Adult-Onset Ataxia and Polyneuropathy: Comprehensive Disease Report

Scope and disease mapping

The requested label is not a consistently maintained standalone disease name. In a Mendelian context, it maps most closely to RFC1 spectrum disorder, especially cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Open Targets identifies this entity as MONDO:0044720 and links it specifically to RFC1 (ENSG00000035928), supported by human genetic evidence including PMID 30926972, PMID 31230722, and ClinGen/ClinVar records. “Adult-onset ataxia and polyneuropathy” can also describe genetically heterogeneous disorders; therefore, a knowledge-base entry should state explicitly that this report concerns RFC1-related disease, not every disorder producing that phenotype. (OpenTargets Search: CANVAS)

The evidence summarized below is aggregated disease-level evidence from cohorts, case series, molecular studies, and ClinicalTrials.gov—not individual EHR data.

Table: This table summarizes the core knowledge-base fields for RFC1 spectrum disorder/CANVAS, the main Mendelian interpretation of adult-onset ataxia and polyneuropathy. It highlights identifiers, causal genetics, phenotype frequencies, diagnostics, 2024 mechanistic insights, prognosis, and current trial status with ontology suggestions and evidence IDs.

1. Disease information

RFC1 disease is an autosomal-recessive, usually late-onset neurodegenerative disorder whose manifestations form a continuum from isolated sensory neuronopathy/neuropathy to combined sensory, cerebellar, and bilateral vestibular dysfunction. The complete triad is termed CANVAS. Other common labels are RFC1 spectrum disorder, RFC1-related disorder, RFC1-associated disease, CANVAS syndrome, and ataxia with chronic cough.

Identifiers and classifications

• MONDO: MONDO:0044720, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome.
• OMIM: CANVAS is commonly indexed as 614575; RFC1 is 102579. Database versions should be checked before ingestion.
• Gene: RFC1, replication factor C subunit 1; Ensembl ENSG00000035928.
• MeSH: no uniquely specific RFC1-CANVAS descriptor was established in the retrieved evidence; broader terms include cerebellar ataxia and peripheral nervous system disease.
• ICD-10/ICD-11: no uniquely disease-specific code was established. Coding generally combines hereditary/degenerative ataxia, polyneuropathy, and vestibular dysfunction. A knowledge base should not assign a single exact ICD code without jurisdictional validation.

The landmark discovery study described a mean onset of 54±9 years (range 35–73) and mean observed disease duration of 11±7 years. Its defining molecular lesion was a biallelic, large intronic RFC1 repeat expansion. (cortese2019biallelicexpansionof pages 4-6)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The principal cause is a germline biallelic nonreference pentanucleotide-repeat expansion in intron 2 of RFC1, usually (AAGGG)n. Typical pathogenic alleles contain approximately 400–2,000 repeats, often near 800–1,000, whereas the reference motif is (AAAAG)n. The expansion lies in the poly-A tail of an AluSx3 element. (cortese2019biallelicexpansionof pages 4-6, gisatulin2020clinicalspectrumof pages 5-9, gisatulin2020clinicalspectrumof pages 1-5)

Pathogenic configurations are population dependent. Besides AAGGG, disease-associated ACAGG and complex Māori-associated (AAAGG)exp(AAGGG)exp alleles have been reported. Consequently, an AAGGG-only assay can miss disease in non-European populations. (curro2024roleofthe pages 4-7, scriba2023rfc1inan pages 3-4)

Rare patients have one expanded allele and a truncating RFC1 variant in trans. Reported variants include c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), and c.2876del (p.Pro959GlnfsTer24). Fibroblasts carrying two tested truncating alleles showed nonsense-mediated decay and reduced RFC1 RNA and protein. Full RFC1 sequencing is therefore appropriate when classic CANVAS accompanies only one detected expansion. (ronco2023truncatingvariantsin pages 1-2)

Risk and modifying factors

• Genetic risk: two pathogenic RFC1 alleles are causal; heterozygous carriers are generally unaffected.
• Repeat size: the strongest established modifier. In 553 expansion carriers, with size measured in 392, larger alleles predicted earlier onset and more severe disease. Earlier neurologic onset had HR 2.06 for the smaller allele and 1.53 for the larger allele; earlier dysarthria/dysphagia had HR 3.40 and 1.71; earlier loss of independent walking had HR 2.78 and 1.60, respectively. Larger repeats were also associated with complex neuropathy, complete CANVAS, and greater vermian atrophy. Repeat size explained only about 6% of onset variability, implying additional modifiers. (curro2024roleofthe pages 10-12, curro2024roleofthe pages 15-17)
• Age: manifestations are age dependent, explaining apparently sporadic presentations and unaffected younger siblings.
• Family history: its absence does not argue strongly against disease because inheritance is recessive and onset is late.

No reproducible sex, lifestyle, occupational, dietary, infectious, or toxic risk factor has been established for genetically confirmed RFC1 disease. No validated protective allele, diet, drug, or environmental exposure is known. Environmental or epigenetic modifiers are plausible because repeat size explains little phenotypic variance, but specific gene–environment interactions remain unproven. The 2024 repeat study found no major meiotic or tissue-specific somatic instability, arguing against marked anticipation driven by unstable expansion growth. (curro2024roleofthe pages 15-17)

3. Phenotypes

The disease is chronic and progressive, but component systems emerge at different times. Sensory neuropathy often precedes cerebellar and vestibular signs; chronic spasmodic cough can precede neurologic disability by years.

• Sensory neuronopathy/neuropathy: hallmark phenotype, generally non-length-dependent, affecting large fibers and proprioception; motor conduction is often preserved. Suggested terms: HP:0009830 peripheral neuropathy, HP:0000763 sensory neuropathy, HP:0003477 impaired vibration sense, HP:0010871 sensory ataxia. It was found in all examined patients in major cohorts. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12)
• Cerebellar ataxia: gait and limb ataxia, dysarthria, impaired pursuit, and cerebellar atrophy; HP:0001251, HP:0002072 chorea only where present, HP:0001260 dysarthria, HP:0002060 cerebellar atrophy. Cerebellar involvement was 80% in the discovery cohort and rose from 72% at first assessment to 84% at follow-up in a later large cohort. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12)
• Bilateral vestibulopathy: oscillopsia, impaired vestibulo-ocular reflex, and imbalance worsened in darkness; HP:0007993 vestibular dysfunction, HP:0007646 bilateral vestibular hypofunction, HP:0010544 oscillopsia. Reported prevalence was 54–75%, depending on cohort and disease stage. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12, gisatulin2020clinicalspectrumof pages 5-9)
• Chronic cough: dry, spasmodic cough, frequently prodromal; HP:0012735. Frequencies ranged from 37% in the initial series to 75% in a 2024 cohort; in the latter it was the initial symptom in 50%. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12)
• Dysautonomia and small-fiber disease: urinary, bowel, cardiovascular, cardiovagal, and sudomotor dysfunction; HP:0000789 autonomic dysfunction, HP:0000020 urinary incontinence where applicable. Dysautonomia occurred in 23% of the discovery series and 62% in a deeply phenotyped natural-history cohort. (cortese2019biallelicexpansionof pages 4-6, traschutz2021naturalhistoryphenotypic pages 1-2)
• Other manifestations: bradykinesia 28%, postural instability 49%, slow vertical saccades 17%, and chorea/dystonia 11% in one cohort. Motor-neuron/motor-neuropathy phenotypes, sleep disorders, cranial neuropathy, and cognitive impairment have been reported but are less securely quantified and may represent spectrum extremes. (traschutz2021naturalhistoryphenotypic pages 1-2)
• Advanced disability: dysarthria/dysphagia increased from 6% to 51% during follow-up. Suggested terms include HP:0002015 dysphagia, HP:0002829 wheelchair dependence, and HP:0040296 aspiration pneumonia. (curro2024roleofthe pages 10-12)

Quality-of-life effects include impaired walking in darkness or on uneven surfaces, falls, oscillopsia, chronic cough, pain or sensory discomfort, loss of driving and employment, dysphagia, and eventual dependence for mobility. RFC1-specific EQ-5D, SF-36, or PROMIS population estimates were not found.

4. Genetic and molecular information

RFC1 encodes the large subunit of replication factor C, a clamp-loader complex involved in DNA replication and repair. The conventional disease genotype is homozygous or compound-heterozygous pathogenic repeat expansion. Variants are germline, not somatic cancer alterations.

Population screening in the discovery study found expanded AAGGG alleles on approximately 0.7% of chromosomes; subsequent estimates range from 0.7% to 4%, depending on ancestry, motif definition, and ascertainment. These figures are allele frequencies, not disease prevalence. (cortese2019biallelicexpansionof pages 4-6, traschutz2021naturalhistoryphenotypic pages 1-2)

Large repeat expansions are not represented reliably by standard SNV/indel nomenclature, and their frequencies are poorly captured by conventional gnomAD short-read variant tables. For knowledge-base purposes, pathogenicity should be assigned at the repeat-configuration level, with motif, size, zygosity, and assay recorded. Benign or uncertain expansions, including AAAAG/AAAGG or interrupted configurations, must not be automatically classified as pathogenic. (gisatulin2020clinicalspectrumof pages 1-5, scriba2023rfc1inan pages 3-4)

No validated modifier gene, disease-specific methylation signature, recurrent chromosomal rearrangement, or pathogenic epigenetic lesion has been established. Rare RFC1 deletions and truncating alleles broaden the allelic spectrum but do not define a recurrent chromosomal syndrome. (ronco2023truncatingvariantsin pages 1-2)

5. Environmental and lifestyle information

RFC1 disease is not known to be caused by infection, radiation, pollution, alcohol, smoking, diet, or occupational exposure. Such factors remain relevant in the differential diagnosis of adult-onset ataxia/polyneuropathy—particularly alcohol, neurotoxic medications, vitamin deficiencies, immune disease, and paraneoplastic processes—but are not demonstrated causal cofactors for biallelic RFC1 disease. No vaccine or pathogen-specific intervention applies.

6. Mechanism and pathophysiology

Causal chain

Biallelic pathogenic RFC1 repeat configuration → repeat-dependent neuronal dysfunction → impaired synaptic development/signaling and selective vulnerability of sensory ganglia, cerebellar circuits, and vestibular pathways → sensory ataxia, cerebellar ataxia, and vestibular areflexia. Downstream degeneration includes Purkinje-cell loss, dorsal-root-ganglionopathy, peripheral small/large-fiber loss, and cerebellar atrophy. Severe Purkinje-cell depletion with Bergmann gliosis has been documented neuropathologically. (cortese2019biallelicexpansionof pages 4-6)

Earlier studies found unchanged RFC1/WDR19 expression and no RFC1 intron retention, leaving mechanism uncertain. (gisatulin2020clinicalspectrumof pages 1-5)

The key 2024 mechanistic development used patient-derived iPSCs and glutamatergic iNeurons. RFC1 expression, splicing, DNA-repair function, DNA-damage accumulation, and UV-repair recovery were not materially abnormal. Reporter constructs permitted pentapeptide-repeat translation, but repeat peptides and convincing RNA-foci toxicity were not consistently demonstrated in patient iNeurons. Conversely, patient neurons had abnormal neuronal-development and synaptic-gene programs, reduced burst rate, burst strength, and firing correlation, and impaired connectivity. Deleting one expanded allele with CRISPR rescued molecular and functional defects; RFC1 knockdown did not reproduce them, and RFC1 replacement did not rescue them. The authors’ abstract conclusion was: “These findings support a repeat-dependent but RFC1 protein–independent cause of neuronal dysfunction in CANVAS.” (maltby2024aagggrepeatexpansions pages 1-2, maltby2024aagggrepeatexpansions pages 13-14, maltby2024aagggrepeatexpansions pages 11-13)

This creates tension with truncating-variant evidence supporting partial RFC1 loss of function. The most defensible current interpretation is that more than one mechanism may operate: repeat-sequence/configuration toxicity is strongly supported in neurons, while RFC1 haploinsufficiency or reduced dosage can contribute in rare compound genotypes. (ronco2023truncatingvariantsin pages 1-2, maltby2024aagggrepeatexpansions pages 1-2)

Suggested annotations: GO:0050808 synapse organization; GO:0007268 chemical synaptic transmission; GO:0006281 DNA repair, with a qualifier that canonical repair dysfunction was not demonstrated; GO:0006950 response to stress; CL:0000540 neuron, CL:0000121 Purkinje cell, CL:0000101 sensory neuron, CL:0000709 retinal?—the latter should not be used without phenotype evidence. Relevant compartments include nucleus, cytoplasm, synapse, and axon.

No validated disease-level epigenomic, proteomic, metabolomic, lipidomic, single-cell, or spatial-transcriptomic signature is yet available. INSIDE-CANVAS is investigating oxidative stress, neurofilament light, mitochondrial function, and patient-derived cells. (NCT07156214 chunk 1)

7. Anatomical structures affected

Primary systems are the peripheral sensory nervous system, cerebellum, and vestibular system.

• Dorsal-root ganglia and sensory peripheral nerves: neuronopathy with large- and small-fiber loss; UBERON:0000044 dorsal root ganglion, UBERON:0001021 nerve, CL:0000101 sensory neuron.
• Cerebellum: Purkinje cells, vermis, and hemispheric circuits; UBERON:0002037 cerebellum, UBERON:0004729 cerebellar vermis, CL:0000121 Purkinje cell.
• Vestibular apparatus/pathways: bilateral vestibular hypofunction; UBERON:0001843 vestibular labyrinth and vestibular nerve/pathway terms.
• Spinal proprioceptive pathways and brainstem oculomotor networks may contribute secondarily.
• Autonomic and cutaneous small fibers are involved in a subset.

MRI showed cerebellar atrophy in 83% of 42 imaged cases in the discovery series. Larger repeats, especially the smaller expanded allele, correlated with greater atrophy of vermian lobules I–V and VI–VII. Disease is generally bilateral/systemic rather than lateralized. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12)

8. Temporal development

Onset is usually insidious in the fifth or sixth decade, but observed onset spans approximately 25–80 years. Cough or sensory symptoms may be the first manifestation; cerebellar and vestibular components accumulate later. (cortese2019biallelicexpansionof pages 4-6, curro2024roleofthe pages 10-12)

A practical staging model is:

1. Prodromal/early: chronic cough, distal or patchy sensory symptoms, imbalance in darkness.
2. Intermediate: sensory ataxia plus cerebellar or vestibular dysfunction; falls and oscillopsia.
3. Established CANVAS: all three systems affected, with dysarthria and reduced independent mobility.
4. Advanced: walking aids or wheelchair use, dysphagia, aspiration risk, and multisystem/autonomic complications.

Mean ataxia progression was approximately 1.3 SARA points/year, although nonlinear MSA-C-like phases of 2.5–5.5 points/year occurred. No spontaneous remission pattern is recognized. (traschutz2021naturalhistoryphenotypic pages 1-2)

9. Inheritance and population

Inheritance is autosomal recessive, with variable expressivity and strongly age-dependent penetrance. Precise lifetime penetrance for each repeat motif and size is not established. Repeat-size correlation supports dose-dependent expressivity. Unlike many repeat diseases, marked meiotic/somatic instability and classic genetic anticipation were not observed. (curro2024roleofthe pages 10-12, curro2024roleofthe pages 15-17)

RFC1 expansions were found in 14% of unselected late-onset ataxia, 67% of an enriched suspected cohort, 68% of clinical CANVAS, and 100% of ataxia-with-chronic-cough cases in one study. These are diagnostic yields, not population prevalence. (traschutz2021naturalhistoryphenotypic pages 1-2)

An Australasian study found pathogenic biallelic expansions in 37/242 (15.3%) neurologic cases, including AAGGG, ACAGG, and Māori-associated configurations. A Japanese hereditary sensory/autonomic neuropathy cohort found biallelic RFC1 expansions in 20/79 (25.3%) cases. These findings demonstrate ancestry-specific motif distributions. (scriba2023rfc1inan pages 3-4)

Population incidence, point prevalence, sex ratio, carrier frequency by ancestry, and survival-adjusted prevalence remain inadequately measured. Consanguinity can increase recessive disease probability but is not required, given relatively common carrier alleles.

10. Diagnostics

Clinical and physiologic evaluation

Evaluate cerebellar signs, sensory modalities, reflexes, gait in darkness, eye movements, autonomic symptoms, chronic cough, and family history. Recommended investigations include:

• Nerve-conduction studies: typically absent/reduced sensory responses with relatively preserved motor conduction.
• Vestibular testing: video head-impulse testing, calorics, rotational chair, vestibular-evoked myogenic potentials, and visually enhanced vestibulo-ocular reflex where available.
• Brain MRI: cerebellar and vermian atrophy; spinal imaging when alternative diagnoses are suspected.
• SARA or ICARS for ataxia, vestibular disability scales, swallowing assessment, and autonomic testing.
• Laboratory exclusion of acquired ataxia/neuropathy: vitamin E/B12/copper, thyroid, diabetes, paraprotein, immune/paraneoplastic studies, toxins, infections, and medication review as clinically indicated.

Genetic testing algorithm

1. Order RFC1 flanking PCR plus motif-specific repeat-primed PCR in adult-onset sensory neuronopathy, CANVAS, bilateral vestibulopathy with neuropathy, or ataxia with chronic cough.
2. Confirm and size large alleles with Southern blot, optical genome mapping, or validated long-read sequencing.
3. If the phenotype is compelling but only one expansion is found, sequence the complete RFC1 coding region and assess deletion/CNV alleles. (ronco2023truncatingvariantsin pages 1-2)
4. If PCR patterns are atypical or ancestry suggests non-AAGGG motifs, use targeted long-read sequencing to resolve motif, interruptions, orientation, and size. The 2023 Australasian study recommended a multistep short-/long-read workflow. (scriba2023rfc1inan pages 3-4)
5. If negative, test other repeat disorders and conventional ataxia/neuropathy genes with a repeat-expansion panel plus WES/WGS. Standard WES alone can miss RFC1 expansions.

The 2024 adult-onset ataxia review summarized the diagnostic challenge: targeted repeat testing remains necessary even when exome or short-read genome sequencing is performed, while long-read sequencing may eventually unify detection. (scriba2023rfc1inan pages 3-4)

Important differentials include Friedreich ataxia, SCA3 and other dominant SCAs, FGF14-GAA/SCA27B, FXTAS, POLG and other mitochondrial disease, spinocerebellar ataxia with axonal neuropathy, hereditary sensory/autonomic neuropathies, immune/paraneoplastic ataxia, superficial siderosis, multiple-system atrophy–cerebellar type, alcohol/toxin-associated disease, and vitamin deficiencies.

Cascade testing is appropriate after molecular confirmation. Population or newborn screening is not recommended; predictive testing of adult relatives requires genetic counseling.

11. Outcome and prognosis

Disease is lifelong and progressive; recovery is not expected, although rehabilitation can improve function and safety. In a large cohort, 54% required a walking aid after a median of 10 years, and 17% required a wheelchair after 14 years. Mortality was 8%; attributed deaths included aspiration pneumonia and complications of immobility. (curro2024roleofthe pages 10-12)

Repeat size is the best current molecular prognostic marker, but it is not deterministic. Baseline multisystem involvement, dysphagia, falls, and rapid SARA progression likely indicate poorer functional prognosis. No validated individual survival calculator exists.

12. Treatment and current applications

There is no approved disease-modifying therapy. Current real-world care is genotype-informed but symptomatic:

• physiotherapy, balance and gait training, vestibular rehabilitation, fall prevention, and mobility aids;
• occupational therapy and home adaptation;
• speech therapy, swallow evaluation, texture modification, and aspiration prevention;
• treatment of neuropathic pain using standard agents when present;
• management of orthostatic, urinary, bowel, and sudomotor symptoms;
• cough assessment and symptomatic management after excluding pulmonary causes;
• nutritional, respiratory, psychological, and social support;
• hearing/vision compensation and driving-safety review;
• genetic counseling and cascade testing.

Suggested NCIT concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Vestibular Rehabilitation, Supportive Care, and Genetic Counseling. No RFC1-specific pharmacogenomic guideline, surgery, cell therapy, ASO, siRNA, or gene-replacement therapy is established.

The 2024 iNeuron result argues that simply restoring RFC1 protein may be insufficient; excision, silencing, or sequence-specific targeting of the expanded repeat is a more mechanistically supported direction, although CRISPR rescue remains preclinical. (maltby2024aagggrepeatexpansions pages 1-2, maltby2024aagggrepeatexpansions pages 11-13)

Clinical research: INSIDE-CANVAS (NCT07156214) began October 14, 2024 and is recruiting. It targets 25 RFC1 patients plus matched controls, with one-year clinical scales, neurophysiology, vestibular testing, brain/spinal MRI, NfL and oxidative-stress biomarkers, fibroblasts, and iPSCs; estimated primary completion is June 30, 2026. It is a biomarker/pathogenesis study, not a proven therapeutic trial. (NCT07156214 chunk 1)

Natural-history modeling estimated that a trial detecting 50% slowing would require approximately 330 participants for one year or 132 for two years. (traschutz2021naturalhistoryphenotypic pages 1-2)

13. Prevention

Primary prevention through lifestyle modification is not available. For families with a known genotype, options include genetic counseling, adult cascade testing, prenatal diagnosis, and preimplantation genetic testing, subject to local ethics and regulation. Because penetrance is age dependent and genotype–phenotype prediction is incomplete, predictive counseling must address uncertainty.

Secondary prevention consists of early molecular diagnosis and surveillance for falls, vestibular failure, autonomic dysfunction, dysphagia, and aspiration. Tertiary prevention includes rehabilitation, mobility aids, home-safety modification, vaccination and respiratory care according to general standards, and prompt treatment of aspiration or immobility complications. No RFC1-specific vaccine or chemoprophylaxis applies.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart caused by orthologous RFC1 intronic pentanucleotide expansions was identified. RFC1 is evolutionarily conserved, but the human disease depends on a specific repeat architecture that may not be conserved across species. Zoonotic transmission is not applicable. A knowledge base should mark affected nonhuman species, breed associations, and natural transmission as not established rather than infer them from RFC1 conservation.

15. Model organisms and experimental systems

The most informative current model is the human patient-derived iPSC/iNeuron system. The 2024 study used four patient and three control lines and an isogenic CRISPR-corrected line. It reproduced neuronal-development, transcriptomic, calcium-signaling, and synaptic-connectivity abnormalities and demonstrated rescue after deletion of one expanded allele. (maltby2024aagggrepeatexpansions pages 13-14, maltby2024aagggrepeatexpansions pages 2-3)

Limitations are important: the neurons were predominantly glutamatergic rather than dorsal-root-ganglion sensory neurons, vestibular neurons, or mature Purkinje cells; the number of lines and isogenic controls was small; and early developmental phenotypes may not reproduce decades-long human degeneration. Pentapeptide products were detected in three of four postmortem cerebella but not convincingly in iNeurons, illustrating model dependence. (maltby2024aagggrepeatexpansions pages 13-14)

No validated mouse, rat, zebrafish, Drosophila, or C. elegans model was established in the retrieved evidence as recapitulating the complete human triad. Priority models include repeat knock-in animals, sensory-neuron and Purkinje-cell differentiation, cerebellar organoids, and isogenic long-repeat systems.

Key recent expert conclusions and exact abstract quotations

• Currò et al., Brain 2024, DOI 10.1093/brain/awad436: “RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype, and severity.” (curro2024roleofthe pages 10-12)
• Maltby et al., Science Advances, September 2024, DOI 10.1126/sciadv.adn2321: “These findings support a repeat-dependent but RFC1 protein–independent cause of neuronal dysfunction in CANVAS, with implications for therapeutic development in this currently untreatable condition.” (maltby2024aagggrepeatexpansions pages 1-2)
• Scriba et al., Brain Communications, July 2023, DOI 10.1093/braincomms/fcad208: the authors found pathogenic expansions in 15.3% of their neurological cohort and concluded that RFC1 expansions make a substantial contribution to Australasian neurological disease, supporting combined short- and long-read diagnostic workflows. (scriba2023rfc1inan pages 3-4)
• Ronco et al., Neurology, January 2023, DOI 10.1212/WNL.0000000000201486, PMID 36478048: “Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions.” (ronco2023truncatingvariantsin pages 1-2)

Evidence gaps

Reliable population incidence and prevalence, motif-specific penetrance, sex ratios, validated quality-of-life norms, environmental modifiers, fluid biomarkers, single-cell/spatial atlases, natural animal disease, robust whole-animal models, and disease-modifying treatment data remain unavailable. Frequencies vary substantially with ascertainment and disease stage; cohort percentages should therefore not be treated as universal penetrance estimates.

References

1. (OpenTargets Search: CANVAS): Open Targets Query (CANVAS, 17 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (traschutz2021naturalhistoryphenotypic pages 1-2): Andreas Traschütz, Andrea Cortese, Selina Reich, Natalia Dominik, Jennifer Faber, Heike Jacobi, Annette M. Hartmann, Dan Rujescu, Solveig Montaut, Andoni Echaniz-Laguna, Sevda Erer, Valerie Cornelia Schütz, Alexander A. Tarnutzer, Marc Sturm, Tobias B. Haack, Nadège Vaucamps-Diedhiou, Helene Puccio, Ludger Schöls, Thomas Klockgether, Bart P. van de Warrenburg, Martin Paucar, Dagmar Timmann, Ralf-Dieter Hilgers, Jose Gazulla, Michael Strupp, German Moris, Alessandro Filla, Henry Houlden, Mathieu Anheim, Jon Infante, A. Nazli Basak, Matthis Synofzik, Banu Özen Barut, Basar Bilgic, Cavit Boz, Cécile Cauquil, Natalie Deininger, Claudia Dufke, Bülent Elibol, Furkan Erbas, Sibel Ertan, Fatma Genc, Ina Giegling, Yesim Parman, Salvatore Rossi, Celal Salcin, Meliha Tan, Hilal Taştekin, Christine Tranchant, Günes Uygun, and Özge Yagcioglu Yassa. Natural history, phenotypic spectrum, and discriminative features of multisystemic rfc1 disease. Neurology, Mar 2021. URL: https://doi.org/10.1212/wnl.0000000000011528, doi:10.1212/wnl.0000000000011528. This article has 193 citations and is from a highest quality peer-reviewed journal.

3. (cortese2019biallelicexpansionof pages 4-6): Andrea Cortese, Roberto Simone, Roisin Sullivan, Jana Vandrovcova, Huma Tariq, Wai Yan Yau, Jack Humphrey, Zane Jaunmuktane, Prasanth Sivakumar, James Polke, Muhammad Ilyas, Eloise Tribollet, Pedro J. Tomaselli, Grazia Devigili, Ilaria Callegari, Maurizio Versino, Vincenzo Salpietro, Stephanie Efthymiou, Diego Kaski, Nick W. Wood, Nadja S. Andrade, Elena Buglo, Adriana Rebelo, Alexander M. Rossor, Adolfo Bronstein, Pietro Fratta, Wilson J. Marques, Stephan Züchner, Mary M. Reilly, and Henry Houlden. Biallelic expansion of an intronic repeat in rfc1 is a common cause of late-onset ataxia. Nature Genetics, 51(4):649-658, Mar 2019. URL: https://doi.org/10.1038/s41588-019-0372-4, doi:10.1038/s41588-019-0372-4. This article has 650 citations and is from a highest quality peer-reviewed journal.

4. (ronco2023truncatingvariantsin pages 1-2): Riccardo Ronco, Cecilia Perini, Riccardo Currò, Natalia Dominik, Stefano Facchini, Alice Gennari, Roberto Simone, Skye Stuart, Sara Nagy, Elisa Vegezzi, Ilaria Quartesan, Amar El-Saddig, Timothy Lavin, Arianna Tucci, Agnieszka Szymura, Luiz Eduardo Novis De Farias, Alexander Gary, Megan Delfeld, Priscilla Kandikatla, Nifang Niu, Sanjukta Tawde, Joseph Shaw, James Polke, Mary M. Reilly, Nick W. Wood, Emmanuele Crespan, Christopher Gomez, Jin Yun Helen Chen, Jeremy Dan Schmahmann, David Gosal, Henry Houlden, Soma Das, and Andrea Cortese. Truncating variants in rfc1 in cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Jan 2023. URL: https://doi.org/10.1212/wnl.0000000000201486, doi:10.1212/wnl.0000000000201486. This article has 69 citations and is from a highest quality peer-reviewed journal.

5. (scriba2023rfc1inan pages 3-4): Carolin K Scriba, Igor Stevanovski, Sanjog R Chintalaphani, Hasindu Gamaarachchi, Roula Ghaoui, Darshan Ghia, Robert D Henderson, Nerissa Jordan, Antony Winkel, Phillipa J Lamont, Miriam J Rodrigues, Richard H Roxburgh, Ben Weisburd, Nigel G Laing, Ira W Deveson, Mark R Davis, and Gianina Ravenscroft. Rfc1 in an australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics. Brain Communications, Jul 2023. URL: https://doi.org/10.1093/braincomms/fcad208, doi:10.1093/braincomms/fcad208. This article has 20 citations and is from a peer-reviewed journal.

6. (curro2024roleofthe pages 10-12): Riccardo Currò, Natalia Dominik, Stefano Facchini, Elisa Vegezzi, Roisin Sullivan, Valentina Galassi Deforie, Gorka Fernández-Eulate, Andreas Traschütz, Salvatore Rossi, Matteo Garibaldi, Mariusz Kwarciany, Franco Taroni, Alfredo Brusco, Jean-Marc Good, Francesca Cavalcanti, Simon Hammans, Gianina Ravenscroft, Richard H Roxburgh, Ricardo Parolin Schnekenberg, Bianca Rugginini, Elena Abati, Arianna Manini, Ilaria Quartesan, Arianna Ghia, Adolfo Lòpez de Munaìn, Fiore Manganelli, Marina Kennerson, Filippo Maria Santorelli, Jon Infante, Wilson Marques, Manu Jokela, Sinéad M Murphy, Paola Mandich, Gian Maria Fabrizi, Chiara Briani, David Gosal, Davide Pareyson, Alberto Ferrari, Ferran Prados, Tarek Yousry, Vikram Khurana, Sheng-Han Kuo, James Miller, Claire Troakes, Zane Jaunmuktane, Paola Giunti, Annette Hartmann, Nazli Basak, Matthis Synofzik, Tanya Stojkovic, Marios Hadjivassiliou, Mary M Reilly, Henry Houlden, and Andrea Cortese. Role of the repeat expansion size in predicting age of onset and severity in rfc1 disease. MedRxiv, 147:1887-1898, Oct 2024. URL: https://doi.org/10.1101/2023.10.15.23297048, doi:10.1101/2023.10.15.23297048. This article has 42 citations.

7. (curro2024roleofthe pages 15-17): Riccardo Currò, Natalia Dominik, Stefano Facchini, Elisa Vegezzi, Roisin Sullivan, Valentina Galassi Deforie, Gorka Fernández-Eulate, Andreas Traschütz, Salvatore Rossi, Matteo Garibaldi, Mariusz Kwarciany, Franco Taroni, Alfredo Brusco, Jean-Marc Good, Francesca Cavalcanti, Simon Hammans, Gianina Ravenscroft, Richard H Roxburgh, Ricardo Parolin Schnekenberg, Bianca Rugginini, Elena Abati, Arianna Manini, Ilaria Quartesan, Arianna Ghia, Adolfo Lòpez de Munaìn, Fiore Manganelli, Marina Kennerson, Filippo Maria Santorelli, Jon Infante, Wilson Marques, Manu Jokela, Sinéad M Murphy, Paola Mandich, Gian Maria Fabrizi, Chiara Briani, David Gosal, Davide Pareyson, Alberto Ferrari, Ferran Prados, Tarek Yousry, Vikram Khurana, Sheng-Han Kuo, James Miller, Claire Troakes, Zane Jaunmuktane, Paola Giunti, Annette Hartmann, Nazli Basak, Matthis Synofzik, Tanya Stojkovic, Marios Hadjivassiliou, Mary M Reilly, Henry Houlden, and Andrea Cortese. Role of the repeat expansion size in predicting age of onset and severity in rfc1 disease. MedRxiv, 147:1887-1898, Oct 2024. URL: https://doi.org/10.1101/2023.10.15.23297048, doi:10.1101/2023.10.15.23297048. This article has 42 citations.

8. (curro2024roleofthe pages 4-7): Riccardo Currò, Natalia Dominik, Stefano Facchini, Elisa Vegezzi, Roisin Sullivan, Valentina Galassi Deforie, Gorka Fernández-Eulate, Andreas Traschütz, Salvatore Rossi, Matteo Garibaldi, Mariusz Kwarciany, Franco Taroni, Alfredo Brusco, Jean-Marc Good, Francesca Cavalcanti, Simon Hammans, Gianina Ravenscroft, Richard H Roxburgh, Ricardo Parolin Schnekenberg, Bianca Rugginini, Elena Abati, Arianna Manini, Ilaria Quartesan, Arianna Ghia, Adolfo Lòpez de Munaìn, Fiore Manganelli, Marina Kennerson, Filippo Maria Santorelli, Jon Infante, Wilson Marques, Manu Jokela, Sinéad M Murphy, Paola Mandich, Gian Maria Fabrizi, Chiara Briani, David Gosal, Davide Pareyson, Alberto Ferrari, Ferran Prados, Tarek Yousry, Vikram Khurana, Sheng-Han Kuo, James Miller, Claire Troakes, Zane Jaunmuktane, Paola Giunti, Annette Hartmann, Nazli Basak, Matthis Synofzik, Tanya Stojkovic, Marios Hadjivassiliou, Mary M Reilly, Henry Houlden, and Andrea Cortese. Role of the repeat expansion size in predicting age of onset and severity in rfc1 disease. MedRxiv, 147:1887-1898, Oct 2024. URL: https://doi.org/10.1101/2023.10.15.23297048, doi:10.1101/2023.10.15.23297048. This article has 42 citations.

9. (gisatulin2020clinicalspectrumof pages 5-9): Maria Gisatulin, Valerija Dobricic, Christine Zühlke, Yorck Hellenbroich, Vera Tadic, Alexander Münchau, Klaus Isenhardt, Katrin Bürk, Melanie Bahlo, Paul J. Lockhart, Katja Lohmann, Christoph Helmchen, and Norbert Brüggemann. Clinical spectrum of the pentanucleotide repeat expansion in the rfc1 gene in ataxia syndromes. Nov 2020. URL: https://doi.org/10.1212/wnl.0000000000010744, doi:10.1212/wnl.0000000000010744. This article has 64 citations and is from a highest quality peer-reviewed journal.

10. (gisatulin2020clinicalspectrumof pages 1-5): Maria Gisatulin, Valerija Dobricic, Christine Zühlke, Yorck Hellenbroich, Vera Tadic, Alexander Münchau, Klaus Isenhardt, Katrin Bürk, Melanie Bahlo, Paul J. Lockhart, Katja Lohmann, Christoph Helmchen, and Norbert Brüggemann. Clinical spectrum of the pentanucleotide repeat expansion in the rfc1 gene in ataxia syndromes. Nov 2020. URL: https://doi.org/10.1212/wnl.0000000000010744, doi:10.1212/wnl.0000000000010744. This article has 64 citations and is from a highest quality peer-reviewed journal.

11. (maltby2024aagggrepeatexpansions pages 1-2): Connor J. Maltby, Amy Krans, Samantha J. Grudzien, Yomira Palacios, Jessica Muiños, Andrea Suárez, Melissa Asher, Sydney Willey, Kinsey Van Deynze, Camille Mumm, Alan P. Boyle, Andrea Cortese, Alain Ndayisaba, Vikram Khurana, Sami J. Barmada, Anke A. Dijkstra, and Peter K. Todd. Aaggg repeat expansions triggerrfc1-independent synaptic dysregulation in human canvas neurons. Sep 2024. URL: https://doi.org/10.1126/sciadv.adn2321, doi:10.1126/sciadv.adn2321. This article has 26 citations and is from a highest quality peer-reviewed journal.

12. (maltby2024aagggrepeatexpansions pages 13-14): Connor J. Maltby, Amy Krans, Samantha J. Grudzien, Yomira Palacios, Jessica Muiños, Andrea Suárez, Melissa Asher, Sydney Willey, Kinsey Van Deynze, Camille Mumm, Alan P. Boyle, Andrea Cortese, Alain Ndayisaba, Vikram Khurana, Sami J. Barmada, Anke A. Dijkstra, and Peter K. Todd. Aaggg repeat expansions triggerrfc1-independent synaptic dysregulation in human canvas neurons. Sep 2024. URL: https://doi.org/10.1126/sciadv.adn2321, doi:10.1126/sciadv.adn2321. This article has 26 citations and is from a highest quality peer-reviewed journal.

13. (maltby2024aagggrepeatexpansions pages 11-13): Connor J. Maltby, Amy Krans, Samantha J. Grudzien, Yomira Palacios, Jessica Muiños, Andrea Suárez, Melissa Asher, Sydney Willey, Kinsey Van Deynze, Camille Mumm, Alan P. Boyle, Andrea Cortese, Alain Ndayisaba, Vikram Khurana, Sami J. Barmada, Anke A. Dijkstra, and Peter K. Todd. Aaggg repeat expansions triggerrfc1-independent synaptic dysregulation in human canvas neurons. Sep 2024. URL: https://doi.org/10.1126/sciadv.adn2321, doi:10.1126/sciadv.adn2321. This article has 26 citations and is from a highest quality peer-reviewed journal.

14. (NCT07156214 chunk 1): Pathogenic Insights and Search for Biomarkers in RFC1-ataxia/CANVAS. Catholic University of the Sacred Heart. 2024. ClinicalTrials.gov Identifier: NCT07156214

15. (maltby2024aagggrepeatexpansions pages 2-3): Connor J. Maltby, Amy Krans, Samantha J. Grudzien, Yomira Palacios, Jessica Muiños, Andrea Suárez, Melissa Asher, Sydney Willey, Kinsey Van Deynze, Camille Mumm, Alan P. Boyle, Andrea Cortese, Alain Ndayisaba, Vikram Khurana, Sami J. Barmada, Anke A. Dijkstra, and Peter K. Todd. Aaggg repeat expansions triggerrfc1-independent synaptic dysregulation in human canvas neurons. Sep 2024. URL: https://doi.org/10.1126/sciadv.adn2321, doi:10.1126/sciadv.adn2321. This article has 26 citations and is from a highest quality peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.