Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative polyglutamine disorder caused by CAG repeat expansion in ATN1. Expanded atrophin-1 drives neuronal intranuclear inclusions, transcriptional dysregulation, and selective degeneration of the dentatorubral and pallidoluysian systems. Clinical presentation is age-dependent: juvenile-onset disease often manifests as progressive myoclonus epilepsy with intellectual disability, whereas adult-onset disease more often presents with progressive cerebellar ataxia, choreoathetosis, and dementia.
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name: Dentatorubral-Pallidoluysian Atrophy
creation_date: "2026-04-08T15:03:27Z"
updated_date: "2026-05-08T21:41:13Z"
category: Mendelian
description: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant
neurodegenerative polyglutamine disorder caused by CAG repeat expansion in
ATN1. Expanded atrophin-1 drives neuronal intranuclear inclusions,
transcriptional dysregulation, and selective degeneration of the
dentatorubral and pallidoluysian systems. Clinical presentation is
age-dependent: juvenile-onset disease often manifests as progressive
myoclonus epilepsy with intellectual disability, whereas adult-onset disease
more often presents with progressive cerebellar ataxia, choreoathetosis, and
dementia.
disease_term:
preferred_term: dentatorubral-pallidoluysian atrophy
term:
id: MONDO:0007435
label: dentatorubral-pallidoluysian atrophy
parents:
- Neurodegenerative Disorders
- Trinucleotide Repeat Disorders
synonyms:
- DRPLA
has_subtypes:
- name: Juvenile-onset DRPLA
classification: clinical_phenotype
description: >-
Earlier-onset phenotype typically presenting before age 20 with epilepsy,
myoclonus, and progressive intellectual disability, usually associated
with longer ATN1 expansions and progressive myoclonus epilepsy.
evidence:
- reference: PMID:41147955
reference_title: "Epilepsy in dentatorubral-pallidoluysian atrophy: A systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The juvenile onset type often presents with epilepsy, including
progressive myoclonic epilepsy (PME).
explanation: >-
Systematic review and meta-analysis confirms epilepsy, often PME, as
the defining juvenile presentation of DRPLA.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Longer CAG repeat lengths of ≥65 are often found in patients with a
progressive myoclonus epilepsy (PME) phenotype of DRPLA consisting of
generalized seizures, myoclonus, and progressive intellectual
disability, and these individuals typically present before the age of
20 (juvenile-onset DRPLA).
explanation: >-
Review links juvenile-onset DRPLA to longer repeats and the classic
PME phenotype.
- name: Adult-onset DRPLA
classification: clinical_phenotype
description: >-
Later-onset phenotype usually beginning in adulthood with progressive
cerebellar ataxia, choreoathetosis, and cognitive decline or dementia,
typically associated with shorter pathogenic repeats than juvenile-onset
disease.
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Typical clinical features of adult-onset disease (≥20 years of age)
include ataxia, cognitive impairment, and choreoathetosis with median
age at onset for these presentations of 38–43 years.
explanation: >-
Review defines the adult-onset clinical subtype by ataxia,
choreoathetosis, and cognitive impairment.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
DRPLA is inherited as an autosomal dominant repeat expansion disorder.
Fully penetrant disease is typically seen at 48 or more CAG repeats,
while alleles in the 35-47 range can show incomplete penetrance.
Anticipation is prominent, especially with paternal transmission.
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal
dominantly inherited disorder characterized by myoclonus, epilepsy,
ataxia, and dementia.
explanation: >-
The review explicitly identifies DRPLA as an autosomal dominantly
inherited disorder.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DRPLA, in common with other microsatellite repeat disorders, shows
genetic anticipation whereby disease symptoms occur earlier and more
severely generation on generation.
explanation: >-
Supports the clinically important anticipation pattern in DRPLA.
prevalence:
- population: Japanese ancestry
percentage: 2-7 per million
notes: >-
DRPLA is classically most often recognized in populations of Japanese
ancestry and appears substantially less common in most non-Asian cohorts.
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DRPLA is most commonly recognized in populations of Japanese
ancestry, with an incidence of 2–7 per million.
explanation: >-
Review provides a population incidence estimate for Japanese ancestry
cohorts.
progression:
- phase: Prodromal stage
notes: >-
Preclinical or prodromal DRPLA can already show subtle executive-language
deficits and localized cerebellar gray matter loss before the full
manifest multisystem neurodegenerative syndrome.
evidence:
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
prodromal patients showed deficits only in phonemic fluency.
explanation: >-
Cohort data support measurable cognitive abnormalities before full
clinical manifestation.
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
prodromal patients showed gray matter loss localized to the bilateral
cerebellar hemispheres.
explanation: >-
MRI findings show that cerebellar structural degeneration is already
detectable in the prodromal stage.
- phase: Juvenile-onset progressive myoclonus epilepsy phenotype
age_range: <20 years
notes: >-
Earlier-onset disease is typically associated with longer repeats and a
progressive myoclonus epilepsy phenotype with generalized or focal
seizures, myoclonus, and intellectual disability.
evidence:
- reference: PMID:41147955
reference_title: "Epilepsy in dentatorubral-pallidoluysian atrophy: A systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The juvenile onset type often presents with epilepsy, including
progressive myoclonic epilepsy (PME).
explanation: >-
Meta-analysis supports epilepsy as the defining clinical feature of
juvenile-onset DRPLA.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Longer CAG repeat lengths of ≥65 are often found in patients with a
progressive myoclonus epilepsy (PME) phenotype of DRPLA consisting of
generalized seizures, myoclonus, and progressive intellectual
disability, and these individuals typically present before the age of
20 (juvenile-onset DRPLA).
explanation: >-
Review defines the hallmark juvenile progression pattern.
- phase: Adult-onset ataxic-choreic phenotype
age_range: ">=20 years"
notes: >-
Adult-onset disease more often begins with progressive cerebellar ataxia,
choreoathetosis, and cognitive decline, while seizures are less common at
presentation.
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with the adult-onset (age ≥ 20) or non-PME phenotype
invariably harbor shorter repeat lengths of <65 repeats and present
with ataxia, choreoathetosis, dementia, and psychiatric features,
with seizures being a rare presenting complaint
explanation: >-
Review distinguishes the adult-onset phenotype from juvenile PME.
- phase: Advanced disease
notes: >-
DRPLA progresses relentlessly after symptom onset, with severe functional
decline, loss of ambulation, and premature death commonly resulting from
pneumonia or status epilepticus.
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical symptoms are progressive, with life expectancy typically
8–16 years from symptom onset.
explanation: >-
Review summarizes the overall relentlessly progressive course.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mean age at death is 49 years (range 18–80 years), median time from
disease onset to death is 15 years, and life expectancy is inversely
correlated with CAG repeat length
explanation: >-
Provides natural-history data on survival and repeat-length effects.
pathophysiology:
- name: ATN1 CAG Repeat Expansion
conforms_to: "polyglutamine_expansion_proteotoxicity#Translated CAG / Polyglutamine Repeat Expansion"
description: >-
DRPLA is initiated by expansion of a CAG trinucleotide repeat in ATN1,
producing an expanded polyglutamine tract in atrophin-1. Larger repeat
sizes are associated with earlier onset and more severe disease,
consistent with repeat-length-dependent toxicity.
gene:
preferred_term: ATN1
term:
id: hgnc:3033
label: ATN1
evidence:
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, inherited
neurodegenerative disorder caused by the expansion of
cytosine-adenine-guanine repeats in ATN1.
explanation: >-
Contemporary cohort study directly states the primary molecular cause
of DRPLA.
- reference: PMID:9124808
reference_title: "Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A significant correlation was found between the age at onset of DRPLA
and the size of the CAG repeat expansion.
explanation: >-
Primary neuropathology study links repeat size to onset timing.
downstream:
- target: Regional CAG Repeat Mosaicism
description: >-
Somatic and regional differences in repeat expansion modify age at
onset and vulnerability.
evidence:
- reference: PMID:9124808
reference_title: "Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found that the expanded alleles were smaller in the cerebellar
cortex than in other brain regions, such as the frontal cortex, in
these three diseases.
explanation: >-
Documents regional somatic differences in CAG repeat size as
a direct consequence of the underlying CAG repeat expansion.
- target: Polyglutamine Atrophin-1 Aggregation
description: >-
Expanded atrophin-1 accumulates as toxic polyglutamine-rich inclusions
in vulnerable neurons.
evidence:
- reference: PMID:41624332
reference_title: "Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that our model-the Atn1 Q112/+ mouse-recapitulates key
features of human DRPLA, including behavioral alterations, reduced
brain size, and aggregate accumulation.
explanation: >-
Humanized mouse with expanded ATN1 CAG repeat directly demonstrates
aggregate accumulation as a causal downstream consequence of the
repeat expansion.
- target: ATN1 Transcriptional Co-repressor Dysregulation
description: >-
Expanded atrophin-1 perturbs transcriptional co-repressor function and
downstream gene-expression programs.
evidence:
- reference: PMID:41624332
reference_title: "Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Treatment with human, but not mouse, ATN1-targeting ASOs provides
remarkable protection from a range of disease-related behavioral
phenotypes and marked rescue of transcriptional dysregulation in the
cerebellum.
explanation: >-
ASO rescue of transcriptional dysregulation by lowering expanded ATN1
establishes the causal link from repeat expansion to transcriptional
dysregulation.
- target: Proteostasis Failure
description: >-
Expanded atrophin-1 impairs autophagy and stress-response pathways that
maintain protein homeostasis.
evidence:
- reference: PMID:41355374
reference_title: "Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DRPLA features motor, cognitive, and epileptic symptoms and shares
pathogenic mechanisms with other polyglutamine (polyQ) disorders,
including protein misfolding, impaired autophagy, and transcriptional
dysregulation.
explanation: >-
Directly links the CAG-expansion/polyQ mechanism to autophagy
impairment and protein misfolding as proteostasis failure.
- name: Regional CAG Repeat Mosaicism
description: >-
Expanded ATN1 alleles show brain-region-specific somatic mosaicism. Lower
expansion in cerebellar and hippocampal granule-cell-rich regions
relative to other brain regions supports cell-type-specific repeat
instability as a contributor to selective vulnerability and age-dependent
phenotype.
evidence:
- reference: PMID:9124808
reference_title: "Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found that the expanded alleles were smaller in the cerebellar
cortex than in other brain regions, such as the frontal cortex, in
these three diseases.
explanation: >-
Demonstrates brain-region-specific somatic CAG mosaicism in DRPLA.
- reference: PMID:9124808
reference_title: "Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These observations suggest that granule cells in the cerebellum and
hippocampus have low levels of CAG repeat expansion, and that other
types of cells exhibit a higher level of CAG repeat expansion, in
spinocerebellar ataxias.
explanation: >-
Supports cell-type-specific repeat expansion as a plausible mechanism
for selective regional vulnerability.
downstream:
- target: Dentatorubral-Pallidoluysian System Degeneration
description: >-
Region-specific repeat instability is consistent with selective
neurodegeneration in vulnerable circuits.
evidence:
- reference: PMID:9124808
reference_title: "Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These observations suggest that granule cells in the cerebellum and
hippocampus have low levels of CAG repeat expansion, and that other
types of cells exhibit a higher level of CAG repeat expansion, in
spinocerebellar ataxias.
explanation: >-
Cell-type-specific repeat mosaicism correlates with the selective
regional vulnerability that defines DRPLA neurodegeneration.
- name: Polyglutamine Atrophin-1 Aggregation
conforms_to: "polyglutamine_expansion_proteotoxicity#Misfolded Polyglutamine Protein Aggregation"
description: >-
Expanded atrophin-1 accumulates in ubiquitinated neuronal intranuclear
and intracytoplasmic inclusions. These polyglutamine-rich aggregates are
a defining neuropathological hallmark of DRPLA and track directly with
the expanded repeat mutation.
biological_processes:
- preferred_term: Inclusion body assembly
term:
id: GO:0070841
label: inclusion body assembly
modifier: INCREASED
locations:
- preferred_term: dentate nucleus
term:
id: UBERON:0002132
label: dentate nucleus
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:10867794
reference_title: "Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings indicate that in DRPLA, the NIFIs in the CDN are an
alteration that is directly related to the causative gene abnormality
(an expanded CAG repeat encoding polyglutamine) and that, from the
molecular point of view, they are distinct from the SLIs in ALS.
explanation: >-
Neuropathology study directly ties dentate nucleus inclusions to the
expanded polyglutamine mutation in DRPLA.
- reference: PMID:41624332
reference_title: "Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that our model-the Atn1 Q112/+ mouse-recapitulates key
features of human DRPLA, including behavioral alterations, reduced
brain size, and aggregate accumulation.
explanation: >-
Fully humanized mouse model independently reproduces aggregate
accumulation as a core DRPLA pathological feature.
downstream:
- target: Dentatorubral-Pallidoluysian System Degeneration
description: >-
Aggregate accumulation accompanies dysfunction and loss of vulnerable
neurons.
evidence:
- reference: PMID:10867794
reference_title: "Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings indicate that in DRPLA, the NIFIs in the CDN are an
alteration that is directly related to the causative gene abnormality
(an expanded CAG repeat encoding polyglutamine) and that, from the
molecular point of view, they are distinct from the SLIs in ALS.
explanation: >-
Ties neuronal intranuclear filamentous inclusions in the dentate
nucleus directly to the polyglutamine mutation, supporting the
causal link from aggregation to dentatorubral system pathology.
- name: ATN1 Transcriptional Co-repressor Dysregulation
conforms_to: "polyglutamine_expansion_proteotoxicity#Transcriptional Dysregulation"
description: >-
ATN1 encodes a transcriptional co-repressor, and pathogenic atrophin-1
disrupts transcriptional networks with downstream dysregulation of
cerebellar gene-expression programs in DRPLA.
gene:
preferred_term: ATN1
term:
id: hgnc:3033
label: ATN1
biological_processes:
- preferred_term: Regulation of transcription by RNA polymerase II
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
modifier: DYSREGULATED
evidence:
- reference: PMID:41355374
reference_title: "Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DRPLA features motor, cognitive, and epileptic symptoms and shares
pathogenic mechanisms with other polyglutamine (polyQ) disorders,
including protein misfolding, impaired autophagy, and transcriptional
dysregulation.
explanation: >-
Cell-model transcriptomic study directly links pathogenic atrophin-1
to transcriptional dysregulation in DRPLA.
- reference: PMID:41624332
reference_title: "Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Treatment with human, but not mouse, ATN1-targeting ASOs provides
remarkable protection from a range of disease-related behavioral
phenotypes and marked rescue of transcriptional dysregulation in the
cerebellum.
explanation: >-
Rescue of cerebellar transcriptional dysregulation by ATN1 lowering
provides functional support for this mechanism in vivo.
downstream:
- target: Dentatorubral-Pallidoluysian System Degeneration
description: >-
Chronic transcriptional dysregulation contributes to neuronal
dysfunction and loss.
evidence:
- reference: PMID:41624332
reference_title: "Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Treatment with human, but not mouse, ATN1-targeting ASOs provides
remarkable protection from a range of disease-related behavioral
phenotypes and marked rescue of transcriptional dysregulation in the
cerebellum.
explanation: >-
ASO-mediated rescue of cerebellar transcriptional dysregulation
alongside behavioral improvement supports causal contribution of
transcriptional dysregulation to the DRPLA neurodegenerative phenotype.
- name: Proteostasis Failure
conforms_to: "polyglutamine_expansion_proteotoxicity#Proteostasis Network Overload"
description: >-
Pathogenic atrophin-1 drives proteotoxic stress with impaired autophagy
and dysregulated oxidative-stress responses, indicating failure of
protein-quality-control pathways in DRPLA.
gene:
preferred_term: ATN1
term:
id: hgnc:3033
label: ATN1
biological_processes:
- preferred_term: Autophagy
term:
id: GO:0006914
label: autophagy
modifier: DECREASED
- preferred_term: Response to oxidative stress
term:
id: GO:0006979
label: response to oxidative stress
modifier: DYSREGULATED
evidence:
- reference: PMID:41355374
reference_title: "Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DRPLA features motor, cognitive, and epileptic symptoms and shares
pathogenic mechanisms with other polyglutamine (polyQ) disorders,
including protein misfolding, impaired autophagy, and transcriptional
dysregulation.
explanation: >-
Cell-model transcriptomic study supports impaired autophagy as a core
component of DRPLA proteostasis failure.
- reference: PMID:41355374
reference_title: "Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Dysregulated pathways also included inflammation, chromatin
remodeling, stress responses, and redox imbalance.
explanation: >-
Supports oxidative-stress dysregulation and broader proteotoxic stress
downstream of mutant atrophin-1.
downstream:
- target: Dentatorubral-Pallidoluysian System Degeneration
evidence:
- reference: PMID:41355374
reference_title: "Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Dysregulated pathways also included inflammation, chromatin
remodeling, stress responses, and redox imbalance.
explanation: >-
Cell-model transcriptomic dysregulation identifies stress response
and redox imbalance as proteostatic failure pathways contributing
to neuronal injury in DRPLA.
description: >-
Chronic proteostatic stress contributes to neuronal dysfunction and
loss.
- name: Dentatorubral-Pallidoluysian System Degeneration
conforms_to: "polyglutamine_expansion_proteotoxicity#Selective Neuronal Dysfunction and Loss"
description: >-
The combined effects of repeat expansion, aggregate formation, and
transcriptional/proteostatic stress drive selective neuronal loss and
astrocytosis in the dentate nucleus, globus pallidus, and red nucleus,
with cerebellar-predominant gray matter loss already detectable in the
prodromal stage and widespread gray matter loss in manifest disease.
locations:
- preferred_term: globus pallidus
term:
id: UBERON:0001875
label: globus pallidus
- preferred_term: dentate nucleus
term:
id: UBERON:0002132
label: dentate nucleus
- preferred_term: red nucleus
term:
id: UBERON:0001947
label: red nucleus
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A CAG repeat expansion in the ATN1 gene results in neuronal
intranuclear inclusions, variable neuronal loss, and astrocytosis in
the globus pallidus, dentate and red nuclei.
explanation: >-
Review summarizes the selective neuropathology that defines DRPLA.
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Magnetic resonance imaging findings revealed widespread gray matter
loss across the whole brain in manifest patients, whereas prodromal
patients showed gray matter loss localized to the bilateral
cerebellar hemispheres.
explanation: >-
Modern cohort data connect selective early cerebellar degeneration to
later widespread neurodegeneration in manifest disease.
phenotypes:
- name: Progressive cerebellar ataxia
category: Neurological
diagnostic: true
notes: >-
Progressive gait and limb ataxia are central manifestations of adult-onset
disease and remain a core clinical clue across the disease course.
phenotype_term:
preferred_term: Progressive cerebellar ataxia
term:
id: HP:0002073
label: Progressive cerebellar ataxia
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal
dominantly inherited disorder characterized by myoclonus, epilepsy,
ataxia, and dementia.
explanation: >-
The abstract identifies ataxia as a core syndrome feature of DRPLA.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Typical clinical features of adult-onset disease (≥20 years of age)
include ataxia, cognitive impairment, and choreoathetosis with median
age at onset for these presentations of 38–43 years.
explanation: >-
Confirms progressive cerebellar ataxia as the dominant adult-onset
phenotype.
- name: Seizures
category: Neurological
notes: >-
Epilepsy is especially prominent in juvenile-onset DRPLA and can include
focal, myoclonic, generalized tonic-clonic, and progressive myoclonic
epilepsy phenotypes.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:41147955
reference_title: "Epilepsy in dentatorubral-pallidoluysian atrophy: A systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Focal seizures were frequently observed (40.0%-76.5%) alongside
myoclonic and generalized tonic-clonic seizures.
explanation: >-
Meta-analysis defines the major seizure phenotypes observed in DRPLA.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal
dominantly inherited disorder characterized by myoclonus, epilepsy,
ataxia, and dementia.
explanation: >-
Review abstract identifies epilepsy as a canonical DRPLA phenotype.
- name: Myoclonus
category: Neurological
notes: >-
Myoclonus is especially characteristic of juvenile-onset disease and may
occur together with seizures as part of the PME phenotype.
phenotype_term:
preferred_term: Myoclonus
term:
id: HP:0001336
label: Myoclonus
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal
dominantly inherited disorder characterized by myoclonus, epilepsy,
ataxia, and dementia.
explanation: >-
Review abstract identifies myoclonus as a defining disease feature.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Longer CAG repeat lengths of ≥65 are often found in patients with a
progressive myoclonus epilepsy (PME) phenotype of DRPLA consisting of
generalized seizures, myoclonus, and progressive intellectual
disability, and these individuals typically present before the age of
20 (juvenile-onset DRPLA).
explanation: >-
Review links myoclonus specifically to the juvenile PME presentation.
- name: Choreoathetosis
category: Neurological
notes: >-
Hyperkinetic involuntary movements are most typical of adult-onset
disease and help distinguish DRPLA from pure cerebellar ataxia syndromes.
phenotype_term:
preferred_term: Choreoathetosis
term:
id: HP:0001266
label: Choreoathetosis
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with the adult-onset (age ≥ 20) or non-PME phenotype
invariably harbor shorter repeat lengths of <65 repeats and present
with ataxia, choreoathetosis, dementia, and psychiatric features,
with seizures being a rare presenting complaint
explanation: >-
Review identifies choreoathetosis as a hallmark adult-onset
manifestation.
- name: Dementia
category: Neurological
notes: >-
Progressive cognitive decline is a common feature of adult-onset disease,
while broader cognitive impairment can already be detected in prodromal
and juvenile cases.
phenotype_term:
preferred_term: Dementia
term:
id: HP:0000726
label: Dementia
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal
dominantly inherited disorder characterized by myoclonus, epilepsy,
ataxia, and dementia.
explanation: >-
Review abstract identifies dementia as a canonical DRPLA phenotype.
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cognitive assessments revealed that 51 manifest patients (96%) and 4
prodromal patients (29%) scored <26 on the Montreal Cognitive
Assessment.
explanation: >-
Large contemporary cohort confirms high burden of cognitive impairment
across manifest and prodromal disease.
- name: Intellectual disability
category: Neurological
notes: >-
Progressive intellectual disability is most strongly associated with
juvenile-onset DRPLA and the longer-repeat PME phenotype.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Longer CAG repeat lengths of ≥65 are often found in patients with a
progressive myoclonus epilepsy (PME) phenotype of DRPLA consisting of
generalized seizures, myoclonus, and progressive intellectual
disability, and these individuals typically present before the age of
20 (juvenile-onset DRPLA).
explanation: >-
Review directly links intellectual disability to juvenile-onset DRPLA.
genetic:
- name: ATN1
association: Causative
gene_term:
preferred_term: ATN1
term:
id: hgnc:3033
label: ATN1
notes: >-
DRPLA is caused by a CAG repeat expansion in exon 5 of ATN1. Normal
alleles are typically 35 repeats or fewer. Alleles with 35-47 repeats are
incompletely penetrant, while 48 or more repeats are typically fully
penetrant. Larger expansions are associated with earlier onset, juvenile
presentation, anticipation, and greater disease severity, especially with
paternal transmission.
evidence:
- reference: PMID:40552560
reference_title: "Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, inherited
neurodegenerative disorder caused by the expansion of
cytosine-adenine-guanine repeats in ATN1.
explanation: >-
Cohort study confirms ATN1 repeat expansion as the causal genetic
lesion.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Repeat lengths ≥48 demonstrate a fully penetrant clinical phenotype,
while alleles of 35–47 repeat length are incompletely penetrant and
have been associated with a milder DRPLA clinical phenotype in a
small number of cases.
explanation: >-
Review provides clinically useful repeat-length thresholds for
penetrance.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This phenomenon is thought to be driven by CAG repeat expansion in
the gametes, particularly in spermatogenesis, as anticipation is more
pronounced on paternal inheritance.
explanation: >-
Supports the strong paternal-transmission effect on anticipation in
DRPLA.
treatments:
- name: Antiseizure Medication Management
description: >-
Symptomatic antiseizure pharmacotherapy is used for DRPLA-associated
generalized, myoclonic, focal, and atonic seizures, especially in
juvenile-onset progressive myoclonus epilepsy.
treatment_term:
preferred_term: anticonvulsant agent therapy
term:
id: MAXO:0000167
label: anticonvulsant agent therapy
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Myoclonic seizures can be managed with carbamazepine or phenytoin, unlike
with other forms of myoclonic epilepsy, while sodium valproate,
perampanel, and zonisamide have been used in the treatment of
generalized seizures.
explanation: >-
Review describes antiseizure medication classes used in DRPLA seizure
management.
- name: Multidisciplinary Rehabilitation and Supportive Care
description: >-
Progressive ataxia, movement disorder, cognitive decline, feeding risk, and
functional impairment are managed with multidisciplinary supportive care,
including physiotherapy, occupational therapy, environmental adaptation, and
palliative support as disease advances.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Education, physiotherapy, occupational therapy, and environmental
adaptation may also be needed at different disease stages.
explanation: >-
Supports staged rehabilitation and supportive care needs across DRPLA
progression.
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Specialist palliative care input is recommended throughout the disease
course, with evidence suggesting particular importance later in disease
course.
explanation: >-
Supports palliative and multidisciplinary care as part of DRPLA
management.
- name: Genetic Counseling
description: >-
Genetic counseling should be offered early because DRPLA is autosomal
dominant, has predictive-testing implications for relatives, and involves
reproductive planning issues related to repeat expansion and anticipation.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:30410817
reference_title: "Dentatorubral-pallidoluysian Atrophy: An Update."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic counseling is ideally undertaken early to ensure families are
aware of the autosomal dominant nature of the disease, to discuss
predictive testing and potential means of family planning.
explanation: >-
Review directly supports early genetic counseling for affected families.
references:
- reference: DOI:10.1002/acn3.51858
title: 'Infantile‐onset parkinsonism, dyskinesia, and developmental delay: do not forget polyglutamine defects!'
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats).
supporting_text: We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats).
evidence:
- reference: DOI:10.1002/acn3.51858
reference_title: 'Infantile‐onset parkinsonism, dyskinesia, and developmental delay: do not forget polyglutamine defects!'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats).
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
- reference: DOI:10.1002/mds.29355
title: Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases.
supporting_text: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases.
evidence:
- reference: DOI:10.1002/mds.29355
reference_title: Atrophin‐1 Function and Dysfunction in Dentatorubral–Pallidoluysian Atrophy
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases.
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
- reference: DOI:10.1007/s00415-020-10218-6
title: 'DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder'
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion.
supporting_text: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion.
evidence:
- reference: DOI:10.1007/s00415-020-10218-6
reference_title: 'DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion.
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
- reference: DOI:10.1007/s12311-024-01703-z
title: 'An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches'
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes.
supporting_text: The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes.
evidence:
- reference: DOI:10.1007/s12311-024-01703-z
reference_title: 'An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes.
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
- reference: DOI:10.1038/s41431-024-01542-w
title: Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes.
supporting_text: To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes.
evidence:
- reference: DOI:10.1038/s41431-024-01542-w
reference_title: Diagnostic uplift through the implementation of short tandem repeat analysis using exome sequencing
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: To date, approximately 50 short tandem repeat (STR) disorders have been identified; yet, clinical laboratories rarely conduct STR analysis on exomes.
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
- reference: DOI:10.1177/26330040241249189
title: 'Establishing resources and increasing awareness to advance research on Dentatorubral-pallidoluysian atrophy toward a treatment: a patient organization perspective'
found_in:
- Dentatorubral-Pallidoluysian_Atrophy-deep-research-falcon.md
findings:
- statement: Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare neurodegenerative disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations.
supporting_text: Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare neurodegenerative disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations.
evidence:
- reference: DOI:10.1177/26330040241249189
reference_title: 'Establishing resources and increasing awareness to advance research on Dentatorubral-pallidoluysian atrophy toward a treatment: a patient organization perspective'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare neurodegenerative disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations.
explanation: Deep research cited this publication as relevant literature for Dentatorubral-Pallidoluysian Atrophy.
DRPLA is an autosomal dominant, progressive, neurodegenerative repeat-expansion disorder caused by a CAG expansion in ATN1 (atrophin-1), and is clinically characterized by cerebellar ataxia, cognitive decline/dementia, myoclonus, epilepsy, chorea/choreoathetosis, and psychiatric manifestations (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4).
Recent (2024) patient-organization perspective emphasizes DRPLA as “an ultra-rare neurodegenerative disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations” and explicitly notes MIM#125370 (prades2024establishingresourcesand pages 1-2).
This entry synthesizes aggregated disease-level resources (systematic review-style neurology update, movement disorders review, patient-organization review, clinical trial registries) and individual patient evidence (case reports, infantile case report) (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2, chen2024dentatorubralpallidoluysianatrophya pages 1-2, baide‐mairena2023infantile‐onsetparkinsonismdyskinesia pages 1-3, NCT07084311 chunk 1).
Primary cause: unstable CAG repeat expansion in exon 5 of ATN1 (chromosome 12p13.31) encoding a polyglutamine-expanded atrophin-1 protein (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5).
Direct abstract quote (neurology update): “Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion.” (published online 26 Oct 2020; Journal of Neurology 2021) (chaudhry2021drplaunderstandingthe pages 1-3).
No protective genetic variants or environmental protective factors were identified in the retrieved sources.
No direct gene–environment interaction evidence was identified in the retrieved sources.
A structured phenotype table with HPO suggestions and age associations is provided below.
| Phenotype (plain language) | Suggested HPO term(s) | Typical age-of-onset association | Supporting evidence / notes |
|---|---|---|---|
| Cerebellar ataxia / gait incoordination | HP:0001251 Ataxia; HP:0002066 Gait ataxia | Both juvenile and adult; often a major presenting feature in adult-onset disease | DRPLA is characterized by progressive cerebellar ataxia; patients with onset after age 20 tend to present with cerebellar ataxia, choreoathetosis, and dementia. Adult-onset cases commonly show ataxia as an early/core feature (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2). |
| Cognitive decline / dementia | HP:0001268 Mental deterioration; HP:0000726 Dementia; HP:0001249 Intellectual disability | Juvenile: developmental delay / intellectual disability more prominent; Adult: cognitive decline and dementia common | Core disease descriptions include cognitive impairment/dementia. Juvenile-onset DRPLA is associated with developmental delay and progressive intellectual disability, whereas adult-onset disease commonly includes dementia/cognitive decline (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2). |
| Myoclonus | HP:0001336 Myoclonus | Strongly associated with juvenile-onset | Juvenile-onset DRPLA typically presents with a “myoclonus phenotype”; juvenile cases are characterized by myoclonus and epilepsy, while adult-onset cases more often show chorea/ataxia/dementia (nowak2023atrophin‐1functionand pages 2-2, chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5). |
| Epilepsy / seizures | HP:0001250 Seizure; HP:0002123 Generalized myoclonic seizure; HP:0002069 Generalized tonic-clonic seizure | Strongly associated with juvenile-onset; uncommon/less frequent in adult-onset, especially after age 40 | Seizures are common in juvenile-onset DRPLA and become less frequent with later onset; juvenile patients may have generalized seizures early and generalized tonic-clonic seizures later. Adult-onset epilepsy is reported but less common (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2). |
| Chorea / choreoathetosis / involuntary movements | HP:0002072 Chorea; HP:0001266 Choreoathetosis; HP:0004305 Athetosis | More typical of adult-onset | Adult-onset DRPLA is characterized by ataxia, choreoathetosis/involuntary movements, cognitive impairment, and personality/psychiatric change. Choreoathetoid movements are one of the classic described phenotypes (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2). |
| Psychiatric symptoms / personality change | HP:0000708 Behavioral abnormality; HP:0000716 Depression; HP:0000738 Hallucinations | More typical of adult-onset, though can occur across forms | Psychiatric manifestations are part of the cardinal feature set. Adult-onset DRPLA commonly includes personality changes and psychiatric symptoms; disease overviews also list psychiatric symptoms among key manifestations (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5). |
| Developmental delay / progressive intellectual disability | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability | Juvenile / infantile | Juvenile-onset DRPLA is characterized by developmental delay and progressive intellectual disability, reflecting the severe neurodevelopmental/neurodegenerative presentation in early-onset disease (prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5). |
| White matter lesions and cerebellar/brainstem atrophy on MRI | HP:0002500 Abnormal cerebral white matter morphology; HP:0001272 Cerebellar atrophy; HP:0002367 Brainstem atrophy | Seen in both; more evident with progression | MRI commonly shows progressive brainstem and cerebellar atrophy and widespread white matter lesions involving cerebrum, thalamus, brainstem, and cerebellum. The DRPLA natural history study uses brain atrophy on MRI (brainstem, superior cerebellar peduncle, cerebellum, thalamus) as a primary outcome (chen2024dentatorubralpallidoluysianatrophya pages 3-5, NCT06273150 chunk 1, chaudhry2021drplaunderstandingthe pages 1-3). |
| Dysphagia / swallowing difficulty | HP:0002015 Dysphagia | Progressive complication; not clearly age-specific in retrieved sources | The ongoing natural history study includes a Clinical Assessment of Dysphagia in Neurodegeneration, indicating dysphagia is clinically relevant for longitudinal phenotyping, although age specificity was not detailed in the retrieved context (NCT06273150 chunk 1). |
| Speech impairment / dysarthria | HP:0001260 Dysarthria; HP:0002167 Slurred speech | Progressive complication; not clearly age-specific in retrieved sources | The natural history study includes a DRPLA-specific speech battery, supporting speech disturbance as a measurable phenotype in clinical follow-up, although retrieved texts did not stratify it by juvenile vs adult onset (NCT06273150 chunk 1). |
| Nystagmus / abnormal eye movements | HP:0000639 Nystagmus; HP:0000640 Gaze-evoked nystagmus | Reported in adult case; age association not established | A 34-year-old adult case showed bilateral upward rotational nystagmus; the authors suggested this may be a clinical sign worth considering, but this appears to be a less established/possibly uncommon phenotype in the retrieved literature (chen2024dentatorubralpallidoluysianatrophya pages 1-2, chen2024dentatorubralpallidoluysianatrophya pages 3-5). |
Table: This table summarizes major clinical and imaging phenotypes of dentatorubral-pallidoluysian atrophy, with suggested HPO mappings and whether each feature is more typical of juvenile- or adult-onset disease. It is useful for knowledge-base phenotype annotation and age-stratified curation.
Key phenotype stratification by age-of-onset: - Juvenile-onset (<20 years) commonly features myoclonus and epilepsy, with developmental delay/intellectual disability and more rapid progression in many reports (prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 2-2). - Adult-onset (>20 years) commonly features progressive ataxia, choreoathetosis/chorea, cognitive impairment/dementia, and psychiatric/personality changes (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 2-2).
Quality-of-life (QoL) impact evidence within this run is mainly inferred from the existence of QoL-focused registry and trial endpoints (CPCHILD; caregiver burden; health economics) rather than validated disease-specific QoL instruments reported in full text (NCT05489393 chunk 1, NCT07084311 chunk 1).
Across major reviews/case literature retrieved here: - Normal alleles: typically ~6–35 CAG repeats (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 1-2). - Incomplete penetrance: often reported for 35–47 repeats (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 1-2). - Full penetrance: typically at ≥48 repeats (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 1-2). - Juvenile/infantile disease correlates with larger expansions (e.g., >70; extreme cases >90) (nowak2023atrophin‐1functionand pages 1-2, nowak2023atrophin‐1functionand pages 2-2).
Recent 2023 primary case data: an infantile-onset case was reported with “the largest ATN1 CAG expansion reported to date (98 repeats)” (Annals of Clinical and Translational Neurology, Jul 2023; https://doi.org/10.1002/acn3.51858) (baide‐mairena2023infantile‐onsetparkinsonismdyskinesia pages 1-3).
A 2022 preclinical DRPLA study (and its framing) highlights the role of somatic repeat instability and references DNA repair modifiers (e.g., MLH1/MSH3/PMS2/FAN1 in context) as a general mechanism affecting age at onset/severity in repeat expansion disorders (Neurobiology of Disease 2022; https://doi.org/10.1016/j.nbd.2021.105604) (hasuike2022cagrepeatbindingsmall pages 1-2).
Evidence converges on predominantly toxic gain-of-function of mutant atrophin-1, with broad downstream cellular dysfunction including transcriptional dysregulation and proteostasis/autophagy defects (nowak2023atrophin‐1functionand pages 4-5, nowak2023atrophin‐1functionand pages 2-2).
No validated environmental triggers, toxins, infectious agents, or lifestyle risk factors specific to DRPLA were identified in the retrieved sources for this run.
Upstream trigger: expansion of CAG repeats in ATN1 → expanded polyQ atrophin-1 (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4).
Intermediate molecular/cellular mechanisms: - Mutant atrophin-1 aggregation and altered protein–protein interactions (nowak2023atrophin‐1functionand pages 1-2). - Transcriptional dysregulation via sequestration/interaction with transcriptional regulators (TBP/CBP/TAFII130/RERE) (nowak2023atrophin‐1functionand pages 4-5). - Proteostasis disruption including autophagy-lysosomal impairment (“canonical autophagy is blocked at the lysosomal level” in the reviewed mechanistic summary) (nowak2023atrophin‐1functionand pages 4-5). - Somatic and germline repeat instability → mosaicism and anticipation, potentially accelerating neuronal dysfunction over time (nowak2023atrophin‐1functionand pages 2-2, chaudhry2021drplaunderstandingthe pages 1-3).
Tissue/circuit vulnerability and clinical output: neuronal dysfunction and neurodegeneration in cerebellar and basal ganglia-related regions (dentate nucleus, globus pallidus, subthalamic nucleus; broader brainstem/white matter involvement), producing ataxia, involuntary movements (chorea/choreoathetosis), epilepsy/myoclonus (especially juvenile onset), and cognitive/psychiatric features (nowak2023atrophin‐1functionand pages 2-2, chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5).
A structured mechanism table with suggested GO/CL/UBERON terms is provided below.
| Level | Mechanism description | Suggested GO biological process / cellular component terms | Suggested CL cell types | Suggested UBERON anatomy | Key supporting citations |
|---|---|---|---|---|---|
| Genetic | DRPLA is caused by an unstable CAG repeat expansion in exon 5 of ATN1 on chromosome 12p13.31. Full penetrance is typically reported at >=48 CAG repeats, with 35-47 repeats described as incompletely penetrant; longer repeats are associated with earlier onset, more severe disease, and anticipation. Somatic and germline repeat instability are central upstream drivers of disease progression. | GO:0003677 DNA binding; GO:0006974 cellular response to DNA damage stimulus; GO:0006310 DNA recombination | CL:0000540 neuron | UBERON:0000955 brain; UBERON:0000073 cerebellum | (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4, hasuike2022cagrepeatbindingsmall pages 1-2, nowak2023atrophin‐1functionand pages 2-2, nowak2023atrophin‐1functionand pages 1-2) |
| Protein | Expanded CAG repeats encode a polyglutamine-expanded atrophin-1 protein that undergoes conformational change, aggregation, and abnormal protein-protein interactions. Mutant atrophin-1 is considered a toxic gain-of-function species; loss of ATN1 alone is not thought to explain disease. Nuclear accumulation/inclusions occur, but are not the sole pathogenic mechanism. | GO:0006508 proteolysis; GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process; GO:0097352 autophagosome maturation; GO:0016604 nuclear body | CL:0000540 neuron | UBERON:0000955 brain | (nowak2023atrophin‐1functionand pages 2-2, nowak2023atrophin‐1functionand pages 7-8, nowak2023atrophin‐1functionand pages 4-5, nowak2023atrophin‐1functionand pages 1-2) |
| Cellular | Mutant atrophin-1 disrupts transcriptional regulation by binding/sequestering transcriptional regulators including TBP, CBP, TAFII130, and RERE, contributing to transcriptional dysregulation and altered chromatin regulation. This is a major downstream mechanism linking repeat expansion to neuronal dysfunction. | GO:0006357 regulation of transcription by RNA polymerase II; GO:0016568 chromatin modification; GO:0005634 nucleus | CL:0000540 neuron | UBERON:0000955 brain | (nowak2023atrophin‐1functionand pages 2-2, nowak2023atrophin‐1functionand pages 4-5, nowak2023atrophin‐1functionand pages 1-2) |
| Cellular | Autophagy-lysosomal dysfunction is implicated in DRPLA pathogenesis; canonical autophagy is reported as blocked at the lysosomal level, with compensatory alternative protein-clearance pathways activated. Impaired clearance promotes persistence of mutant ATN1 and cellular degeneration. | GO:0006914 autophagy; GO:0007040 lysosome organization; GO:0005773 vacuole; GO:0005764 lysosome | CL:0000540 neuron | UBERON:0000955 brain | (nowak2023atrophin‐1functionand pages 4-5) |
| Pathway | Calcium signaling and neuronal excitability may be perturbed, including reported ITPR1 downregulation; this may contribute to cerebellar dysfunction, myoclonus, and seizures, especially in juvenile-onset disease. | GO:0007204 positive regulation of cytosolic calcium ion concentration; GO:0006816 calcium ion transport | CL:0000540 neuron; CL:0000127 Purkinje cell | UBERON:0002037 cerebellar cortex | (nowak2023atrophin‐1functionand pages 7-8, nowak2023atrophin‐1functionand pages 4-5) |
| Cellular / network | Neurons are especially susceptible to polyQ-mediated toxicity, and DRPLA likely reflects selective vulnerability within cerebello-basal ganglia-thalamic circuitry rather than uniform brain involvement. Repeat-length-dependent phenotypes support circuit-level toxicity. | GO:0050890 cognition; GO:0007611 learning or memory; GO:0050804 modulation of chemical synaptic transmission | CL:0000540 neuron | UBERON:0000955 brain; UBERON:0001896 dentate nucleus; UBERON:0001874 globus pallidus; UBERON:0002038 thalamus | (prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4, nowak2023atrophin‐1functionand pages 2-2) |
| Tissue | Neuropathology prominently affects the dentate nucleus, globus pallidus (especially the lateral segment), subthalamic nucleus, brainstem, and cerebral/cerebellar white matter. These tissue-level changes correspond to ataxia, chorea, cognitive decline, and epilepsy. | GO:0014003 oligodendrocyte development; GO:0042552 myelination; GO:0007417 central nervous system development | CL:0000540 neuron; CL:0000127 Purkinje cell; CL:0002603 oligodendrocyte | UBERON:0001896 dentate nucleus; UBERON:0001874 globus pallidus; UBERON:0001906 subthalamic nucleus; UBERON:0002298 brainstem; UBERON:0001348 white matter | (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 2-2) |
| Imaging / biomarker | Ongoing prospective natural-history work operationalizes downstream tissue injury using MRI atrophy and fluid biomarkers. The DRPLA NHBS measures atrophy particularly in the brainstem, superior cerebellar peduncle, cerebellum, and thalamus, and tracks plasma/CSF NfL as a biomarker of neurodegeneration. | GO:0097421 liver?; GO:0042552 myelination; GO:0007409 axonogenesis; GO:0005886 plasma membrane | CL:0000540 neuron; CL:0000127 Purkinje cell | UBERON:0002298 brainstem; UBERON:0011177 superior cerebellar peduncle; UBERON:0000073 cerebellum; UBERON:0001897 thalamus | (NCT06273150 chunk 1) |
| Therapeutic mechanism | Preclinical evidence supports targeting the repeat itself: the small molecule naphthyridine-azaquinolone (NA) binds slipped CAG-repeat structures, induces repeat contraction, reduces mutant ATN1 aggregation, and improves motor coordination in a DRPLA mouse model. This supports somatic repeat instability as a disease-modifying target. | GO:0006281 DNA repair; GO:0036297 interstrand cross-link repair; GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | CL:0000540 neuron | UBERON:0002435 striatum; UBERON:0000955 brain | (hasuike2022cagrepeatbindingsmall pages 1-2, hasuike2022cagrepeatbindingsmall pages 2-3) |
| Translational / systems | Real-world DRPLA research infrastructure now includes patient registry, iPSC and fibroblast resources, and humanized mouse models to connect upstream molecular mechanisms with longitudinal clinical outcomes and therapy development, especially ATN1-lowering strategies. | GO:0007399 nervous system development; GO:0031644 regulation of neurological system process | CL:0000540 neuron; CL:0002327 fibroblast | UBERON:0000955 brain | (prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4) |
Table: This table summarizes DRPLA mechanisms across genetic, protein, cellular, pathway, and tissue levels, with suggested ontology terms and anatomical mappings. It is useful for converting narrative disease biology into structured knowledge-base annotations linked to supporting evidence.
The DRPLA natural history/biomarker study operationalizes structural degeneration by focusing on atrophy in brainstem, superior cerebellar peduncle, cerebellum, and thalamus (NCT06273150 chunk 1).
DRPLA is progressive; repeat length correlates with earlier onset, more severe phenotype, and poorer prognosis (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, nowak2023atrophin‐1functionand pages 1-2).
A striking example of early-onset severity is the 98-repeat infantile case, which presented at 4 months and had fatal outcome at 17 months (baide‐mairena2023infantile‐onsetparkinsonismdyskinesia pages 1-3).
Recent hereditary ataxia diagnostic guidance (2024) stresses that adult-onset hereditary cerebellar ataxia workups often require (i) targeted testing for STR expansions (including DRPLA) plus (ii) sequencing approaches for conventional variants, and highlights long-read sequencing as a likely future transformer of diagnostic yield (https://doi.org/10.1007/s12311-024-01703-z) (rudaks2024anupdateon pages 1-2, rudaks2024anupdateon pages 10-12).
| Diagnostic domain | Test / approach | What it detects or assesses in DRPLA | Key findings / practical use | Limitations / notes |
|---|---|---|---|---|
| Confirmatory genetics | ATN1 CAG repeat sizing by targeted repeat-expansion testing (PCR/capillary electrophoresis; orthogonal confirmation) | Detects pathogenic CAG expansion in exon 5 of ATN1 | Central confirmatory test for suspected DRPLA; reviewed sources note normal alleles typically 6-35, incomplete penetrance around 35-47, and full penetrance generally at >=48 repeats. Case reports show diagnosis from pathogenic repeat sizes such as 62 repeats. Recommended early in the workup of hereditary ataxia or compatible multisystem neurodegenerative phenotypes. (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, chen2024dentatorubralpallidoluysianatrophya pages 1-2) | First-line test when phenotype/family history suggests DRPLA; molecular testing in European ataxia cohorts may be prioritized when ataxia co-occurs with chorea, dementia, or myoclonic epilepsy. (ber2003prevalenceofdentatorubralpallidoluysian pages 1-2) |
| Expanded genetic screening | STR analysis from exome data using tools such as ExpansionHunter + REViewer | Screens exome datasets for pathogenic repeat expansions, including ATN1 | 2024 study showed that adding STR analysis to exome pipelines identified previously missed diagnoses, including 3 DRPLA cases, supporting exome-based STR calling as a useful secondary diagnostic strategy in undiagnosed neurogenetic disease. (yoon2024diagnosticupliftthrough pages 1-2) | Not a replacement for orthogonal confirmation; coverage and mapping limitations can produce false positives/false negatives, so confirmatory repeat testing remains necessary. (yoon2024diagnosticupliftthrough pages 1-2) |
| Future/advanced genetics | Long-read sequencing | Improved characterization of repeat expansions and complex variant structure | 2024 hereditary ataxia review highlights long-read sequencing as a likely transformative technology for adult-onset hereditary ataxias because it can better resolve STR expansions than standard short-read methods; relevant when routine STR testing and NGS are nondiagnostic or when multiple variant classes are suspected. (rudaks2024anupdateon pages 1-2, rudaks2024anupdateon pages 10-12) | Not yet standard in many clinical settings; access and implementation remain limited. (rudaks2024anupdateon pages 1-2, rudaks2024anupdateon pages 10-12) |
| Clinical diagnostic framing | Phenotype-led diagnostic assessment | Integrates age at onset, movement disorder pattern, epilepsy, cognition, psychiatric features, family history, and ancestry | DRPLA should be considered in patients with juvenile-onset epilepsy/myoclonus/ataxia or adult-onset ataxia, choreoathetosis, cognitive decline, psychiatric symptoms, especially with autosomal dominant family history or anticipation. (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5, prades2024establishingresourcesand pages 2-4) | No universally standardized standalone clinical criteria were identified in the retrieved DRPLA literature; diagnosis remains genotype-supported. (chen2024dentatorubralpallidoluysianatrophya pages 3-5) |
| Neuroimaging | Brain MRI | Assesses structural changes and supports differential diagnosis | Common findings include brainstem and cerebellar atrophy and widespread cerebral/cerebellar white-matter lesions; lesions may involve the cerebrum, brainstem, thalamus, and cerebellum. MRI abnormalities may be mild early and more nonspecific later, so imaging is supportive rather than definitive. (chen2024dentatorubralpallidoluysianatrophya pages 3-5, chaudhry2021drplaunderstandingthe pages 1-3) | MRI is variable across stage and age group; not pathognomonic, and early imaging may be subtle. (chaudhry2021drplaunderstandingthe pages 1-3, chen2024dentatorubralpallidoluysianatrophya pages 3-5) |
| Imaging biomarkers in current research | Volumetric MRI / longitudinal atrophy measurement | Tracks disease progression and candidate trial endpoints | The ongoing natural-history/biomarker study uses MRI to quantify atrophy over 3 years, particularly in the brainstem, superior cerebellar peduncle, cerebellum, and thalamus, indicating these are current real-world imaging biomarker targets. (NCT06273150 chunk 1) | Research-use longitudinal biomarker strategy; not yet a validated standalone diagnostic biomarker. (NCT06273150 chunk 1) |
| Epilepsy workup | EEG and seizure phenotyping | Characterizes seizure type, burden, and electroclinical pattern, especially in juvenile-onset disease | Seizures are common in juvenile-onset DRPLA; epilepsy evaluation is therefore important in suspected pediatric/juvenile cases and in adults with myoclonus or unexplained seizures plus ataxia/cognitive decline. Current interventional ASO work in one participant uses EEG-measured seizure length and seizure tracking as primary outcomes, underscoring clinical relevance. (chaudhry2021drplaunderstandingthe pages 1-3, NCT07084311 chunk 1) | EEG findings are useful for symptom characterization and treatment monitoring but are not diagnostic of DRPLA without molecular confirmation. (NCT07084311 chunk 1, chaudhry2021drplaunderstandingthe pages 1-3) |
| Differential-diagnosis testing strategy | Hereditary ataxia workflow: common SCA repeat panel + DRPLA testing, then NGS/WES/WGS if negative | Distinguishes DRPLA from other dominant and sporadic ataxias | 2024 ataxia guidance recommends testing for common dominant STR ataxias and DRPLA early in adults with hereditary cerebellar ataxia, followed by broader sequencing if repeat expansion testing is negative. (rudaks2024anupdateon pages 1-2, rudaks2024anupdateon pages 10-12) | DRPLA prevalence is low in Europe, so selective testing based on phenotype may improve efficiency in low-prevalence settings. (ber2003prevalenceofdentatorubralpallidoluysian pages 1-2) |
| Epidemiology-informed testing | Targeted DRPLA testing in selected ataxia cohorts | Helps decide when DRPLA testing is high yield | European prevalence study found DRPLA was very rare in a large White ataxia series (0.25% overall in both AD cerebellar ataxia families and sporadic ataxia cases), supporting selective testing when hallmark features such as chorea, dementia, or myoclonic epilepsy accompany ataxia. (ber2003prevalenceofdentatorubralpallidoluysian pages 1-2) | Low yield in unselected European ataxia cohorts; geographic/ancestral context matters. (chaudhry2021drplaunderstandingthe pages 1-3, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2) |
| Fluid / molecular biomarkers | Plasma and CSF NfL, plus tau, GFAP, UCH-L1 | Candidate biomarkers for neurodegeneration and progression | The DRPLA Natural History and Biomarkers Study prospectively measures plasma/CSF neurofilament light (NfL) as a primary biomarker and tau, GFAP, UCH-L1 as secondary biomarkers, reflecting the current translational biomarker strategy in DRPLA. (NCT06273150 chunk 1) | These biomarkers are under study and not yet established as routine diagnostic standards for DRPLA. (NCT06273150 chunk 1) |
| Multimodal trial-readiness phenotyping | SARA, INAS, upper-limb testing, speech and dysphagia batteries, biospecimen collection | Quantifies clinical severity and progression for research and future trials | Current real-world implementation includes prospective annual assessments of SARA, non-ataxia signs, hand function, speech, dysphagia, and broad biosample collection (blood, serum, plasma, CSF, saliva, urine, feces, fibroblasts), creating a structured biomarker/endpoint framework for future interventional studies. (NCT06273150 chunk 1) | Primarily a research infrastructure rather than routine clinical diagnosis, but highly relevant for standardizing future care and trial endpoints. (NCT06273150 chunk 1) |
Table: This table summarizes the main diagnostic modalities currently used or emerging for dentatorubral-pallidoluysian atrophy, spanning confirmatory genetics, imaging, EEG/epilepsy assessment, and biomarker strategies. It is useful for distinguishing routine clinical diagnosis from research-stage trial-readiness tools and shows where recent 2024 evidence is changing practice.
DRPLA may mimic Huntington disease and other hereditary SCAs, particularly in adult-onset chorea/ataxia/dementia phenotypes (chaudhry2021drplaunderstandingthe pages 1-3, ber2003prevalenceofdentatorubralpallidoluysian pages 1-2). The low yield in unselected European ataxia cohorts supports selective testing when ataxia co-occurs with hallmark features such as chorea, dementia, or myoclonic epilepsy (ber2003prevalenceofdentatorubralpallidoluysian pages 1-2).
The retrieved sources in this run mainly provide qualitative prognostic relationships rather than survival curves or standardized mortality rates.
Evidence gap: robust statistics on life expectancy, survival rates, or longitudinal disability trajectories in large modern cohorts were not available in the retrieved full text for this run.
No disease-modifying therapy is available in the retrieved clinical literature; management is symptomatic and supportive, with emphasis on seizures/myoclonus (juvenile onset), movement disorders, and multidisciplinary care (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2).
| Treatment / approach | Clinical role | Mechanism / rationale | Evidence type | Key evidence / implementation notes | Suggested MAXO term(s) | Citations |
|---|---|---|---|---|---|---|
| Levetiracetam | Symptomatic seizure control | Antiseizure medication used for DRPLA-associated epilepsy/myoclonus; favored over sodium-channel blockers in recent evidence synthesis | Systematic review / meta-analysis | In DRPLA-related epilepsy, levetiracetam was reported more frequently as effective than sodium channel blockers; epilepsy is especially important in juvenile-onset disease (chaudhry2021drplaunderstandingthe pages 1-3) | MAXO:0000106 seizure management; MAXO:0000127 anticonvulsant therapy | (chaudhry2021drplaunderstandingthe pages 1-3) |
| Perampanel | Symptomatic seizure control | AMPA-receptor antagonist antiseizure therapy for refractory seizures / myoclonus | Review citing case evidence | A 2023 review notes a 2017 single-patient experience in a 13-year-old with continuous myoclonic seizures in whom perampanel led to seizure cessation and some intellectual recovery, though it was not expected to alter neurodegeneration (nowak2023atrophin‐1functionand pages 7-8) | MAXO:0000106 seizure management; MAXO:0000127 anticonvulsant therapy | (nowak2023atrophin‐1functionand pages 7-8) |
| Buspirone | Symptomatic treatment for movement/balance symptoms | Serotonergic anxiolytic used empirically for symptom relief; mechanism in DRPLA not established | Case report | A 2024 case report described buspirone 5 mg three times daily, but after 6 months there was no significant symptomatic improvement in that patient (chen2024dentatorubralpallidoluysianatrophya pages 1-2) | MAXO:0001298 symptomatic treatment | (chen2024dentatorubralpallidoluysianatrophya pages 1-2) |
| Rehabilitation and multidisciplinary supportive care | Supportive / functional management | Physical, occupational, speech/swallowing, and general supportive care to preserve function and quality of life in progressive ataxia/neurodegeneration | Review / natural-history implementation | Current DRPLA research infrastructure includes upper-limb testing, speech assessment, and dysphagia assessment, supporting real-world multidisciplinary management needs; recent ataxia reviews emphasize physical, speech, and occupational therapy as core care in hereditary ataxias (NCT06273150 chunk 1, rudaks2024anupdateon pages 1-2) | MAXO:0000011 physical therapy; MAXO:0000058 occupational therapy; MAXO:0000370 speech therapy; MAXO:0001103 dysphagia management | (NCT06273150 chunk 1, rudaks2024anupdateon pages 1-2) |
| Personalized ATN1-targeting antisense oligonucleotide (nL-ATN1-002) | Experimental disease-modifying therapy | ATN1-lowering ASO intended to reduce mutant atrophin-1 expression and downstream toxicity | Interventional trial registry | Ongoing single-participant open-label Phase 1/2 study for genetically confirmed ATN1-related DRPLA; primary outcomes track seizure length/frequency and safety over 24 months (NCT07084311) (NCT07084311 chunk 1) | MAXO:0000197 antisense oligonucleotide therapy; MAXO:0001526 personalized therapy | (NCT07084311 chunk 1) |
| ATN1-lowering ASO strategies (programmatic approach) | Experimental disease-modifying therapy | Gene-silencing/downregulation approach targeting the root cause by lowering ATN1 expression | Patient-organization perspective / translational review | CureDRPLA prioritizes ATN1-downregulation strategies and has funded preclinical work and infrastructure to accelerate these therapies toward the clinic; no approved disease-modifying therapy currently exists (prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4) | MAXO:0000197 antisense oligonucleotide therapy; MAXO:0001445 gene expression inhibition therapy | (prades2024establishingresourcesand pages 1-2, prades2024establishingresourcesand pages 2-4) |
| CAG repeat-binding small molecule naphthyridine-azaquinolone (NA) | Experimental disease-modifying therapy | Binds slipped CAG-repeat DNA structures, induces repeat contraction, reduces mutant ATN1 aggregation, and improves motor phenotype in model systems | Preclinical mouse study | In DRPLA transgenic mice, long-term intracerebroventricular NA treatment produced repeat contraction and improved motor coordination, supporting somatic repeat instability as a therapeutic target (hasuike2022cagrepeatbindingsmall pages 1-2, hasuike2022cagrepeatbindingsmall pages 2-3) | MAXO:0000014 drug treatment; MAXO:0001445 gene expression inhibition therapy | (hasuike2022cagrepeatbindingsmall pages 1-2, hasuike2022cagrepeatbindingsmall pages 2-3) |
| Broader ASO / nucleic acid therapeutic development for polyQ disease | Experimental platform strategy | RNA-targeting therapies aim to lower toxic polyQ proteins across monogenic repeat-expansion disorders | Review | Polyglutamine disorders, including DRPLA, are considered strong candidates for ASO-based gene-targeting therapy because toxic gain-of-function is central and no disease-modifying therapy is approved (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2) | MAXO:0000197 antisense oligonucleotide therapy | (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 1-2) |
Table: This table summarizes current symptomatic management and emerging disease-modifying strategies for DRPLA, spanning antiseizure therapy, supportive rehabilitation, and experimental ATN1-targeted or repeat-targeted approaches. It is useful for distinguishing routine care from translational and clinical-trial-stage therapeutics.
No primary prevention (in the sense of preventing the mutation) is available for DRPLA; however, prevention of transmission and morbidity is possible via genetic services: - Genetic counseling and cascade testing are relevant given autosomal dominant inheritance and anticipation (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4). - Registry-based engagement and natural history programs (below) support secondary/tertiary prevention through earlier recognition, standardized monitoring, and future trial readiness (NCT05489393 chunk 1, NCT06273150 chunk 1).
No naturally occurring DRPLA-like disease in non-human species was identified in the retrieved sources for this run.
CureDRPLA-funded resources include: - Human cellular models: patient iPSCs (heterozygous for a 67 CAG expansion) and fibroblast cultures (prades2024establishingresourcesand pages 2-4). - Mouse models: a fully humanized mouse model expressing human ATN1 from the mouse locus (two lines expressing 112 and 70 pure CAG repeats) (prades2024establishingresourcesand pages 2-4).
A preclinical therapeutic study used DRPLA transgenic mice with multiple CAG-length sublines (including Q113), enabling repeat-length–dependent phenotyping and treatment testing (hasuike2022cagrepeatbindingsmall pages 2-3).
The following clinical studies and real-world infrastructures are active implementations relevant to DRPLA care and research.
| Study / implementation | NCT ID | Study type | Sponsor / organization | Status | Start date | Enrollment | Key outcomes / biomarkers / real-world use | URL |
|---|---|---|---|---|---|---|---|---|
| DRPLA Natural History and Biomarkers Study (DRPLA NHBS) | NCT06273150 | Observational, prospective cohort | University College London; collaborators: University of North Carolina, Chapel Hill and NYU Langone Health | Recruiting | 2022-05-01 | 225 | Annual 3-year natural history study in adult, pediatric, and remote arms; primary outcomes include SARA, brain MRI atrophy, and plasma/CSF neurofilament light (NfL); secondary measures include INAS, upper-limb function, speech battery, dysphagia assessment, and plasma/CSF tau, GFAP, and UCH-L1; biospecimens include blood, serum, plasma, CSF, saliva, urine, feces, and fibroblasts. Designed to support future DRPLA clinical trials (NCT06273150 chunk 1) | https://clinicaltrials.gov/study/NCT06273150 |
| CureDRPLA Global Patient Registry | NCT05489393 | Observational patient registry, prospective cohort | CureDRPLA; collaborator: Ataxia UK | Recruiting | 2021-03-01 | 100 | Longitudinal global registry collecting patient- or caregiver-reported demographics, diagnosis, medical history, activities of daily living, functional mobility, disease burden, quality of life, and health economics; available in multiple languages and intended to identify a well-characterized cohort for retrospective/prospective research and connect patients with future studies/trials. Represents real-world patient data infrastructure for DRPLA research (NCT05489393 chunk 1) | https://clinicaltrials.gov/study/NCT05489393 |
| Personalized Antisense Oligonucleotide for a Single Participant With ATN1 Gene Mutation | NCT07084311 | Interventional, open-label Phase 1/2, single participant | n-Lorem Foundation; collaborator: Hawaii Pacific Neuroscience | Active, not recruiting | 2024-10-24 | 1 | Personalized ASO (nL-ATN1-002) for genetically confirmed ATN1-related DRPLA; primary outcomes focus on seizure length by EEG and seizure frequency/medication use; secondary outcomes include quality of life and caregiver burden (CPCHILD), health/comorbidity checklist, and safety/tolerability monitoring with neurologic exams and laboratory/CSF assessments over 24 months. Real-world implementation of individualized ASO therapy in ultra-rare disease (NCT07084311 chunk 1) | https://clinicaltrials.gov/study/NCT07084311 |
Table: This table summarizes key DRPLA clinical research and implementation efforts spanning natural history/biomarker studies, a global patient registry, and a personalized ASO interventional trial. It is useful for understanding the current translational landscape, including recruitment status, biomarkers, and trial-readiness infrastructure.
CureDRPLA’s overview figure and its table of funded resources (including patient iPSCs, humanized mice, and natural history/biomarker study elements) provide a concise depiction of the field’s current translational infrastructure (prades2024establishingresourcesand media bcf421d5, prades2024establishingresourcesand media b4717146).
| Disease name | Common synonyms / alternative names | OMIM / MIM | MONDO | Orphanet | Causal gene | Inheritance | Key notes |
|---|---|---|---|---|---|---|---|
| Dentatorubral-pallidoluysian atrophy | DRPLA; dentatorubral pallidoluysian atrophy; hereditary DRPLA; classified within the spinocerebellar ataxia group / autosomal dominant cerebellar ataxia type IV in disease mappings (chaudhry2021drplaunderstandingthe pages 1-3, OpenTargets Search: Dentatorubral-pallidoluysian atrophy,DRPLA-ATN1) | MIM/OMIM #125370 (prades2024establishingresourcesand pages 1-2) | MONDO:0007435 / MONDO_0007435 (OpenTargets Search: Dentatorubral-pallidoluysian atrophy,DRPLA-ATN1) | Orphanet 101 / Orphanet_101 (OpenTargets Search: Dentatorubral-pallidoluysian atrophy,DRPLA-ATN1) | ATN1 (atrophin-1), chromosome 12p13.31; disease-causing CAG repeat expansion in exon 5 (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4) | Autosomal dominant (chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4) | Ultra-rare neurodegenerative polyglutamine disorder characterized by ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations; full penetrance typically reported at >=48 CAG repeats, with incomplete penetrance at 35-47 repeats in reviewed sources (prades2024establishingresourcesand pages 1-2, chaudhry2021drplaunderstandingthe pages 1-3, prades2024establishingresourcesand pages 2-4) |
Table: This table summarizes the core disease-normalization fields for dentatorubral-pallidoluysian atrophy, including accepted identifiers, synonyms, causal gene, and inheritance. It is useful for building a standardized disease knowledge base entry anchored to curated and review-supported sources.
References
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(NCT07084311 chunk 1): Personalized Antisense Oligonucleotide for A Single Participant With ATN1 Gene Mutation. n-Lorem Foundation. 2024. ClinicalTrials.gov Identifier: NCT07084311
(chen2024dentatorubralpallidoluysianatrophya pages 3-5): Xin Chen, Wenwen Xiang, Lijun Xu, Jiahao Zhao, Ye Yu, Qing Ke, Zhipeng Liu, and Li Gan. Dentatorubral-pallidoluysian atrophy: a case report and review of literature. Journal of Medical Case Reports, Sep 2024. URL: https://doi.org/10.1186/s13256-024-04745-3, doi:10.1186/s13256-024-04745-3. This article has 0 citations and is from a peer-reviewed journal.
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(hasuike2022cagrepeatbindingsmall pages 1-2): Yuhei Hasuike, Hana Tanaka, Terence Gall-Duncan, Mustafa Mehkary, Kazuhiko Nakatani, Christopher E. Pearson, Shoji Tsuji, Hideki Mochizuki, and Masayuki Nakamori. Cag repeat-binding small molecule improves motor coordination impairment in a mouse model of dentatorubral–pallidoluysian atrophy. Neurobiology of Disease, 163:105604, Feb 2022. URL: https://doi.org/10.1016/j.nbd.2021.105604, doi:10.1016/j.nbd.2021.105604. This article has 24 citations and is from a domain leading peer-reviewed journal.
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(NCT06273150 chunk 1): Dentatorubral-pallidoluysian Atrophy Natural History and Biomarkers Study. University College, London. 2022. ClinicalTrials.gov Identifier: NCT06273150
(NCT05489393 chunk 1): CureDRPLA Global Patient Registry. CureDRPLA. 2021. ClinicalTrials.gov Identifier: NCT05489393
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(hasuike2022cagrepeatbindingsmall pages 2-3): Yuhei Hasuike, Hana Tanaka, Terence Gall-Duncan, Mustafa Mehkary, Kazuhiko Nakatani, Christopher E. Pearson, Shoji Tsuji, Hideki Mochizuki, and Masayuki Nakamori. Cag repeat-binding small molecule improves motor coordination impairment in a mouse model of dentatorubral–pallidoluysian atrophy. Neurobiology of Disease, 163:105604, Feb 2022. URL: https://doi.org/10.1016/j.nbd.2021.105604, doi:10.1016/j.nbd.2021.105604. This article has 24 citations and is from a domain leading peer-reviewed journal.
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(prades2024establishingresourcesand media b4717146): Silvia Prades, Andrea Compton, and Jeffrey B. Carroll. Establishing resources and increasing awareness to advance research on dentatorubral-pallidoluysian atrophy toward a treatment: a patient organization perspective. Therapeutic Advances in Rare Disease, Jan 2024. URL: https://doi.org/10.1177/26330040241249189, doi:10.1177/26330040241249189. This article has 1 citations.