Spinocerebellar ataxia type 1

Summary

Spinocerebellar ataxia type 1 (MONDO:0008119) is a disease caused by ATXN1 (GenCC Strong), with 1 cohort gene and 13 clinical trials. Top therapeutic interventions include troriluzole and rimtuzalcap.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATXN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 40
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.5	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000514	Slow saccadic eye movements	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001350	Slurred speech	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002483	Bulbar signs	Frequent (30-79%)
HP:0007001	Loss of Purkinje cells in the cerebellar vermis	Frequent (30-79%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Frequent (30-79%)
HP:0007377	Abnormality of somatosensory evoked potentials	Frequent (30-79%)
HP:0007928	Abnormal flash visual evoked potentials	Frequent (30-79%)
HP:0025331	Upgaze palsy	Frequent (30-79%)
HP:0025401	Staring gaze	Frequent (30-79%)
HP:0030216	Inertia	Frequent (30-79%)
HP:0040129	Abnormal nerve conduction velocity	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0002075	Dysdiadochokinesis	Occasional (5-29%)
HP:0002141	Gait imbalance	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002363	Abnormal brainstem morphology	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0006801	Hyperactive deep tendon reflexes	Occasional (5-29%)
HP:0007338	Hypermetric saccades	Occasional (5-29%)
HP:0010831	Impaired proprioception	Occasional (5-29%)
HP:0410011	Abnormality of masticatory muscle	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 1
Mondo ID	MONDO:0008119
OMIM	164400
Orphanet	98755
DOID	DOID:0050954
ICD-11	2071487961
NCIT	C129982
SNOMED CT	715748006
UMLS	C0752120
MedGen	155703
GARD	0004071
Is cancer (heuristic)	no

Also known as: ATXN1 autosomal dominant cerebellar ataxia type I · autosomal dominant cerebellar ataxia type I caused by mutation in ATXN1 · OPCA1 · OPCA4 · SCA1 · Sca1 · spinocerebellar ataxia 1 · spinocerebellar ataxia type 1

Data availability: 17 ClinVar variants · 3 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › Huntington disease and related disorders › Huntington disease-like syndrome › spinocerebellar ataxia type 1

Related subtypes (9): Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 2, Huntington disease-like 3, neuroferritinopathy, spinocerebellar ataxia type 17, neuroacanthocytosis, Huntington disease-like syndrome due to C9ORF72 expansions, childhood-onset benign chorea with striatal involvement

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

17 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 conflicting classifications of pathogenicity, 3 likely benign, 1 benign/likely benign, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
8071	NM_000332.4(ATXN1):c.589CAG[36_38] (p.Gln208[36_38])	ATXN1	Pathogenic	no assertion criteria provided
1678655	NM_001128164.2(ATXN1):c.772G>T (p.Gly258Cys)	ATXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210502	NM_001128164.2(ATXN1):c.621G>T (p.Gln207His)	ATXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931497	NM_001128164.2(ATXN1):c.609G>T (p.Gln203His)	ATXN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3780659	NC_000001.11:g.16001455_16001460dup		Uncertain significance	criteria provided, single submitter
3780669	NC_000001.11:g.16001459_16001461dup		Uncertain significance	criteria provided, single submitter
210505	NM_001128164.2(ATXN1):c.630G>T (p.Gln210His)	ATXN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
210507	NM_001128164.2(ATXN1):c.636G>T (p.Gln212His)	ATXN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2688657	NM_001128164.2(ATXN1):c.1502C>T (p.Ala501Val)	ATXN1	Uncertain significance	criteria provided, single submitter
3064693	NM_001128164.2(ATXN1):c.641_642insTCAGCA (p.Gln213_Gln214insHisGln)	ATXN1	Uncertain significance	criteria provided, single submitter
4078091	NM_001128164.2(ATXN1):c.677_678insGCAGCAGCAGCAGCACCA (p.Gln225_His226insGlnGlnGlnGlnGlnHis)	ATXN1	Uncertain significance	criteria provided, single submitter
932128	NM_001128164.2(ATXN1):c.1804G>T (p.Ala602Ser)	ATXN1	Uncertain significance	criteria provided, single submitter
3780662	NC_000001.11:g.16001459_16001461del		Likely benign	criteria provided, single submitter
3780665	NC_000001.11:g.16001411_16001413dup		Likely benign	criteria provided, single submitter
218439	NM_001128164.2(ATXN1):c.588GCA[14] (p.Gln208dup)	ATXN1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
522259	NM_001128164.2(ATXN1):c.2150C>T (p.Ala717Val)	ATXN1	Likely benign	criteria provided, multiple submitters, no conflicts
522332	NM_001128164.2(ATXN1):c.636GCA[16] (p.Gln224_Gln225dup)	ATXN1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ATXN1	Strong	Autosomal dominant	spinocerebellar ataxia type 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN1	Orphanet:98755	Spinocerebellar ataxia type 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATXN1	HGNC:10548	ENSG00000124788	P54253	Ataxin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATXN1	Ataxin-1	Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATXN1	Other/Unknown	no		Ataxin_AXH_dom, Ataxin-1_N, Ataxin_AXH_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATXN1	295	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATXN1	4,465

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATXN1	P54253	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of insulin-like growth factor receptor signaling pathway	1	2106.5×	0.006	ATXN1
nuclear export	1	1532.0×	0.006	ATXN1
positive regulation of glial cell proliferation	1	702.2×	0.006	ATXN1
insulin-like growth factor receptor signaling pathway	1	495.6×	0.006	ATXN1
excitatory postsynaptic potential	1	443.5×	0.006	ATXN1
lung alveolus development	1	351.1×	0.006	ATXN1
visual learning	1	306.4×	0.006	ATXN1
adult locomotory behavior	1	300.9×	0.006	ATXN1
learning	1	280.9×	0.006	ATXN1
social behavior	1	271.8×	0.006	ATXN1
RNA processing	1	218.9×	0.007	ATXN1
memory	1	183.2×	0.008	ATXN1
brain development	1	79.5×	0.016	ATXN1
transcription by RNA polymerase II	1	70.5×	0.017	ATXN1
negative regulation of DNA-templated transcription	1	31.6×	0.036	ATXN1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.060	ATXN1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	ATXN1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATXN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATXN1

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)
ATXN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE3	2
PHASE2	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03378414	PHASE2	NOT_YET_RECRUITING	Umbilical Cord Mesenchymal Stem Cells Therapy (19#iSCLife®-SA) for Patients With Spinocerebellar Ataxia
NCT05822908	PHASE1/PHASE2	RECRUITING	A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05826171	Not specified	ACTIVE_NOT_RECRUITING	Priming Motor Learning Through Exercise in People With Spinocerebellar Ataxia
NCT01060371	Not specified	UNKNOWN	Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
NCT01470729	Not specified	COMPLETED	Biomarkers in Autosomal Dominant Cerebellar Ataxia
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia
NCT03487367	Not specified	UNKNOWN	Clinical Trial Readiness for SCA1 and SCA3
NCT04153110	Not specified	COMPLETED	Cerebello-Spinal tDCS as Rehabilitative Intervention in Neurodegenerative Ataxia
NCT04268147	Not specified	COMPLETED	Instrumented Data Exchange for Ataxia Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRORILUZOLE	3	3
RIMTUZALCAP	2	1