Abstract
BackgroundA 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.MethodsWe 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.ResultsThe 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 (τb = 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 (τb = − 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.ConclusionsThis 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.
Highlights
Chronic polyneuropathy is a common neurological disorder, occurring in at least 4% of the middle-aged and elderly population and increasing in prevalence with age
The distinctive biallelic Replication Factor C subunit 1 (RFC1) intronic mutation and expansion of the pentanucleotide AAGGG associated with CANVAS is a striking finding in this study investigating a cohort of selected Chronic Idiopathic Axonal Polyneuropathy” (CIAP) patients
The clinical picture of a slowly progressive sensory ataxia associated with a length-dependent neuropathy with hypoesthesia, neuropathic pain and autonomic disturbances observed in our RFC1-positive population shares remarkable similarity to the peripheral involvement described in previous CANVAS series [8, 14], frequently reported in other neuropathies
Summary
Chronic polyneuropathy is a common neurological disorder, occurring in at least 4% of the middle-aged and elderly population and increasing in prevalence with age. Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) is a complex and presumably rare ataxic disorder occurring in middle-aged or older individuals, recently associated to a biallelic intronic pentanucleotide repeat expansion of a mutated AluSx3 element (AAGGGexp) of the Replication Factor C subunit 1 (RFC1) gene (Online Resource 1) [5]. We report a retrospective cross-sectional study examining the prevalence of the RFC1 expansion in biopsyinvestigated CIAP patients according to their clinical presentations. 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. 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
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