Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease

Traschutz, Andreas; Cortese, Andrea; Reich, Selina; Dominik, Natalia; Faber, Jennifer; Jacobi, Heike; Hartmann, Annette M.; Rujescu, Dan; Montaut, Solveig; Echaniz-Laguna, Andoni; Erer, Sevda; Schutz, Valerie Cornelia; Tarnutzer, Alexander A.; Sturm, Marc; Haack, Tobias B.; Vaucamps-Diedhiou, Nadege; Puccio, Helene; Schols, Ludger; Klockgether, Thomas; Warrenburg, Bart P. van de; Paucar, Martin; Timmann, Dagmar; Hilgers, Ralf-Dieter; Gazulla, Jose; Strupp, Michael; Moris, German; Filla, Alessandro; Houlden, Henry; Anheim, Mathieu; Infante, Jon; Basak, A. Nazli und Synofzik, Matthis (2021): Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. In: Neurology, Bd. 96, Nr. 9, E1369-E1382

Abstract

Objective To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (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 sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with >= 2 features of CANVAS or ataxia with chronic cough (ACC) and (2) 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 Asian individuals and even by whole-exome sequencing. 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 or dystonia (11%). Ataxia progression was approximate to 1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up <= 9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per 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. Classification of Evidence This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0028-3878
• Sprache: Englisch