English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

CANVAS caused by RFC1 biallelic expansions is a major cause of inheritedsensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS canbe associated with atypical features. We clinically and geneticallycharacterized 50 patients, selected based on the presence of sensoryneuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primedPCR, and Southern blotting of long-range PCR products, a newly developedmethod. Neuropathological characterization was performed on the brain andspinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)nexpansion in RFC1. In addition to the core CANVAS phenotype (sensoryneuronopathy, cerebellar syndrome, and vestibular impairment), we observedchronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%),dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was foundfor 24 of 38 patients (63.1%). First motor neuron signs, such as briskreflexes, extensor plantar responses, and/or spasticity, were present in 29% ofpatients, second motor neuron signs, such as fasciculations, wasting, weakness,or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensoryneuronopathy was observed in 19% of patients. Among six non-RFC1 patients, onecarried a heterozygous AAGGG expansion and a pathogenic variant in GRM1.Neuropathological examination of one RFC1 patient with an enriched phenotype,including parkinsonism, dysautonomia, and cognitive decline, showed posteriorcolumn and lumbar posterior root atrophy. Degeneration of the vestibulospinaland spinocerebellar tracts was mild. We observed marked astrocytic gliosis andaxonal swelling of the synapse between first and second motor neurons in theanterior horn at the lumbar level. The cerebellum showed mild depletion ofPurkinje cells, with empty baskets, torpedoes, and astrogliosis characterizedby a disorganization of the Bergmann's radial glia. We found neuronal loss inthe vagal nucleus. The pars compacta of the substantia nigra was depleted, withwidespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus,entorhinal cortex, and amygdala. We propose new guidelines for the screening ofRFC1 expansion, considering different expansion motifs. Here, we developed anew method to more easily detect pathogenic RFC1 expansions. We report frequentmotor neuron involvement and different neuronopathy subtypes. Parkinsonism wasmore prevalent in this cohort than in the general population, 10% versus theexpected 1% (p < .001). We describe, for the first time, the spinal cordpathology in CANVAS, showing the alteration of posterior columns and roots,astrocytic gliosis and axonal swelling, suggesting motor neuron synapticdysfunction.

Motor neuron pathology in CANVAS due to RFC1 expansions