RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

Abstract

Background: A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. "Chronic Idiopathic Axonal Polyneuropathy" (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations.

Methods: We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years.

Results: The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τ_b = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio-POR 6.73 CI 95% 2.79-16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τ_b = - 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03-58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17-22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups.

Conclusions: This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Keywords: Cerebellar Ataxia; Chronic Idiopathic Axonal Neuropathy; Neuropathy; Replication factor C subunit 1; Vestibular Areflexia Syndrome.

Fig. 1

Study flow diagram

Fig. 2

Prevalence of RFC1 expansion mutations according to clinical presentation. Bar charts showing carriers of biallelic a AAAAG, b AAAGG, c AAGGG and d compound or non-canonical pentanucleotide RFC1 expansion mutations in patients with Chronic Idiopathic Axonal Polyneuropathy grouped by clinical presentation. Error bar: 95% CI for within-group proportions

Fig. 3

Nerve fiber distribution according to axon diameter. a The bimodal distribution observed in middle-aged (dark shade) and elderly controls (grey shade) is lost in RFC1-positive neuropathy cases (box: first and third quartile; middle bar: median; upper/lower whisker: either 1.5 interquartile range or maximum/minimum observed values); b scatterplot of estimated surviving large and small myelinated fibers: extreme loss of large fibers but variable involvement of small myelinated fibers is observed

Fig. 4

Representative cases from sural nerve pathology studies. Sural nerve biopsy revealed a diffuse depletion of large myelinated fibers that was similar in severity between patients, instead small myelinated fibers appeared relatively preserved in less affected nerves (a–b). Regeneration clusters were observed in a single instance and associated with mild disease (asterisks, a). Active degeneration was uncommon. Toluidine blue-stained semithin cross sections of sural nerve, bar = 20 µm; inbox: fraction of surviving small (S) and large (L) myelinated fibers compared to control average