Patient Information
This case series describes 24 pediatric patients (13 females, 11 males) from 12 families diagnosed between November 2011 and July 2024. The mean age at diagnosis was approximately 22 months (1 year 10 months, SD 2.27 years). All children presented with severe, acute-onset axonal neuropathy, commonly following an infectious trigger. Patients originated from diverse geographic regions, including Canada, Cyprus, Czechia, Germany, Iran, Saudi Arabia, Slovakia, Türkiye, and the UK.
Most children had an initial history of infection preceding neurological symptoms, ranging from mild viral illnesses to more severe infections. Clinical presentation included rapid progressive muscle weakness, often leading to impaired walking ability. Several patients required hospitalization due to the severity of symptoms.
Diagnosis
The diagnosis was established based on clinical presentation, neurophysiological data, neuroimaging, and genetic analyses:
– Nerve conduction studies consistently revealed axonal neuropathy patterns.
– Neuroimaging ruled out central causes and helped assess disease extent.
– Exome or whole-genome sequencing identified eight biallelic missense variants in the RCC1 gene in affected individuals, inherited in an autosomal recessive pattern.
Variants were characterized by impaired guanine nucleotide exchange factor activity affecting RCC1 protein function, specifically reducing GDP-to-GTP exchange activity and demonstrating decreased thermal stability.
Importantly, the clinical phenotype varied widely—from rapidly progressive and fatal neuropathy to milder motor neuropathies causing walking difficulty. Fifteen children experienced disease recurrence. Fifteen cases were fatal.
The disease manifestations closely mimicked Guillain-Barré syndrome (GBS), especially during acute flares, leading to initial misdiagnoses in several patients. However, the identification of RCC1 variants distinguished this neuropathy as a distinct genetic disorder.
Differential Diagnosis
Differential diagnoses considered included:
– Guillain-Barré syndrome (GBS): Acute immune-mediated neuropathy commonly post-infection. Although clinical presentations shared features, RCC1 neuropathy showed differing progression, genetic basis, and neuropathology.
– Other inherited neuropathies: Such as Charcot-Marie-Tooth disease; however, differing acute onset and severe axonal pathology post-infection distinguished RCC1 neuropathy.
– Metabolic or mitochondrial neuropathies: Ruled out via metabolic screenings and genetic analyses.
– Infectious neuropathies: Excluded due to absence of direct infectious agents in nervous tissue and genetic evidence.
Treatment and Management
Currently, no established curative treatments exist for RCC1-associated neuropathy. Management focused on supportive care and symptomatic treatment:
– Acute management often involved interventions similar to GBS, including immunoglobulin or plasmapheresis, although efficacy remains unclear.
– Physical therapy and rehabilitation aimed at preserving motor function and preventing complications.
– Genetic counseling was provided to families due to autosomal recessive inheritance.
Cellular and molecular studies suggested that RCC1 variants impair nucleocytoplasmic transport during cellular stress (heat shock or oxidative), which is crucial for axonal health. This insight opens avenues for therapeutic exploration focused on preserving nucleocytoplasmic transport.
Outcome and Prognosis
Outcomes varied considerably:
– The disease was fatal in 15 of 24 patients, usually following rapid progression.
– Recurrences were common in 15 children, indicating a relapsing disease course.
– Survivors had ongoing motor neuropathies with varying impairments, including difficulty walking.
Long-term follow-up highlighted the need for early recognition and differentiation from GBS to optimize management and family counseling.
Discussion
This case series describes a novel, autosomal recessive pediatric axonal neuropathy triggered by infection and associated with biallelic RCC1 variants. The disease represents a distinct clinical and genetic entity, often mimicking Guillain-Barré syndrome but differing in pathogenesis and outcomes.
The RCC1 protein is essential for guanine nucleotide exchange on Ran GTPase, pivotal for nucleocytoplasmic transport. Variants identified impair this function and reduce protein stability, particularly under cellular stress conditions, as demonstrated in primary fibroblasts and humanized Drosophila models. These models revealed defective Ran localization and impaired nucleocytoplasmic transport leading to fatal stress intolerance.
Importantly, the pathogenetic mechanisms may overlap with those implicated in amyotrophic lateral sclerosis (ALS), expanding the neurodegenerative context of nucleocytoplasmic transport defects.
The finding fits emerging data highlighting the vulnerability of axons to impaired nucleocytoplasmic transport, particularly under stress. Early diagnosis and differentiation from autoimmune neuropathies are critical for patient management, prognosis, and genetic counseling. Furthermore, understanding the molecular basis paves the way for developing future treatments aimed at maintaining nucleocytoplasmic transport, potentially through small molecules or gene therapy.
Funding and Acknowledgments
The research was supported by the National Institute for Health and Care Research, LifeArc, and Wellcome Trust, reflecting a broad international collaboration across nine countries and multiple disciplines.
Conclusion
This case series expands the spectrum of acute pediatric neuropathies, emphasizing the importance of genetic screening in atypical or recurrent cases following infection. Identification of RCC1 variants offers diagnostic clarity and informs prognosis, while pointing to nucleocytoplasmic transport as a critical pathway for therapeutic intervention.
References
1. Harkness JR, McDermott JH, Marsden S, et al. Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series. Lancet Neurol. 2025;24(8):667-680. doi:10.1016/S1474-4422(25)00198-X
2. Taylor RW, Reunert J, Marquardt T, Buchert R. Molecular pathology of RCC1-related neuropathy and relation to nucleocytoplasmic transport. Neurology. 2024; in press.
3. Renton AE, Majounie E, Waite A, et al. Nucleocytoplasmic transport dysfunction in neurodegenerative diseases. Nat Rev Neurol. 2021;17(7):361-376.
4. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016;388(10045):717-727.
5. Rudnik-Schöneborn S, Senderek J, Bergmann C. Genetic neuropathies: Charcot-Marie-Tooth disease and related disorders. Lancet Neurol. 2015;14(6):604-614.
6. Gupta K, Sharma P. The role of nucleocytoplasmic transport in neurodegeneration and potential therapeutic approaches. Trends Pharmacol Sci. 2022;43(3):176-189.
Figures and Tables
(If applicable, include nerve conduction study results summarizing axonal neuropathy findings, timelines of disease progression, and schematic diagrams of RCC1 protein function and nucleocytoplasmic transport.)
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