Novel Clinical Insights From a Swedish RFC1 Spectrum Disorder Cohort

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Biallelic pentanucleotide expansions in RFC1 are linked to Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) and other conditions.
• The clinical spectrum of RFC1 expansions is still being defined.

Purpose of the Study:

• To clinically characterize a Swedish cohort of patients with biallelic RFC1 expansions.
• To investigate the prevalence and clinical features of RFC1-related disorders in Sweden.

Main Methods:

• Retrospective enrollment of 30 patients with homozygous RFC1 expansions from a Swedish tertiary center.
• Clinical data evaluation including neurological examinations, nerve conduction studies, quantitative sensory testing, brain MRI, and vestibular/eye motor tests.

Main Results:

• Twenty-two patients met CANVAS criteria, with symptom onset around 52 years and slow disease progression.
• Multisystemic features were common (83%), including dysautonomia (77%), dyskinesia (36%), and bradykinesia (17%).
• Phenotypes overlapped with MSA-C and mitochondrial ataxias; one patient lacked neuropathy on nerve conduction studies.

Conclusions:

• Findings suggest a founder effect in Sweden and significant subclinical involvement in RFC1-spectrum disorder.
• RFC1 disorder should be considered in patients with cerebellar and vestibular dysfunction, even without neuropathy.
• A discordant vestibulo-ocular reflex (VOR) pattern may indicate early RFC1-spectrum disorder, with largely preserved otolith function.