Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Summary

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (MONDO:0044720) is a disease caused by RFC1 (GenCC Strong), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RFC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 27
• Phenotypes (HPO): 16
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0008568	Vestibular areflexia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome
Mondo ID	MONDO:0044720
MeSH	C564296
OMIM	608088, 614575
Orphanet	504476, 139564
DOID	DOID:0070148
SNOMED CT	717825008
UMLS	C3281223
MedGen	482853
GARD	0017937
Is cancer (heuristic)	no

Also known as: CABV syndrome · CANVAS · cerebellar ataxia with bilateral vestibulopathy syndrome · cerebellar ataxia, neuropathy, and vestibular areflexia syndrome · hereditary sensory and autonomic neuropathy type 1 with cough and gastroesophageal reflux · hereditary sensory and autonomic neuropathy type 1B · hereditary sensory and autonomic neuropathy type IB · hereditary sensory neuropathy type IB · HSAN with cough and gastroesophageal reflux · HSAN1B · HSN1B · neuropathy, hereditary sensory and autonomic, type 1B · neuropathy, hereditary sensory, type IB

Data availability: 27 ClinVar variants · 3 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 1 › cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Related subtypes (5): neuropathy, hereditary sensory and autonomic, type 1A, neuropathy, hereditary sensory and autonomic, type 1C, neuropathy, hereditary sensory, type 1D, hereditary sensory neuropathy-deafness-dementia syndrome, neuropathy, hereditary sensory, type 1F

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

27 retrieved; paginated sample, class counts are floors:

11 pathogenic, 5 benign, 4 not provided, 3 uncertain significance, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703247	NM_002913.5(RFC1):c.1147C>T (p.Arg383Ter)	RFC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577534	NM_002913.5(RFC1):c.1162C>T (p.Arg388Ter)	RFC1	Pathogenic	no assertion criteria provided
2577535	NM_002913.5(RFC1):c.575del (p.Asn192fs)	RFC1	Pathogenic	no assertion criteria provided
2577536	NM_002913.5(RFC1):c.2535+2T>C	RFC1	Pathogenic	no assertion criteria provided
2577537	NM_002913.5(RFC1):c.2690+1G>A	RFC1	Pathogenic	no assertion criteria provided
3370519	RFC1, (ACAGG)n REPEAT EXPANSION	RFC1	Pathogenic	no assertion criteria provided
4531160	RFC1, (AGGGC)n AND (AAGGC)n REPEAT EXPANSION	RFC1	Pathogenic	no assertion criteria provided
625839	NC_000004.12:g.39348425AARRG[(400_2000)]	RFC1	Pathogenic	no assertion criteria provided
625876	NC_000004.11:g.39350045_39350099delinsAAGGG[(400_2000)]	RFC1	Pathogenic	no assertion criteria provided
625877	NC_000004.12:g.39348425_39348479delinsAAAGG[400_2000]	RFC1	Pathogenic	no assertion criteria provided
986302	NC_000004.12:g.39348425AAAGG[10_25]AAGGG[n]	RFC1	Pathogenic	no assertion criteria provided
997970	NC_000004.12:g.39348425AAGGG[(400_2000)]	RFC1	Pathogenic	no assertion criteria provided
431175	NM_001331036.3(ELF2):c.10G>A (p.Ala4Thr)	ELF2	Likely pathogenic	criteria provided, single submitter
3341312	NM_002913.5(RFC1):c.1255del (p.Glu419fs)	RFC1	Likely pathogenic	criteria provided, single submitter
3341313	NM_002913.5(RFC1):c.2111-1G>C	RFC1	Likely pathogenic	criteria provided, single submitter
1030298	NM_002913.5(RFC1):c.398A>G (p.Asn133Ser)	RFC1	Uncertain significance	criteria provided, single submitter
3068189	NM_002913.5(RFC1):c.2936C>T (p.Ala979Val)	RFC1	Uncertain significance	criteria provided, single submitter
3892280	NM_002913.5(RFC1):c.2014G>A (p.Val672Met)	RFC1	Uncertain significance	criteria provided, single submitter
1327948	NM_002913.5(RFC1):c.2808+36C>G	RFC1	Benign	criteria provided, multiple submitters, no conflicts
1327949	NM_002913.5(RFC1):c.2541A>G (p.Pro847=)	RFC1	Benign	criteria provided, multiple submitters, no conflicts
1327950	NM_002913.5(RFC1):c.331+25G>T	RFC1	Benign	criteria provided, multiple submitters, no conflicts
1327951	NM_002913.5(RFC1):c.4-26G>A	RFC1	Benign	criteria provided, multiple submitters, no conflicts
996307	NM_002913.5(RFC1):c.132+2923=	RFC1	Benign	no assertion criteria provided
996308	NM_001204747.1:c.132+2923_2927AAAAG[(12_200)]	RFC1	not provided	no classification provided
996309	NM_001204747.1:c.132+2923_2927AAAGG[(40_1000)]	RFC1	not provided	no classification provided
996310	NM_001204747.1:c.132+2923_2927ACAGG[(400_2000)]	RFC1	not provided	no classification provided
996311	NM_001204747.1:c.132+2923_2927AAGGG[(400_2000)]	RFC1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RFC1	Strong	Autosomal recessive	cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RFC1	Orphanet:504476	Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RFC1	HGNC:9969	ENSG00000035928	P35251	Replication factor C subunit 1	gencc,clinvar
ELF2	HGNC:3317	ENSG00000109381	Q15723	ETS-related transcription factor Elf-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RFC1	Replication factor C subunit 1	Subunit of the replication factor C (RFC) complex which acts during elongation of primed DNA templates by DNA polymerases delta and epsilon, and is necessary for ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto prime…
ELF2	ETS-related transcription factor Elf-2	Isoform 1 transcriptionally activates the LYN and BLK promoters and acts synergistically with RUNX1 to transactivate the BLK promoter.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RFC1	Enzyme (other)	yes	3.6.4.B8	BRCT_dom, AAA+_ATPase, ATPase_AAA_core
ELF2	Transcription factor	no		Ets_dom, TF_Elf_N, WH-like_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
adrenal tissue	1
ventricular zone	1
colonic epithelium	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RFC1	278	ubiquitous	marker	calcaneal tendon, ventricular zone, adrenal tissue
ELF2	276	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RFC1	2,184
ELF2	1,258

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RFC1	P35251	4
ELF2	Q15723	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 regulates transcription of genes involved in BCR signaling	1	951.7×	0.008	ELF2
Polymerase switching	1	407.9×	0.008	RFC1
Translesion synthesis by REV1	1	356.9×	0.008	RFC1
Translesion synthesis by POLI	1	335.9×	0.008	RFC1
Translesion synthesis by POLK	1	317.2×	0.008	RFC1
Translesion Synthesis by POLH	1	300.5×	0.008	RFC1
PCNA-Dependent Long Patch Base Excision Repair	1	259.6×	0.008	RFC1
Gap-filling DNA repair synthesis and ligation in GG-NER	1	219.6×	0.008	RFC1
Polymerase switching on the C-strand of the telomere	1	211.5×	0.008	RFC1
Recognition of DNA damage by PCNA-containing replication complex	1	190.3×	0.008	RFC1
Termination of translesion DNA synthesis	1	173.0×	0.008	RFC1
Dual Incision in GG-NER	1	129.8×	0.010	RFC1
HDR through Homologous Recombination (HRR)	1	95.2×	0.012	RFC1
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.012	RFC1
Dual incision in TC-NER	1	86.5×	0.012	RFC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere maintenance via telomerase	1	366.4×	0.009	RFC1
DNA-templated DNA replication	1	280.9×	0.009	RFC1
positive regulation of DNA-templated transcription	2	27.9×	0.009	RFC1, ELF2
DNA repair	1	31.9×	0.062	RFC1
negative regulation of DNA-templated transcription	1	15.8×	0.090	ELF2
cell differentiation	1	14.6×	0.090	ELF2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.125	RFC1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ELF2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RFC1	1	2
ELF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RFC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RFC1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RFC1	3.6.4.B8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	RFC1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	RFC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ELF2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ELF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04153110	Not specified	COMPLETED	Cerebello-Spinal tDCS as Rehabilitative Intervention in Neurodegenerative Ataxia
NCT05621200	Not specified	COMPLETED	Transcranial Alternating Current Stimulation (tACS) in Patients With Ataxia