Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

Abstract

Background and objectives: The RFC1 spectrum has become considerably expanded as multisystemic features beyond the triad of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) have started to be unveiled, although many still require clinical replication. Here, we aimed to clinically characterize a cohort of RFC1-positive patients by addressing both classic and multisystemic features. In a second part of this study, we prospectively assessed small nerve fibers (SNF) and autonomic function in a subset of these RFC1-related patients.

Methods: We retrospectively enrolled 67 RFC1-positive patients from multiple neurologic centers in Portugal. All patients underwent full neurologic and vestibular evaluation, as well as neuroimaging and neurophysiologic studies. For SNF and autonomic testing (n = 15), we performed skin biopsies, quantitative sensory testing, sudoscan, sympathetic skin response, heart rate deep breathing, and tilt test.

Results: Multisystemic features beyond CANVAS were present in 82% of the patients, mainly chronic cough (66%) and dysautonomia (43%). Other features included motor neuron (MN) affection and motor neuropathy (18%), hyperkinetic movement disorders (16%), sleep apnea (6%), REM and non-REM sleep disorders (5%), and cranial neuropathy (5%). Ten patients reported an inverse association between cough and ataxia severity. A very severe epidermal denervation was found in skin biopsies of all patients. Autonomic dysfunction comprised cardiovascular (67%), cardiovagal (54%), and/or sudomotor (50%) systems.

Discussion: The presence of MN involvement, motor neuropathy, small fiber neuropathy, or extrapyramidal signs should not preclude RFC1 testing in cases of sensory neuronopathy. Indeed, the RFC1 spectrum can overlap not only with multiple system atrophy but also with hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, and feeding dystonia phenotypes. Some clinical-paraclinical dissociations can pose diagnostic challenges, namely large and small fiber neuropathy and sudomotor dysfunction which are usually subclinical.

Figure 1. Clinical Features at Disease Onset and During Progression

(A) Symptoms at onset and during progression in 67 RFC1-positive patients. Patients could have multiple combinations of symptoms. (B) Age of onset of each symptom. The vertical line in boxes represents median age, in years, and box edges represent lower and upper quartiles. Whiskers correspond to maximum and minimum ages.

Figure 2. Neurologic Examination of RCF1-Positive Patients at Most Recent Evaluation

Body distribution of affected sensory modalities and reflex evaluation is detailed. HIT = head impulse test; LL = lower limbs; UL = upper limbs; ULL = upper and lower limbs.

Figure 3. MRI Features of RFC1 Disease

Axial (A) and sagittal (B) T2-weighted and axial T2*–weighted (C) brain MRI of 2 RFC1-positive patients. Both have T2-hyperintensity of bilateral globus pallidum (arrow heads), more evident in the patient in Figure A; no correspondent signal abnormalities on T2* MRI or brain CT were found (not shown). The patient in Figure B also showed occipital cortico-subcortical small black dots in T2* (arrows), suggesting microhemorrhages (flow voids excluded).

Figure 4. RFC1 Spectrum Disorder

Phenotypic classification after clinical and paraclinical study, according to (1) sensory, cerebellar, and vestibular dysfunctions and (2) involvement of other systems (multisystemic RFC1, outer circle, vs nonmultisystemic RFC1, inner circle).