Parkinson's disease and multiple system atrophy are gateways to RFC1-related disorders

Biallelic pathogenic expansions of the RFC1 gene are the genetic cause of cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome. Sensory neuropathy is the most common symptom, but the clinical impairments and gateways to RFC1-related diseases are extremely variable. We genotyped patients with parkinsonism to test the hypothesis that this condition is another such gateway. We screened four cohorts of patients with parkinsonism (n = 2037) for pathogenic expansions in the RFC1 gene. In patients bearing two pathogenic expansions, we excluded the possibility of other pathogenic variants by exome sequencing. We detected 10/2037 (0.5%) biallelic (AAGGG)n RFC1 expansions. The initial diagnosis was Parkinsons disease in five patients, multiple system atrophy in three and atypical parkinsonism in two. Phenotypes perfectly mimicking Parkinsons disease and multiple system atrophy defined according to the international diagnostic criteria may serve as gateways to some RFC1-related disorders. These results could modify the diagnostic and management of these two diseases. The diagnosis and follow-up of patients with parkinsonism should include searches for typical features evocative of a RFC1-relative disease, such as sensory neuropathy or chronic cough. Nerve conduction studies should be conducted in patients with unexplained symptoms of neuropathic pain or sensory neuropathy. We also suggest that RFC1 screening should be performed in patients with atypical parkinsonism or multiple system atrophy with a long survival. Trial Registration Information: The PREDISTIM cohort is registered with ClinicalTrials.gov: NCT02360683 Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/25332961v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@89b54borg.highwire.dtl.DTLVardef@dd503aorg.highwire.dtl.DTLVardef@1be1faaorg.highwire.dtl.DTLVardef@110fcd9_HPS_FORMAT_FIGEXP M_FIG C_FIG MSA = multiple system atrophy; PD = Parkinsons disease; RFC1 = replication factor C subunit 1