Motor, Extrapyramidal, and Cognitive Involvement in RFC1 Disease

Background and objectives: Biallelic intronic repeat expansions in the replication factor C subunit 1 (RFC1) gene are a common cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome and other late-onset ataxias. Recent evidence suggests a broader phenotypic spectrum. This systematic review and meta-analysis evaluated the prevalence and features of motor neuron, extrapyramidal, and cognitive involvement in RFC1 disease. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies reporting motor neuron, extrapyramidal, or cognitive involvement in RFC1 disease from inception to March 2025. Eligible sources comprised research articles and case reports/series on genetically confirmed cases. Extracted data included publication details, study design, location, and individual participant data (IPD) covering demographics, signs, and symptoms. When needed, IPD were obtained from corresponding authors. Random-effects models were used to estimate pooled prevalences (95% CIs). Univariable mixed-effects logistic regression accounted for clustering within studies, with multivariable models including variables with p < 0.10 in univariate analyses. Results: Of 729 articles, 37 were included in the systematic review and 36 (874 patients) in the proportion meta-analyses. For IPD meta-analysis, 30 cohorts provided data on 312 patients (mean age 66.91 ± 10.76 years; median disease duration 12 [interquartile range 7-18] years; 51.5% male). Upper and lower motor neuron signs were present in 18% (95% CI 6%-34%) and 11% (95% CI 2%-24%). Patients with the ACAGG pentanucleotide repeat expansion (biallelic or compound heterozygous with an AAGGG expansion) had higher odds of muscle atrophy (OR 17.90, p 0.001) and weakness (OR 11.69, p 0.001); men had an increased likelihood of muscle atrophy (OR 2.71, p = 0.038). The pooled prevalence of parkinsonism and cognitive impairment was 8% (95% CI 1%-18%) and 31% (95% CI 13%-53%), with prominent executive-attention deficits. Cognitive decline was more likely with longer disease duration (OR 1.04, p = 0.047) and in biallelic AAGGG carriers vs ACAGG (ACAGGexp: OR 0.13, p = 0.041). Discussion: Motor neuron, extrapyramidal, and cognitive involvement may extend the phenotypic spectrum of RFC1 disease. Still, their true prevalence remains uncertain due to heterogeneity across studies, with potential overestimation from publication bias favoring atypical cases and underestimation when subtle signs are not systematically investigated. Larger multicenter cohorts with standardized assessments are needed to clarify their clinical relevance.