Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.
Cortese, Andrea Tozza, Stefano Yau, Wai Yan Rossi, Salvatore Beecroft, Sarah J Jaunmuktane, Zane Dyer, Zoe Ravenscroft, Gianina Lamont, Phillipa J Mossman, Stuart Chancellor, Andrew Maisonobe, Thierry Pereon, Yann Cauquil, Cecile Colnaghi, Silvia Mallucci, Giulia Curro, Riccardo Tomaselli, Pedro J Thomas-Black, Gilbert Sullivan, Roisin Efthymiou, Stephanie Rossor, Alexander M Laurá, Matilde Pipis, Menelaos Horga, Alejandro Polke, James Kaski, Diego Horvath, Rita Chinnery, Patrick F Marques, Wilson Tassorelli, Cristina Devigili, Grazia Leonardis, Lea Wood, Nick W Bronstein, Adolfo Giunti, Paola Züchner, Stephan Stojkovic, Tanya Laing, Nigel Roxburgh, Richard H Houlden, Henry Reilly, Mary M
Cortese A, etal., Brain. 2020 Feb 1;143(2):480-490. doi: 10.1093/brain/awz418.
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.