Bi- and Mono-Allelic RFC1 Expansion in a North American Cohort With Idiopathic Axonal Neuropathy

RFC1 biallelic repeat expansion is increasingly recognized as a cause of chronic idiopathic axonal polyneuropathy (CIAP), but it remains challenging to know who to test. This study aims to determine the prevalence of biallelic and monoallelic RFC1 expansions and their corresponding neuropathy phenotypes in CIAP patients and identify discriminators of RFC1 expansion status.

The cross-sectional Peripheral Neuropathy Research Registry was queried for individuals with CIAP and tested for RFC1 expansions. Associations between RFC1 biallelic and monoallelic status and clinical history, neurologic examination findings, fiber type involvement (exam-based), electrodiagnostic (EDX) patterns (sensory, sensorimotor, motor), and the presence of sensory neuronopathy (Camdessanche criteria) were determined.

A total of 788 participants were enrolled in the study, of whom 18 had biallelic RFC1 expansions (2.3%) and 62 had monoallelic RFC1 expansions (7.9%). All biallelic RFC1 patients had a mixed fiber neuropathy, 27.8% had weakness on examination, and 44.4% had motor EDX abnormalities. Our study identified five factors associated with RFC1 biallelic status: (1) abnormal upper limb vibration (OR 4.65, 95% CI 1.20-18.13), (2) abnormal sensory EDX studies (OR 4.65, 95% CI 1.11-24.29), (3) sensory-only polyneuropathy on EDX (OR 7.17, 95% CI 1.69-38.15), (4) sensory neuronopathy (OR 3.64, 95% CI 1.16-11.19) (AUCs = 0.80-0.81 for biallelic and 0.69-0.71 for monoallelic), and (5) body mass index (OR 0.88, 95% CI 0.78-0.97).

The prevalence of biallelic RFC1 expansion is lower in this North American CIAP population compared to previous studies. Motor involvement was frequent. Discrimination of biallelic status was good, but poor for monoallelic status.