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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.

  • Cortese, Andrea1, 2
  • Tozza, Stefano1, 3
  • Yau, Wai Yan1
  • Rossi, Salvatore1, 4
  • Beecroft, Sarah J5
  • Jaunmuktane, Zane6
  • Dyer, Zoe7
  • Ravenscroft, Gianina5
  • Lamont, Phillipa J8
  • Mossman, Stuart9
  • Chancellor, Andrew10
  • Maisonobe, Thierry11
  • Pereon, Yann12
  • Cauquil, Cecile13
  • Colnaghi, Silvia14
  • Mallucci, Giulia14
  • Curro, Riccardo2
  • Tomaselli, Pedro J15
  • Thomas-Black, Gilbert6
  • Sullivan, Roisin1
  • And 22 more
  • 1 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
  • 2 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. , (Italy)
  • 3 Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy. , (Italy)
  • 4 Department of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCSS, Rome, Italy; Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy. , (Italy)
  • 5 Centre for Medical Research University of Western Australia, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia. , (Australia)
  • 6 Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
  • 7 Auckland District Health Board (ADHB), Auckland, New Zealand; Centre of Brain Research Neurogenetics Research Clinic, University of Auckland, New Zealand. , (New Zealand)
  • 8 Neurogenetic Unit, Royal Perth Hospital, Perth, West Australia, Australia. , (Australia)
  • 9 Department of Neurology, Wellington Hospital, Wellington 6021, New Zealand. , (New Zealand)
  • 10 Department of Neurology, Tauranga Hospital, Private Bag, Cameron Road, Tauranga 3171, New Zealand. , (New Zealand)
  • 11 Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Department of Neurophysiology, Paris France. , (France)
  • 12 CHU Nantes, Reference Centre for Neuromuscular Diseases, Hôtel-Dieu, Nantes, France. , (France)
  • 13 Department of Neurology, CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre, France. , (France)
  • 14 IRCCS Mondino Foundation, Pavia, Italy. , (Italy)
  • 15 Department of Neurology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil. , (Brazil)
  • 16 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 17 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • 18 UO Neurologia I, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy. , (Italy)
  • 19 Division of Neurology, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia. , (Slovenia)
  • 20 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
  • 21 Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires, Nord/Est/Ile-de-France, Inserm UMR_S 974, Paris, France. , (France)
  • 22 Neurogenetics Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, Australia. , (Australia)
Published Article
Oxford University Press
Publication Date
Feb 01, 2020
DOI: 10.1093/brain/awz418
PMID: 32040566


Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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