2024-01-232024-01-232021-03-02Erer, S. (2021). "Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease". Neurology, 96(9), E1369-E1382.0028-38781526-632Xhttps://www.neurology.org/doi/10.1212/WNL.0000000000011528https://hdl.handle.net/11452/39276Çalışmada 32 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır.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.eninfo:eu-repo/semantics/closedAccessVestibular areflexia syndromeCerebellar-ataxiaNeuropathyCohugDiagnosisRepeatCanvasAdultAgedAtaxiaBilateral vestibulopathyCohort studiesDisease progressionDNA repeat expansionEuropeExomeFemaleGenetic testingHumansMagnetic resonance imagingMaleMiddle agedMultiple system atrophyPhenotypePredictive value of testsReplication protein CTurkeyVestibular diseasesArticle0006570545000202-s2.0-85101586876E1369E138296933495376https://doi.org/10.1212/WNL.0000000000011528Clinical NeurologyMachado-Joseph Disease; Spinocerebellar Ataxias; PolyglutamineRepetitive DNAReplication factor CRFC1 protein, humanAdultAgedAtaxiaBilateral vestibulopathyCohort analysisDiagnostic imagingDisease exacerbationEuropeExomeFemaleGenetic screeningGeneticsHumanMaleMiddle agedNuclear magnetic resonance imagingPhenotypePredictive valueShy drager syndromeTurkey (bird)Vestibular disorder