RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia.

Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.

Beijer D ，Dohrn MF ，De Winter J ，Fazal S ，Cortese A ，Stojkovic T ，Fernández-Eulate G ，Remiche G ，Gentile M ，Van Coster R ，Dufke C ，Synofzik M ，De Jonghe P ，Züchner S ，Baets J ... -  《-》

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

Sánchez-Tejerina D ，Alvarez PF ，Laínez E ，Martinez VG ，Santa-Cruz DI ，Verdaguer L ，Gratacòs M ，Seoane JL ，Raguer N ，Hernández-Vara J ，Llauradó A ，Sotoca J ，Salvado M ，Arumi EG ，Tizzano EF ，Juntas R ... -  《-》

Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

Miyatake S ，Yoshida K ，Koshimizu E ，Doi H ，Yamada M ，Miyaji Y ，Ueda N ，Tsuyuzaki J ，Kodaira M ，Onoue H ，Taguri M ，Imamura S ，Fukuda H ，Hamanaka K ，Fujita A ，Satoh M ，Miyama T ，Watanabe N ，Kurita Y ，Okubo M ，Tanaka K ，Kishida H ，Koyano S ，Takahashi T ，Ono Y ，Higashida K ，Yoshikura N ，Ogata K ，Kato R ，Tsuchida N ，Uchiyama Y ，Miyake N ，Shimohata T ，Tanaka F ，Mizuguchi T ，Matsumoto N ... -  《-》

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.

Cortese A ，Curro' R ，Vegezzi E ，Yau WY ，Houlden H ，Reilly MM ... -  《-》

Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late-onset ataxia.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) has been recently linked to biallelic expansions of a pentanucleotide repeat in the replication factor C subunit 1 (RFC1) gene. Herein, we sought to investigate the presence of pathological RFC1 expansions in selected Greek patients with late-onset ataxia and delineate the phenotypic spectrum of genetically confirmed CANVAS in the Greek population. We screened genetically a total of 77 selected index patients, 67 originating from a cerebellar ataxia cohort and 10 from a hereditary neuropathy cohort. We identified five index cases (6.5%) with biallelic pathological RFC1 expansions, two in the cerebellar ataxia cohort (3%) and three in the neuropathy cohort (30%). Overall, four out of five of cases with full-blown CANVAS and one case with sensory ataxic neuropathy had biallelic pathological expansions. The phenotypic spectrum of positive cases (including two affected siblings) was consistent with previous reports and implied that the sensory neuropathy may be the earliest feature in genetically confirmed CANVAS. Screening for biallelic RFC1 expansions is recommended in all cases with late-onset ataxia of unknown cause, particularly when a sensory neuropathy is present.

Kontogeorgiou Z ，Kartanou C ，Tsirligkani C ，Anagnostou E ，Rentzos M ，Stefanis L ，Karadima G ，Koutsis G ... -  《-》