Association of biallelic RFC1 expansion with early-onset Parkinson's disease

Abstract

<p>Background and Purpose: The biallelic repeat expansion (AAGGG)<sub>exp</sub> in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)<sub>exp</sub> and includes now various nonclassical phenotypes. Biallelic (AAGGG)<sub>exp</sub> in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. Methods: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)<sub>exp</sub> was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)<sub>exp</sub> was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. Results: Three patients were found with the biallelic (AAGGG)<sub>exp</sub> in RFC1 giving a frequency of 1.10% (0.23%–3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40–48 years and their disease course had been unremarkable apart from the early onset. Conclusions: Our results suggest that (AAGGG)<sub>exp</sub> in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.</p>