| Domain | Core finding | Quantitative details | Ontology suggestions | Evidence |
|---|---|---:|---|---|
| Disease identity | Adult-onset ataxia and polyneuropathy in this Mendelian context maps best to **RFC1 spectrum disorder / CANVAS** = **cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome**; **MONDO:0044720** | Open Targets links MONDO:0044720 to **RFC1** with literature support | MONDO:0044720; HPO: HP:0001251 Ataxia, HP:0009830 Peripheral neuropathy, HP:0007646 Bilateral vestibular hypofunction | (pqac-00000000, pqac-00000003) |
| Inheritance / causal gene | Usually **autosomal recessive**; primary cause is **biallelic intronic RFC1 pentanucleotide repeat expansion** in intron 2 | Typical pathogenic motif **AAGGG**; reported pathogenic spectrum also includes population-specific **ACAGG** and Māori-associated configurations; compound heterozygosity with truncating RFC1 variants also reported | Gene: RFC1; HPO: HP:0000007 Autosomal recessive inheritance | (pqac-00000001, pqac-00000008, pqac-00000009) |
| Variant / molecular lesion | Pathogenic alleles are large nonreference intronic repeat expansions; truncating coding variants can act in trans with one expansion in rare cases | Expansion size about **~400–2,000 repeats** (median ~1,000) in early discovery work; 2024 data show repeat size modifies onset/severity | SO: tandem repeat expansion; intron variant | (pqac-00000001, pqac-00000002, pqac-00000010) |
| Typical onset / course | **Adult onset**, usually insidious and slowly progressive multisystem neurodegeneration | Mean onset **54±9 y** (range **35–73**) in 2019 series; median onset **54 y** (range **25–80**) in 2024 cohort; progression about **1.3 SARA points/year** | HPO: HP:0003581 Adult onset, HP:0003676 Progressive neurologic deterioration | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Core phenotype: sensory neuropathy / neuronopathy | Hallmark feature; often presents as sensory ataxic neuropathy and may precede full CANVAS | **All tested/examined cases** had sensory neuropathy in major cohorts; in 2024 cohort **24%** had isolated sensory neuropathy and **38%** complex neuropathy | HPO: HP:0009830 Peripheral neuropathy, HP:0002355 Difficulty walking; UBERON: dorsal root ganglion | (pqac-00000001, pqac-00000002, pqac-00000006) |
| Core phenotype: cerebellar ataxia | Cerebellar dysfunction is common but not universal early; often evolves over time | Cerebellar involvement **80%** in 2019 series; cerebellar signs **72%** at first assessment and **84%** at follow-up in 2024 cohort | HPO: HP:0001251 Ataxia, HP:0002060 Cerebellar atrophy; UBERON: cerebellum | (pqac-00000001, pqac-00000002) |
| Core phenotype: vestibular dysfunction | Bilateral vestibular areflexia/hypofunction is a defining axis of CANVAS but may be incomplete early | Bilateral vestibular areflexia **54%** in 2019 series; **75%** in 2024 cohort | HPO: HP:0007993 Vestibular dysfunction, HP:0007646 Bilateral vestibular hypofunction; UBERON: vestibular labyrinth | (pqac-00000001, pqac-00000002, pqac-00000004) |
| Core phenotype: chronic cough | Highly discriminative associated symptom and may precede neurologic signs | **37%** in 2019 series; **75% overall** and initial symptom in **50%** in 2024 cohort; ACC phenotype can be highly suggestive | HPO: HP:0012735 Chronic cough | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Core phenotype: dysautonomia / small-fiber involvement | Autonomic and small-fiber involvement are common in multisystem disease | Autonomic involvement **23%** in 2019 series; dysautonomia **62%** in 2021 natural history study; 2023 Portuguese cohort: multisystem features beyond CANVAS in **82%**, dysautonomia **43%**, severe epidermal denervation in all biopsied patients | HPO: HP:0000789 Autonomic dysfunction; CL: sensory neuron; UBERON: skin, peripheral nerve | (pqac-00000001, pqac-00000003) |
| Other multisystem phenotypes | Can overlap with parkinsonism/MSA-C, movement disorder, cranial or motor neuron features | Bradykinesia **28%**, postural instability **49%**, slow vertical saccades **17%**, chorea/dystonia **11%** in 2021 study; motor neuron/motor neuropathy **18%** in 2023 Portuguese cohort | HPO: HP:0002067 Bradykinesia, HP:0002136 Dysphagia, HP:0001260 Dysarthria | (pqac-00000003) |
| Diagnostics | Diagnosis relies on targeted **RFC1 repeat testing** plus phenotype-specific neurologic workup | Methods reported: flanking PCR, **repeat-primed PCR**, duplex PCR, **Southern blot**, fragment analysis, Sanger sequencing, short-read screening, targeted **long-read sequencing**; MRI/CT showed cerebellar atrophy in **83%** of 42 cases | HPO: HP:0003401 Cerebellar MRI abnormality; UBERON: cerebellar vermis | (pqac-00000001, pqac-00000005, pqac-00000009) |
| Diagnostic yield / testing strategy | RFC1 testing should be prioritized in adult-onset ataxia with sensory neuropathy, vestibular failure, or chronic cough | Prevalence in enriched cohorts: **67%** in suspected cohort, **68%** in clinical CANVAS, **100%** in ataxia with chronic cough, **14%** in unselected late-onset ataxia; Australasian cohort found pathogenic expansions in **15.3% (37/242)** | HPO-guided testing: ataxia + neuropathy + cough + vestibular dysfunction | (pqac-00000003, pqac-00000009) |
| Key 2024 mechanism | Patient iPSC-derived neurons support **repeat-dependent, RFC1-protein-independent synaptic dysfunction** | 2024 Science Advances study found normal RFC1 splicing/expression and intact DNA repair, no consistent RNA foci/peptide toxicity in iNeurons, but reduced neuronal development/synaptic connectivity; **CRISPR deletion of one expanded allele rescued deficits**, RFC1 knockdown did not phenocopy, and RFC1 re-expression did not rescue | GO: synapse organization, chemical synaptic transmission; CL: glutamatergic neuron; UBERON: cerebellum/peripheral nervous system | (pqac-00000011, pqac-00000012, pqac-00000014) |
| Genotype–phenotype modifier (2024) | Repeat size is a prognostic modifier | Larger smaller allele HR **2.06** and larger allele HR **1.53** for earlier neurologic onset; loss of independent walking HR **2.78** (smaller allele) and **1.60** (larger allele); dysarthria/dysphagia HR **3.40** and **1.71**; larger expansions associated with more severe vermian atrophy | HPO: HP:0001260 Dysarthria, HP:0002015 Dysphagia; UBERON: cerebellar vermis | (pqac-00000002, pqac-00000010) |
| Prognosis | Chronic progressive disability; some premature mortality in advanced disease | In 2024 cohort **54%** required walking aids after median **10 y**, **17%** wheelchairs after **14 y**; mortality **8%**, with disease-related deaths including aspiration pneumonia/immobility complications | HPO: HP:0002829 Wheelchair dependence, HP:0040296 Aspiration pneumonia | (pqac-00000002, pqac-00000003) |
| Current treatment / trial status | **No established disease-modifying therapy**; care is supportive and multidisciplinary; RFC1-specific biomarker/natural-history trial is recruiting | Trial planning estimate: **330** total patients for 1-year or **132** for 2-year study to detect 50% slowing; **NCT07156214** recruiting from **2024-10-14**, primary completion **2026-06-30**, evaluating scales, NfL/oxidative stress biomarkers, imaging, and patient-derived cells | NCIT: supportive care; physical therapy/rehabilitation; biomarker study | (pqac-00000003, pqac-00000015) |


*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.*