RGD Reference Report - Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. - Rat Genome Database

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

Authors: 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 
Citation: Cortese A, etal., Brain. 2020 Feb 1;143(2):480-490. doi: 10.1093/brain/awz418.
RGD ID: 41404728
Pubmed: (View Article at PubMed) PMID:32040566
DOI: Full-text: 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.

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Rfc1  (replication factor C subunit 1)

Genes (Mus musculus)
Rfc1  (replication factor C (activator 1) 1)

Genes (Homo sapiens)
RFC1  (replication factor C subunit 1)

Additional Information