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

Background and Purpose: The biallelic repeat expansion (AAGGG)(exp) 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)(exp) and includes now various nonclassical phenotypes. Biallelic (AAGGG)(exp) 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)(exp) was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)(exp) 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)(exp) 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)(exp) 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.

Automated summary

Recent study found that repeat expansion is a rare cause of early-onset Parkinson's disease. Among a nationwide cohort of Finnish patients, 1.10% had biallelic repeat expansion in the RFC1 gene.