Abstract Details

Title Ataxia And Cough Are Indicative For Biallelic RFC1 Repeat Expansions In Hereditary Sensory And Autonomic Neuropathy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S29 - Preclinical and Observational Studies of Neuromuscular Diseases (2:48 PM-3:00 PM)

Poster/Presentation
Number 010

Background Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a disease of mostly unknown genetic cause. Despite the increased use of high-throughput methods like whole-exome-sequencing (WES), a substantial portion of HSAN patients remain genetically unsolved. Biallelic repeat expansions in RFC1 have recently been associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (Cortese et al, 2019) and variable partial phenotypic clusters thereof (Traschütz et al, 2021).

Objective To unlock the genetic basis of hereditary sensory and autonomic neuropathy (HSAN) with chronic cough.

Design/Methods We characterized a cohort of 12 unsolved WES-negative HSAN families all presenting with chronic cough. After negative WES, we performed a repeat-primed PCR to detect intronic RFC1 expansions.

Results In these patients, 75% carried biallelic expansions of the AAGGG motif in RFC1. Compared to RFC1-/- cases, RFC1+/+ patients presented more consistently with autonomic and positive sensory symptoms. Afferent ataxia was more severe, whereas cerebellar ataxia was less common (25%), but very specific in the RFC1+/+ cohort if present.

Conclusions We here unravel a frequent genetic basis of the so far elusive syndrome of HSAN with chronic cough, as the diagnostic yield of RFC1 screening was surprisingly high in this WES-negative cohort. Intriguingly, in three families with presumed dominant inheritance, we show that several families follow in fact a pseudo-dominant inheritance pattern. In these families, children of an affected homozygous individual and a heterozygous carrier have a 50% chance of being homozygous, likely due to the relatively high carrier rate of RFC1 repeat expansions in the general population. Thus, we conclude that chronic cough and ataxia are strong indicators for RFC1-neuropathy, a new diagnosis within the neuropathy-ataxia spectrum disorders, and that RFC1 expansions are a relatively common cause of HSAN with chronic cough that can easily be overseen by routine genetic diagnosis procedures.

Authors/Disclosures
Danique Beijer, PhD (University of Miami) PRESENTER	Dr. Beijer has nothing to disclose.
Maike Dohrn, MD (Department of Neurology, RWTH Aachen University Hospital)	Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea, Alnylam, Pfizer, Amicus. Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus, Akcea. Dr. Dohrn has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Akcea, Alnylam, Pfizer. The institution of Dr. Dohrn has received research support from Pfizer. Dr. Dohrn has received research support from German Research Foundation.
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Gauthier Remiche, MD	Dr. Remiche has nothing to disclose.
Matthis Synofzik (Hertie-Institute for Clinical Brain Research)	Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Orphayzme Pharmaceuticals. The institution of Matthis Synofzik has received research support from EJPRD.
	No disclosure on file
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
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