Solveig Montaut1, Nadège Diedhiou2,3, Pauline Fahrer4, Cécilia Marelli5,6, Benoit Lhermitte7, Laura Robelin8,9, Marie Claire Vincent4, Lucas Corti10, Guillaume Taieb10, Odile Gebus4, Gabrielle Rudolf4,11, Julien Tarabeux12, Nicolas Dondaine12, Matthieu Canuet13, Marilyne Almeras14, Mehdi Benkirane15,16, Lise Larrieu15,16, Jean-Baptiste Chanson17, Aleksandra Nadaj-Pakleza17, Andoni Echaniz-Laguna18,19, Cécile Cauquil18, Béatrice Lannes8, Jamel Chelly11,12,20, Mathieu Anheim4,2,20, Hélène Puccio2,3, Christine Tranchant4,2,20. 1. Department of Neurology, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg, France. solveig.montaut@gmail.com. 2. INSERM, U1258/CNRS, UMR7104, Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Illkirch, France. 3. University of Strasbourg, Strasbourg, France. 4. Department of Neurology, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg, France. 5. Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic Diseases, Department of Neurology, Montpellier University Hospital, Montpellier, France. 6. Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, University of Montpellier, Montpellier, France. 7. Inserm U1198 MMDN, University of Montpellier, Montpellier, France. 8. Department of Pathology, Strasbourg University Hospital, Strasbourg, France. 9. Tumoral Signaling and Therapeutics Targets Team, Laboratory Bioimaging and Pathologies, UMR CNRS 7021, Faculty of Pharmacy, University of Strasbourg, Illkirch, France. 10. Department of Neurology, Montpellier University Hospital, Montpellier, France. 11. CNRS U 7104-Inserm U1258, Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Illkirch, France. 12. Laboratoire de Diagnostic Génétique, Strasbourg University Hospital, Strasbourg, France. 13. Department of Pneumology, Strasbourg University Hospital, Strasbourg, France. 14. Palliative Care Department, Strasbourg University Hospital, Strasbourg, France. 15. Laboratoire de Génétique Moléculaire, IURC, Montpellier University Hospital, Montpellier, France. 16. Equipe Accueil EA7402, University of Montpellier, Montpellier, France. 17. Neuromuscular Referential Center, Department of Neurology, Strasbourg University Hospital, Strasbourg, France. 18. Department of Neurology, APHP, French National Reference Center for Rare Neuropathies (NNERF), Bicêtre University Hospital, Le Kremlin Bicêtre, France. 19. INSERM U1195, Paris-Saclay University, Le Kremlin Bicêtre, France. 20. Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, Strasbourg, France.
Abstract
OBJECTIVE: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). METHODS: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. RESULTS: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. CONCLUSION: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
OBJECTIVE: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). METHODS: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. RESULTS: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. CONCLUSION: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
Authors: T Bogdan; T Wirth; A Iosif; A Schalk; S Montaut; C Bonnard; G Carre; O Lagha-Boukbiza; C Reschwein; E Albugues; S Demuth; H Landsberger; M Einsiedler; T Parratte; A Nguyen; F Lamy; H Durand; P Fahrer; P Voulleminot; K Bigaut; J B Chanson; G Nicolas; J Chelly; C Cazeneuve; M Koenig; C Bund; I J Namer; S Kremer; N Calmels; C Tranchant; M Anheim Journal: J Neurol Date: 2022-07-23 Impact factor: 6.682
Authors: Marie Beaudin; Mario Manto; Jeremy D Schmahmann; Massimo Pandolfo; Nicolas Dupre Journal: Nat Rev Neurol Date: 2022-03-24 Impact factor: 42.937
Authors: Cleo C van Diemen; Helga Westers; Bart P van de Warrenburg; Fatemeh Ghorbani; Jelkje de Boer-Bergsma; Corien C Verschuuren-Bemelmans; Maartje Pennings; Eddy N de Boer; Berry Kremer; Els K Vanhoutte; Jeroen J de Vries; Raymond van de Berg; Erik-Jan Kamsteeg; Dineke S Verbeek Journal: J Neurol Date: 2022-07-21 Impact factor: 6.682