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Lookup NU author(s): Professor Wyatt YueORCiD, Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 This is an Open Access article under the CC BY 4.0 licenseBackground: The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families. Methods: For this case series, we identified children affected by a severe, acute-onset axonal neuropathy following infection through an international research consortium of paediatric neurologists and clinical geneticists from nine countries (Canada, Cyprus, Czechia, Germany, Iran, Saudi Arabia, Slovakia, Türkiye, and the UK). Clinical assessments included nerve conduction studies and neuroimaging. We did exome or genome sequencing in DNA samples from all patients. We characterised the proteins encoded by the genetic variants by use of thermal stability and enzymatic assays, using recombinantly expressed proteins. We assessed cellular protein transport under heat or oxidative stress by use of immunofluorescence in primary fibroblasts, obtained from patients. We generated a humanised Drosophila knock-in model to assess the effects of stress on the in vivo function of RCC1. Findings: Between Nov 2, 2011, and July 10, 2024, we identified 24 individuals from 12 families who had severe, acute-onset axonal neuropathy following infection (13 female and 11 male patients, with a mean age at diagnosis of 1 year 10 months [SD 2·27]). Eight biallelic missense variants in RCC1 were identified in affected individuals with autosomal recessive inheritance. Patients had variable phenotypes, ranging from rapidly progressive fatal axonal neuropathy to mild motor neuropathy with impaired walking. Neurological presentation was often secondary to an infection, resulting in initial misdiagnoses of Guillain-Barré syndrome in several patients. 15 children had disease recurrence. The disease was fatal in 15 patients. The RCC1 variants in these patients code for proteins that alter GDP-to-GTP exchange activity and have reduced thermal stability in vitro. In primary fibroblasts, heat shock or oxidative stress revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model of the disease revealed a fatal intolerance to oxidative stress. Interpretation: We describe an autosomal recessive, acute-onset paediatric axonal neuropathy, seemingly triggered by infection, that affects individuals with biallelic RCC1 variants. In these children, the disease can mimic Guillain-Barré syndrome. The pathological mechanisms underlying this novel axonal neuropathy might overlap with those of amyotrophic lateral sclerosis. Cellular studies indicate that RCC1 variants affect nucleocytoplasmic transport, which is crucial for healthy axonal function. Future studies should be directed at pre-symptomatic treatment by exploring ways to maintain nucleocytoplasmic transport. Funding: National Institute for Health and Care Research, LifeArc, and Wellcome Trust.
Author(s): Harkness JR, McDermott JH, Marsden S, Jamieson P, Metcalfe KA, Khan N, Macken WL, Pitceathly RDS, Record CJ, Maroofian R, Kleopa K, Christodoulou K, Sabir A, Islam L, Santra S, Durmusalioglu EA, Atik T, Isik E, Cogulu O, Urquhart JE, Beaman GM, Demain LA, Jackson A, Blakes AJM, Byers HJ, Bennett H, Lin W-H, Adamson A, Patel S, Yue WW, Taylor RW, Reunert J, Marquardt T, Buchert R, Haack T, Losch H, Ryba L, Lassuthova P, Valkovicova R, Haberlova J, Lauerova B, Trusikova E, Polavarapu K, Kilicarslan OA, Lochmuller H, Zamani M, Chamanrou N, Shariati G, Sadeghian S, Azizimalamiri R, Maddirevula S, AlMuhaizea M, Alkuraya FS, Horvath R, Gungor S, Manzur A, Munot P, Matthews R, Banka S, Reilly MM, Bennett D, O'Keefe RT, Newman WG
Publication type: Article
Publication status: Published
Journal: The Lancet Neurology
Year: 2025
Volume: 24
Issue: 8
Pages: 667-680
Print publication date: 01/08/2025
Online publication date: 16/07/2025
Acceptance date: 02/04/2025
Date deposited: 28/07/2025
ISSN (print): 1474-4422
ISSN (electronic): 1474-4465
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/S1474-4422(25)00198-X
DOI: 10.1016/S1474-4422(25)00198-X
Data Access Statement: The variants were submitted to Clinvar with the following accession numbers SCV004231856–SCV004231862 and SUB14705452. Research on the de-identified patient data from the 100 000 Genomes Project used in this Article can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers can contact research-network@genomicsengland.co.uk or access the relevant information on the Genomics England website. Exome sequencing data are not publicly available as informed consent was not provided for this purpose. Human fibroblasts are primary cells and therefore a limited resource. Availability is through the corresponding author, subject to technical constraints and completion of a material transfer agreement ...
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