RCC1 neuropathy mimics childhood axonal Guillain-Barré syndrome with variable clinical severity and survival.

AIM: To assess the phenotype and genotype of 10 new patients with biallelic RCC1 variants who presented with axonal neuropathy, and assess functional consequences in vitro. METHOD: In this retrospective, multicentre, observational study, we identified 10 individuals from six families with biallelic RCC1 missense variants who had previously developed axonal neuropathy (six males and females females; mean age 20.2 months, SD 21.0 months, range 58.0 months). Survival analyses were performed using data from the current cohort and previously reported patients. The functional consequences of five new missense variants (p.Leu38Val, p.Ala98Val, p.Arg139His, p.Arg217Trp, p.Gly380Arg) were assessed using thermal stability, guanosine triphosphate exchange factor activity, and nucleocytoplasmic transport rescue assays. RESULTS: Most patients presented in early childhood with infection-triggered acute motor axonal neuropathy. We also identified patients with mild chronic neuropathy and early-onset neurodevelopmental disease. Statistical analysis indicated that disease onset at or before 2 years of age was associated with poorer survival (p = 0.047). Functional studies revealed that new variants reduced protein thermal stability, guanosine triphosphate exchange factor activity, and Ran nucleocytoplasmic localization. INTERPRETATION: RCC1 neuropathy presents a broader clinical spectrum than previously recognized, with ascertainment previously biased for children with severe rapid-onset disease. Our findings support dysfunction of nucleocytoplasmic transport as a pathogenic mechanism in axonal neuropathy. Earlier age at onset was associated with poorer prognosis, which may guide management in future paediatric patients.