University of Oulu

Ylikotila P, Sipilä J, Alapirtti T, et al. Association of biallelic RFC1 expansion with early-onset Parkinson's disease. Eur J Neurol. 2023;30:1256-1261. doi:10.1111/ene.15717

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

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Author: Ylikotila, Pauli1,2; Sipilä, Jussi1,3; Alapirtti, Tiina4;
Organizations: 1Clinical Neurosciences, University of Turku, Turku, Finland
2Neurocenter Turku University Hospital, Turku, Finland
3Department of Neurology, Siun Sote North Karelia Central Hospital, Joensuu, Finland
4Department of Neurology, Kanta-Häme Central Hospital, Hämeenlinna, Finland
5Department of Neurology, Lapland Central Hospital, Rovaniemi, Finland
6Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
7Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan
8Research Unit of Clinical Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
9Neurocenter, Neurology, Oulu University Hospital, Oulu, Finland
10Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: John Wiley & Sons, 2023
Publish Date: 2023-08-25


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.

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Series: European journal of neurology
ISSN: 1351-5101
ISSN-E: 1468-1331
ISSN-L: 1351-5101
Volume: 30
Issue: 5
Pages: 1256 - 1261
DOI: 10.1111/ene.15717
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
Funding: This study was funded in part by grants from the Sigrid Jusélius Foundation, the Terttu Foundation, the Yrjö Jahnsson Foundation and the Finnish Parkinson Foundation and from the Japan Agency for Medical Research and Development (AMED) (grant numbers JP22ek0109486, JP22ek0109549, JP22ek0109348) and JSPS Kakenhi (grant numbers JP20K07907, JP 21K0786). The study has received funding from the Medical Research Center Oulu and state research funding from Oulu University Hospital.
Dataset Reference: Sequence data cannot be made publicly available because of restrictions imposed by the EU and Finnish General Data Protection Regulation (GDPR). Access to sequence data can be applied from the Innovation Agent of the University of Oulu ( Qualified researchers will be required to complete ‘Material and data transfer agreement for the transfer of human materials (personal data)’. Genetic variation data have been submitted to ClinVar (SCV002600060). Other data are available within the article.
Copyright information: © 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.