Matthis Synofzik Journal: J Neurol Date: 2018-07-02 Impact factor: 4.849
Authors: Christina Zarouchlioti; David A Parfitt; Wenwen Li; Lauren M Gittings; Michael E Cheetham Journal: Philos Trans R Soc Lond B Biol Sci Date: 2018-01-19 Impact factor: 6.237