Dentatorubral-pallidoluysian atrophy

Summary

Dentatorubral-pallidoluysian atrophy (MONDO:0007435) is a disease caused by ATN1 (GenCC Strong), with 1 cohort gene and 5 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Japan) [Orphanet-validated]
• Causal gene: ATN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15
• Phenotypes (HPO): 26
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.48	Japan	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated
Point prevalence	1-9 / 1 000 000	0.71	United Kingdom	Not yet validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0001138	Optic neuropathy	Frequent (30-79%)
HP:0001152	Saccadic smooth pursuit	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002345	Action tremor	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0010867	Dyssynergia	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0012048	Oromandibular dystonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dentatorubral-pallidoluysian atrophy
Mondo ID	MONDO:0007435
OMIM	125370
Orphanet	101
DOID	DOID:0060162
NCIT	C122653
SNOMED CT	68116008
UMLS	C0751781
MedGen	155630
GARD	0005643
Is cancer (heuristic)	no

Also known as: dentatorubral-pallidoluysian atrophy · Dentatorubropallidoluysian atrophy · DRPLA · haw River syndrome · Naito Oyanagi disease · Naito-Oyanagi disease · NOD

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records · 8 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 › dentatorubral-pallidoluysian atrophy

Related subtypes (9): Machado-Joseph disease, spinocerebellar ataxia type 1, 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

15 retrieved; paginated sample, class counts are floors:

4 conflicting classifications of pathogenicity, 4 pathogenic, 2 likely benign, 2 uncertain significance, 1 pathogenic/likely pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
587700	Single allele		Pathogenic	no assertion criteria provided
1027368	NM_001940.4(ATN1):c.3182TGCACC[3] (p.1061LH[3])	ATN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37031	NM_001007026.1(ATN1):c.1462CAG[49_55] (p.Gln488[49_55])	ATN1	Pathogenic	no assertion criteria provided
590267	NG_008047.1:g.17267CAG[(54-68)]	ATN1	Pathogenic	no assertion criteria provided
38905	NM_001007026.1(ATN1):c.1462CAG[(90_93)] (p.Gln488[(90-93)])	LOC109461484	Pathogenic	no assertion criteria provided
210377	NM_001007026.1(ATN1):c.1462CAG[17] (p.Gln488[17])	ATN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2642645	NM_001940.4(ATN1):c.1464GCA[20] (p.Gln498_Gln502dup)	ATN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3453412	NM_001940.4(ATN1):c.2782C>T (p.Pro928Ser)	ATN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
599473	NM_001940.4(ATN1):c.1464GCA[16] (p.Gln502dup)	LOC109461484	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582516	NM_001940.4(ATN1):c.1604C>A (p.Ser535Tyr)	ATN1	Uncertain significance	criteria provided, single submitter
3764532	NM_001940.4(ATN1):c.1467_1468del (p.Gln490fs)	LOC109461484	Uncertain significance	criteria provided, single submitter
3780521	NC_000014.8:g.7045933_7045938dup		Likely benign	criteria provided, single submitter
38904	NM_001007026.1(ATN1):c.1462CAG[(6_35)] (p.Gln488[(6-35)])	ATN1	Benign	no assertion criteria provided
1174682	NM_001940.4(ATN1):c.1464GCA[14] (p.Gln502del)	LOC109461484	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1187119	NM_001940.4(ATN1):c.1467G>A (p.Gln489=)	LOC109461484	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ATN1	Strong	Autosomal dominant	dentatorubral-pallidoluysian atrophy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATN1	Orphanet:101	Dentatorubral pallidoluysian atrophy

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
ATN1	HGNC:3033	ENSG00000111676	P54259	Atrophin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATN1	Atrophin-1	Transcriptional 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)
ATN1	Other/Unknown	no		Atrophin-like, Atrophin-1

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
adenohypophysis	1
right hemisphere of cerebellum	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATN1	223	ubiquitous	marker	right hemisphere of cerebellum, adenohypophysis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATN1	1,732

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATN1	P54259	49.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTEN Regulation	1	228.4×	0.014	ATN1
Regulation of PTEN gene transcription	1	178.4×	0.014	ATN1
Intracellular signaling by second messengers	1	91.4×	0.018	ATN1
PIP3 activates AKT signaling	1	66.8×	0.019	ATN1
Signal Transduction	1	10.2×	0.098	ATN1

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
cell killing	1	8426.0×	0.001	ATN1
maintenance of cell polarity	1	2407.4×	0.002	ATN1
response to food	1	495.6×	0.007	ATN1
determination of adult lifespan	1	432.1×	0.007	ATN1
post-embryonic development	1	205.5×	0.011	ATN1
neuron apoptotic process	1	185.2×	0.011	ATN1
male gonad development	1	156.0×	0.011	ATN1
multicellular organism growth	1	137.0×	0.011	ATN1
central nervous system development	1	115.4×	0.012	ATN1
cell migration	1	61.5×	0.020	ATN1
spermatogenesis	1	35.2×	0.031	ATN1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	ATN1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATN1	5	Binding:5

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	ATN1

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)
ATN1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	3
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06706388	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for A Single Participant With ATN1 Gene Mutation
NCT07084311	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide for A Single Participant With ATN1 Gene Mutation
NCT07221760	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide for A Single Participant (nL62541) With ATN1 Gene Mutation
NCT05489393	Not specified	RECRUITING	CureDRPLA Global Patient Registry
NCT06273150	Not specified	RECRUITING	Dentatorubral-pallidoluysian Atrophy Natural History and Biomarkers Study