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

Abstract: 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.

Repository: Dryad

 Publication date: 09/12/2020

 DOI: 10.5061/dryad.1vhhmgqrd

 Full citation: Traschütz, A., Cortese, A., Reich, S., Dominik, N., Faber, J., Jacobi, H., Hartmann, A., Rujescu, D., Montaut, S., Echaniz-Laguna, A., Erer, S., Schütz, V., C., Tarnutzer, A., Sturm, M., Haack, T., Vaucamps-Diedhiou, N., Puccio, H., Schöls, L., Klockgether, T., Bart P., Martin, K., Timmann, D., Hilgers, R. D., Gazulla, J., Strupp, M., Moris, G., Filla, A., Houlden, H., Anheim, M., Infante, J., Basak, A. N., & Synofzik, M. (2020). Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease. [Dataset]. (Version 1). Dryad. https://doi.org/10.5061/dryad.1vhhmgqrd

Authorship

TRASCHÜTZ, ANDREAS

CORTESE, ANDREA

REICH, SELINA

DOMINIK, NATALIA

FABER, JENNIFER

JACOBI, HEIKE

HARTMANN, ANNETTE M.

RUJESCU, DAN

MONTAUT, SOLVEIG

ECHANIZ-LAGUNA, ANDONI

ERER, SEVDA

SCHÜTZ, VALERIE CORNELIA

TARNUTZER, ALEXANDER A.

STURM, MARC

HAACK, TOBIAS B.

VAUCAMPS-DIEDHIOU, NADÈGE

PUCCIO, HELENE

SCHÖLS, LUDGER

KLOCKGETHER, THOMAS

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