Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease

Objective: To delineate the full phenotypic spectrum, discriminative
features, piloting longitudinal progression data, and sample size
calculations of RFC1-repeat expansions, recently identified as causing
cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
Methods: Multimodal RFC1 repeat screening (PCR, southern blot,
whole-exome/genome (WES/WGS)-based approaches) combined with
cross-sectional and longitudinal deep-phenotyping in (i) cross-European
cohort A (70 families) with ≥2 features of CANVAS and/or
ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families)
with unselected late-onset ataxia. Results: Prevalence of RFC1-disease was
67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and
100% in ACC. RFC1-disease was also identified in Western and Eastern
Asians, and even by WES. Visual compensation, sensory symptoms, and cough
were strong positive discriminative predictors (>90%) against
RFC1-negative patients. The phenotype across 70 RFC1-positive patients was
mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia
(28%) (=overlap with cerebellar-type multiple system atrophy [MSA-C]),
postural instability (49%), slow vertical saccades (17%), and chorea
and/or dystonia (11%). Ataxia progression was ~1.3 SARA points/year (32
cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean
3.1]), but also included early falls, variable non-linear phases of
MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment
trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total
to detect 50% reduced progression. Conclusions: RFC1-disease is frequent
and occurs across continents, with CANVAS and ACC as highly diagnostic
phenotypes, yet as variable, overlapping clusters along a continuous
multisystemic disease spectrum, including MSA-C-overlap. Our natural
history data help to inform future RFC1-treatment trials.