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

Autor:	Pilliod J; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Moutton S; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Lavie J; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Maurat E; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Hubert C; Functional Genomics Center, University of Bordeaux, Bordeaux, France., Bellance N; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Anheim M; 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., Forlani S; Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France., Mochel F; 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., N'Guyen K; Department of Medical Genetics, Timone Hospital, Marseille, France., Thauvin-Robinet C; Genetics Center, Dijon University Hospital Center, Dijon, France., Verny C; Nantes Angers le Mans University and Neurology Service, CNRS UMR6214, INSERM U1083, University Hospital Center, Angers, France., Milea D; Ophthalmology Service, Angers University Hospital Center, Angers, France and Singapore National Eye Centre, Singapore Eye Research Institute, Duke-National University of Singapore, Singapore., Lesca G; Genetics Service, Lyon University Hospital Center, Lyon, France., Koenig M; Molecular Genetics Laboratory, INSERM U827, Montpellier Regional University Hospital Center, Montpellier, France., Rodriguez D; 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., Houcinat N; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Van-Gils J; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Durand CM; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Guichet A; Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France., Barth M; Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France., Bonneau D; Neuropediatrics Service, Armand Trousseau Hospital, Public Hospital Network of Paris, Sorbonne Universities-Pierre and Marie Curie University, Paris, France., Convers P; Nantes Angers le Mans University and Department of Biochemistry and Genetics, University Hospital Center, Angers, France., Maillart E; Clinical Neurophysiology Service, Saint-Étienne University Hospital Center, Saint-Étienne, France., Guyant-Marechal L; Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France., Hannequin D; Neurology Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France., Fromager G; Clinical Genetics Unit, Rouen University Hospital Center, Rouen, France., Afenjar A; Rare Diseases Reference Center 'Defects and Congenital Diseases of the Cerebellum,' Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.; Neurologist, Caen, France., Chantot-Bastaraud S; Rare Diseases Reference Center 'Defects and Congenital Diseases of the Cerebellum,' Armand Trousseau Hospital, Public Hospital Network of Paris, Paris, France.; Neurologist, Caen, France., Valence S; 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., Charles P; Genetics Service, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France., Berquin P; Amiens University Hospital Center, Pediatric Neurology Activity Center, Amiens, France., Rooryck C; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Bouron J; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Brice A; 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., Lacombe D; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Rossignol R; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Stevanin G; 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., Benard G; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France., Burglen L; 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., Durr A; 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., Goizet C; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.; Medical Genetics Service, Pellegrin University Hospital Center, Bordeaux, France., Coupry I; Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Bordeaux, France.
Jazyk:	angličtina
Zdroj:	Annals of neurology [Ann Neurol] 2015 Dec; Vol. 78 (6), pp. 871-86. Date of Electronic Publication: 2015 Nov 14.
DOI:	10.1002/ana.24509
Abstrakt:	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. (© 2015 American Neurological Association.)
Databáze:	MEDLINE
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