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 (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. 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.

Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy

“…Clinically, predominant sensory dysfunctions, particularly in pain and vibration sensations, together with severe sensory nerve impairment revealed by NCS, suggest the diagnosis of HSAN, although cerebellar ataxia and atrophy were noted in 11/20 cases as well; 25% of our patients with [(AAGGG)exp/(AAGGG)exp] developed mild muscle weakness, more frequently in distal muscles, which is significantly different from the European study ( p < 0.05) ( 8 ), but echo to another study in Italy, where (AAGGG)exp was also detected in patients with sensorimotor neuropathy ( 10 ), as well as our in-house observation (paper in press). Taken together, RFC1 repeat expansion screening should also be recommended for the most common inherited peripheral neuropathy, hereditary motor and sensory neuropathy, or Charcot-Marie-Tooth disease.…”

“…Thereafter, another pathogenic pentanucleotide repeat, ACAGG, was uncovered from multiple Asia-Pacific regions (6,7). RFC1-related clinical spectrum has been expanded, including, but not limited to, multiple system atrophy, sensorypure neuropathy, and sensory-predominant neuropathy (8)(9)(10)(11)(12). Also in 2019, we demonstrated the association between a GGC repeat expansion of 5'-untranslated region (UTR) in the NOTCH2NLC gene and neuronal intranuclear inclusion disease (NIID), characterized by eosinophilic intranuclear inclusions in the nervous system, skin, and visceral organs (13)(14)(15).…”

Prevalence of intronic repeat expansions in RFC1 in Dutch patients with CANVAS and adult-onset ataxia

“…Following these results, various studies have screened regional CANVAS and adult-onset ataxia cohorts for the biallelic (AAGGG) n repeat expansion [5][6][7][8][9][10][11][12][13][14][15] (Supplementary Table 1). In all these studies, the frequency of the biallelic (AAGGG) n repeat expansion was higher in CANVAS cohorts compared to late-onset ataxia cohorts.…”

Comprehensive Genetic Analyses of Inherited Peripheral Neuropathies in Japan: Making Early Diagnosis Possible

“…Several patients had chronic cough (3/7, 42.9%), autonomic neuropathy (5/15, 33.3%), muscle cramps (4/9, 44.4%), and hyperCKemia (7/13, 53.8%). RFC1 -related neuropathy is often accompanied by chronic cough and autonomic disturbance [ 6 , 35 ], which are suggestive signs of RFC1 -related disorders among IPNs. To date, hyperCKemia and muscle cramps have been reported only in patients carrying (ACAGG)exp [ 13 , 33 ].…”

“…Recessive intronic pentanucleotide repeat AAGGG expansions of replication factor complex subunit 1 ( RFC1 ) were demonstrated as a genetic basis of cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome (CANVAS) in 2019 [ 4 ]. Thereafter, the clinical spectrum of RFC1 -related disorders was extended, including, but not limited to, pure sensory or sensory-dominant neuropathy and motor neuronopathy [ 5 , 6 , 7 ]. Thus, RFC1 analysis becomes essential for IPN diagnosis.…”