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

Andrea Cortese, Stefano Tozza, Wai Yan Yau, Salvatore Rossi, Sarah J. Beecroft, Zane Jaunmuktane, Zoe Dyer, Gianina Ravenscroft, Phillipa J. Lamont, Stuart Mossman, Andrew Chancellor, Thierry Maisonobe, Yann Pereon, Cecile Cauquil, Silvia Colnaghi, Giulia Mallucci, Riccardo Curro, Pedro J. Tomaselli, Gilbert Thomas-Black, Roisin SullivanStephanie Efthymiou, Alexander M. Rossor, Matilde Laurá, Menelaos Pipis, Alejandro Horga, James Polke, Diego Kaski, Rita Horvath, Patrick F. Chinnery, Wilson Marques, Cristina Tassorelli, Grazia Devigili, Lea Leonardis, Nick W. Wood, Adolfo Bronstein, Paola Giunti, Stephan Züchner, Tanya Stojkovic, Nigel Laing, Richard H. Roxburgh, Henry Houlden, Mary M. Reilly

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)480-490
Number of pages11
JournalBrain : a journal of neurology
Issue number2
Publication statusPublished - Feb 1 2020


  • cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS)
  • chronic cough
  • repeat expansion
  • RFC1
  • sensory neuropathy

ASJC Scopus subject areas

  • Clinical Neurology


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