Journal
BRAIN
Volume 143, Issue -, Pages 480-490Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz418
Keywords
sensory neuropathy; cerebellar ataxia; neuropathy; vestibular areflexia syndrome (CANVAS); chronic cough; RFC1; repeat expansion
Categories
Funding
- Medical Research Council [MR/179744]
- Wellcome Trust [204841/Z/16/Z]
- Fondazione CARIPLO
- Inherited Neuropathy Consortium (INC), NIH Rare Diseases Clinical Research Network (RDCRN) [U54NS065712]
- Wellcome Trust Postdoctoral Fellowship for Clinicians [110043/Z/15/Z]
- Medical Research Council (MRC), MRC Centre [G0601943]
- National Institutes of Neurological Diseases and Stroke and office of Rare Diseases [U54NS065712]
- Ataxia UK
- MSA Trust
- MDUK
- Muscular Dystrophy Association (MDA)
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Rosetree Trust
- Inherited Neuropathy Consortium
- Liuzzi Foundation
- Australian National Health and Medical Research Council (NHMRC)
- Medical Research Council Mitochondrial Biology Unit [MC_UU_00015/9]
- Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
- Evelyn Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Medical Research Council (UK) [MR/N025431/1]
- Newton Fund (UK/Turkey) [MR/N027302/1]
- European Research Council [309548]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- MRC [MR/N010035/1, G1000848, G0601943, MR/S01165X/1, MR/T001712/1, 1936823, MR/N025431/1, MR/N025431/2] Funding Source: UKRI
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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.
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