Comprehensive phenotyping of RFC1 -related disorder: integrating electrophysiological, brain imaging, and otoneurological data in deep phenotyping

TL;DR

This study explores the diverse symptoms of RFC1-related ataxia using brain imaging, electrophysiology, and balance tests to improve diagnosis.

Contribution

The study introduces a multidisciplinary approach to phenotyping RFC1-related disorder, enhancing diagnostic accuracy in atypical cases.

Findings

15 patients with RFC1 expansions showed varied neurological and vestibular symptoms.

Comprehensive testing revealed peripheral neuropathy and cerebellar dysfunction in most patients.

Brain MRI showed vermian atrophy in some patients, highlighting imaging's role in diagnosis.

Abstract

The syndrome defined by cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS) has been previously described as a cause of late-onset ataxia. With the discovery of biallelic expansion in the replication factor C subunit 1 (
RFC1
) gene as its underlying genetic cause, this syndrome and the broader gene disease became more clinically heterogeneous and one of the most common genetic causes of ataxia in adults.

To characterize the phenotypic spectrum of
RFC1
expansion using a multidisciplinary approach combining neurological, otoneurological, and neuroimaging assessments.

A retrospective cohort study comprising patients with a genetically confirmed diagnosis of biallelic
RFC1
repeat expansions was conducted. Data related to neurological examination, video head impulse test (vHIT), caloric tests, posturography, electromyography/nerve conduction studies and brain magnetic resonance imaging (MRI) were considered.

We included 15 patients, of whom 10 (66.7%) presented with the complete clinical triad. At neurological examination, 13 patients showed signs of peripheral neuropathy. Cerebellar dysfunction was observed in 12, whereas postural instability was seen in 11. Electromyography/nervous conduction studies revealed peripheral neuropathy in all of the cases, while bilateral vestibular dysfunction was confirmed in approximately half of them. The mean balance values from the posturography were lower in the majority (
n
 = 14). In the imaging assessment (
n
 = 11), 6 patients displayed significant vermian atrophy, predominantly in the anterior/dorsal regions, while the other 5 patients showed moderate atrophy.

This study underscores the clinical importance of comprehensive phenotyping and multimodal diagnostic approaches—including neurological, otoneurological, electrophysiological, and imaging assessments—in enhancing diagnostic precision, especially when neurological examination findings are inconclusive or in atypical/incomplete clinical presentations.

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