Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion
Open Access
- 1 February 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 143 (2), 480-490
- https://doi.org/10.1093/brain/awz418
Abstract
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.Keywords
Funding Information
- Medical Research Council (MR/179744)
- Wellcome Trust (204841/Z/16/Z)
- Fondazione CARIPLO and the Inherited Neuropathy Consortium
- Inc
- NIH
- Rare Diseases Clinical Research Network
- RDCRN (U54NS065712)
- Wellcome Trust (110043/Z/15/Z)
- Medical Research Council
- MRC (G0601943)
- National Institutes of Neurological Diseases and Stroke (U54NS065712)
- the Muscular Dystrophy Association
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Inherited Neuropathy Consortium
- Liuzzi Foundation
- National Health and Medical Research Council
- NHMRC
- Wellcome Trust (212219/Z/18/Z)
- NIHR Senior Investigator
- Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9)
- International Centre for Genomic Medicine in Neuromuscular Disease
- National Institute for Health Research
- NIHR
- Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- NHS
- NIHR
- Department of Health
- Wellcome Senior Investigator (109915/Z/15/Z)
- Medical Research Council (MR/N025431/1)
- Newton Fund (MR/N027302/1)
- European Research Council (309548)
- Wellcome Trust (201064/Z/16/Z)
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