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

Abstract

Background and purpose 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. Methods 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. Results 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%). Conclusions 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.

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 ].…”

Clinical and paraclinical features of small fiber neuropathy in Sjögren’s syndrome

“…Analysis of clinical symptoms at disease onset revealed that the initially reported symptoms of patients with SFN do not differ between idiopathic SFN and SFN associated with Sjögren’s syndrome. This symptom overlap might also be amplified through autonomic involvement of SFN which can lead to dry eyes and mouth symptoms [ 30 , 31 ]. Also, neither assessment of CSF parameters such as cell count, total protein, Q-albumin, lactate, nor evaluation for oligoclonal bands was helpful in distinguishing the groups.…”

Genetic pain loss disorders

“…Another study revealed a high number of individuals with RFC1 repeat expansion in a preselected cohort of patients with sensory CIAP (53%), but also some patients with minor and pronounced motor involvement 125 . RFC1 repeat expansions have also been described in patients with HSAN, cough and ataxia 127 . RFC1 encodes the large subunit of replication factor C, which is required for eukaryotic DNA replication and repair.…”