Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series

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dc.contributor.authorHarkness, J. Robert
dc.contributor.authorMcdermott, John H.
dc.contributor.authorMarsden, Shea
dc.contributor.authorJamieson, Peter
dc.contributor.authorMetcalfe, Kay A.
dc.contributor.authorKhan, Naz
dc.contributor.authorMacken, William L.
dc.date.accessioned2026-04-04T13:37:51Z
dc.date.available2026-04-04T13:37:51Z
dc.date.issued2025
dc.departmentİnönü Üniversitesi
dc.description.abstractBackground 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, T & uuml;rkiye, 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 227]). 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-Barr & eacute; 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-Barr & eacute; 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. Copyright (c) 2025 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
dc.description.sponsorshipNational Health Service (NHS) - NIHR [301748]; NHS England; Wellcome Trust; Cancer Research UK; Medical Research Council; Bioimaging Facility at the University of Manchester
dc.description.sponsorshipNational Institute for Health and Care Research, LifeArc, and Wellcome Trust.
dc.identifier.endpage680
dc.identifier.issn1474-4422
dc.identifier.issn1474-4465
dc.identifier.issue8
dc.identifier.orcid0000-0002-0260-7020
dc.identifier.orcid0000-0001-8764-1289
dc.identifier.orcid0009-0009-8329-6065
dc.identifier.orcid0000-0002-8527-2210
dc.identifier.orcid0000-0002-5408-0013
dc.identifier.pmid40683276
dc.identifier.scopus2-s2.0-105010708400
dc.identifier.scopusqualityQ1
dc.identifier.startpage667
dc.identifier.urihttps://hdl.handle.net/11616/110110
dc.identifier.volume24
dc.identifier.wosWOS:001609073000001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.ispartofLancet Neurology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250329
dc.subjectGuillain-Barre-Syndrome
dc.subjectCycle Gene Rcc1
dc.subjectNucleotide Exchange
dc.subjectNucleocytoplasmic Transport
dc.subjectOxidative-Stress
dc.subjectNuclear Export
dc.subjectDrosophila
dc.subjectRan
dc.subjectMechanism
dc.subjectParaquat
dc.titleAcute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series
dc.typeArticle

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