Huntington disease-like 2 (HDL2) is a rare autosomal dominant neurodegenerative HD phenocopy caused by a pathogenic CTG/CAG repeat expansion in JPH3. Reported cases have overwhelmingly involved people with definite or probable African ancestry and the disorder presents with progressive movement, cognitive, and psychiatric decline.
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name: Huntington disease-like 2
creation_date: "2026-04-11T00:31:29Z"
updated_date: "2026-05-10T06:01:28Z"
description: >-
Huntington disease-like 2 (HDL2) is a rare autosomal dominant
neurodegenerative HD phenocopy caused by a pathogenic CTG/CAG repeat
expansion in JPH3. Reported cases have overwhelmingly involved people with
definite or probable African ancestry and the disorder presents with
progressive movement, cognitive, and psychiatric decline.
category: Genetic
parents:
- Neurodegenerative Disorder
- Movement Disorder
synonyms:
- HDL2
- Huntington disease-like type 2
- Huntington's disease-like 2
disease_term:
preferred_term: Huntington disease-like 2
term:
id: MONDO:0011671
label: Huntington disease-like 2
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: "HDL2 is inherited in an autosomal dominant manner."
explanation: >-
GeneReviews explicitly states the inheritance pattern for HDL2.
Evidence source is OTHER because this is a GeneReviews synthesis
rather than a primary cohort report.
progression:
- phase: Relentless progressive neurodegeneration
age_range: typically midlife onset
notes: >-
HDL2 typically begins in midlife and progresses over 10 to 20 years with
convergent motor, emotional, and cognitive decline.
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Huntington disease-like 2 (HDL2) typically presents in midlife with
a relentless progressive triad of movement, emotional, and cognitive
abnormalities that lead to death within ten to 20 years.
explanation: >-
This review directly supports the typical age at onset and relentless
progression of HDL2.
pathophysiology:
- name: JPH3 trinucleotide repeat expansion
description: >-
HDL2 is initiated by a pathogenic CTG/CAG repeat expansion localized to
a variably spliced exon of JPH3, the gene encoding junctophilin-3.
downstream:
- target: Toxic JPH3 repeat RNA accumulation
- target: Reduced JPH3 expression
evidence:
- reference: PMID:11694876
reference_title: "A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We now report the cloning of this expansion and its localization to a
variably spliced exon of JPH3 (encoding junctophilin-3), a gene
involved in the formation of junctional membrane structures.
explanation: >-
Original discovery paper localizing the HDL2-causing repeat expansion
to JPH3.
- reference: PMID:38114648
reference_title: "Huntington disease-like 2: insight into neurodegeneration from an African disease."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease
caused by an expanded trinucleotide repeat in the JPH3 gene
(encoding junctophilin 3) that shows remarkable clinical similarity
to HD.
explanation: >-
Recent review confirming JPH3 repeat expansion as the defining
molecular lesion of HDL2.
- name: Toxic JPH3 repeat RNA accumulation
description: >-
Expanded JPH3 repeat-containing transcripts are implicated in HDL2
through a toxic RNA gain-of-function mechanism involving CUG-repeat RNA.
downstream:
- target: Frontostriatal neurodegeneration
evidence:
- reference: PMID:22367996
reference_title: "Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
We have previously demonstrated the potential pathogenic properties
of JPH3 transcripts containing expanded CUG repeats.
explanation: >-
This mechanistic study supports RNA-mediated toxicity from expanded
JPH3 transcripts in HDL2. Evidence source is OTHER because the cited
statement is a mechanistic synthesis rather than a direct clinical or
model-organism result in this abstract.
- reference: PMID:38114648
reference_title: "Huntington disease-like 2: insight into neurodegeneration from an African disease."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The pathogenesis of HDL2 remains unclear but it is proposed to occur
through several mechanisms, including loss of protein function and
RNA and/or protein toxicity.
explanation: >-
Independent review-level support for multifactorial pathogenesis in
HDL2.
- name: Reduced JPH3 expression
description: >-
HDL2 brain shows reduced JPH3 transcript and full-length protein
expression, consistent with partial loss of junctophilin-3 function and
impaired neuronal calcium-handling biology.
biological_processes:
- preferred_term: regulation of cytosolic calcium ion concentration
term:
id: GO:0051480
label: regulation of cytosolic calcium ion concentration
downstream:
- target: Frontostriatal neurodegeneration
evidence:
- reference: PMID:22367996
reference_title: "Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, JPH3 transcripts and full-length JPH3 protein are decreased
in HDL2 brain, and Jph3 hemizygous and null mice exhibit abnormal
motor function.
explanation: >-
Human postmortem cortical tissue from HDL2 shows reduced JPH3
transcript and protein abundance, supporting loss of junctophilin-3
expression in the disorder.
- reference: PMID:22367996
reference_title: "Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Jph3 hemizygous and null mice exhibit abnormal motor function.
explanation: >-
Mouse loss-of-function data support a pathogenic contribution from
reduced JPH3 activity.
- name: Frontostriatal neurodegeneration
description: >-
HDL2 causes prominent degeneration of the striatum and cerebral cortex,
and MRI volumetry shows widespread intracerebral atrophy with relatively
smaller thalamic volumes than in matched HD cohorts.
locations:
- preferred_term: striatum
term:
id: UBERON:0002435
label: striatum
- preferred_term: cerebral cortex
term:
id: UBERON:0000956
label: cerebral cortex
- preferred_term: thalamus
term:
id: UBERON:0001897
label: dorsal plus ventral thalamus
evidence:
- reference: PMID:15835282
reference_title: "Huntington's disease like-2: review and update."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Like HD, the neuropathology of HDL2 features prominent cortical and
striatal atrophy and intranuclear inclusions.
explanation: >-
Review summarizing the characteristic cortical and striatal
neurodegeneration of HDL2.
- reference: PMID:30682531
reference_title: "Emerging differences between Huntington's disease-like 2 and Huntington's disease: A comparison using MRI brain volumetry."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, intracerebral volumes were smaller in both affected groups
compared to the control group. Comparing the HDL2 and HD groups
across multiple covariates, cortical and subcortical volumes were
similar with the exception that the HDL2 thalamic volumes were
smaller.
explanation: >-
Human MRI study confirming widespread intracerebral atrophy in HDL2
and identifying relatively greater thalamic volume loss.
histopathology:
- name: Intranuclear inclusion bodies
finding_term:
preferred_term: intranuclear inclusion bodies
term:
id: HP:0020068
label: Intranuclear inclusion bodies
description: >-
HDL2 neuropathology includes characteristic intranuclear inclusions in
affected brain tissue, paralleling the inclusion pathology seen in
Huntington disease.
evidence:
- reference: PMID:15835282
reference_title: "Huntington's disease like-2: review and update."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Like HD, the neuropathology of HDL2 features prominent cortical and
striatal atrophy and intranuclear inclusions.
explanation: >-
Review-level neuropathology evidence supports intranuclear inclusions
as a characteristic histopathologic finding in HDL2.
phenotypes:
- name: Chorea
frequency: VERY_FREQUENT
description: >-
Chorea is the most consistently reported hyperkinetic motor manifestation
of HDL2.
phenotype_term:
preferred_term: chorea
term:
id: HP:0002072
label: Chorea
evidence:
- reference: PMID:28339400
reference_title: "A Systematic Review of the Huntington Disease-Like 2 Phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Chorea was noted in 48/57 cases (84%)."
explanation: >-
Systematic review of published HDL2 cases shows chorea is a very
frequent motor phenotype.
- name: Dementia
frequency: FREQUENT
description: >-
Progressive cognitive decline frequently evolves to dementia in HDL2.
phenotype_term:
preferred_term: dementia
term:
id: HP:0000726
label: Dementia
evidence:
- reference: PMID:28339400
reference_title: "A Systematic Review of the Huntington Disease-Like 2 Phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dementia was reported in 74% patients, and Parkinsonism in 37%."
explanation: >-
Systematic review supports dementia as a frequent cognitive outcome
in HDL2.
- name: Parkinsonism
frequency: FREQUENT
description: >-
Hypokinetic features including rigidity and bradykinesia are common in
HDL2 and can contribute substantially to disability.
phenotype_term:
preferred_term: parkinsonism
term:
id: HP:0001300
label: Parkinsonism
evidence:
- reference: PMID:28339400
reference_title: "A Systematic Review of the Huntington Disease-Like 2 Phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dementia was reported in 74% patients, and Parkinsonism in 37%."
explanation: >-
Systematic review supports parkinsonism as a frequent motor feature
in HDL2.
- name: Psychiatric symptoms
frequency: VERY_FREQUENT
description: >-
Psychiatric disease is a core part of the HDL2 phenotype and commonly
includes mood disturbance and behavioral change.
phenotype_term:
preferred_term: atypical behavior
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:28339400
reference_title: "A Systematic Review of the Huntington Disease-Like 2 Phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Psychiatric features were reported in 44 out of 47 cases."
explanation: >-
Systematic review shows psychiatric manifestations are very frequent
across reported HDL2 cases.
- reference: PMID:33044188
reference_title: "The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington's Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
HDL2 patients presented with psychiatric symptoms involving mood
disturbances and behavioural changes that were not significantly
different from those in the HD group.
explanation: >-
Cross-sectional neuropsychiatric study confirms mood and behavioral
disturbance as part of the psychiatric phenotype.
genetic:
- name: JPH3 CTG/CAG repeat expansion
association: Causative
gene_term:
preferred_term: JPH3
term:
id: hgnc:14203
label: JPH3
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: "HDL2 is inherited in an autosomal dominant manner."
explanation: >-
The causative JPH3 repeat expansion follows autosomal dominant
inheritance in affected families.
notes: >-
HDL2 is caused by a heterozygous pathogenic CTG/CAG repeat expansion in a
variably spliced exon of JPH3. Fully penetrant disease alleles are
generally 40 or more repeats, and founder haplotype studies support a
shared African origin for the mutation.
evidence:
- reference: PMID:11694876
reference_title: "A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We recently described a disorder termed Huntington disease-like 2
(HDL2) that completely segregates with an unidentified CAG/CTG
expansion in a large pedigree (W).
explanation: >-
Original pedigree study showing segregation of the pathogenic repeat
expansion with HDL2.
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The diagnosis of HDL2 is established in a proband with
characteristic clinical findings and heterozygous expansion of 40 or
more CTG trinucleotide repeats in JPH3 identified by molecular
genetic testing.
explanation: >-
GeneReviews gives the disease-defining molecular threshold used in
current diagnostic practice.
- reference: PMID:26079385
reference_title: "Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
JPH3 haplotype studies in 31 families, mainly from South Africa and
North America, provide evidence for a founder mutation and support a
common African origin for all HDL2 patients.
explanation: >-
This multicenter family study supports the founder-haplotype and
African-origin context of HDL2 mutations.
diagnosis:
- name: Molecular testing for JPH3 repeat expansion
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
description: >-
Confirmatory testing for suspected HDL2 in an HD phenocopy, especially
when HTT testing is negative and African ancestry is present.
results: >-
Heterozygous expansion of 40 or more CTG repeats in JPH3 establishes the
diagnosis.
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The diagnosis of HDL2 is established in a proband with
characteristic clinical findings and heterozygous expansion of 40 or
more CTG trinucleotide repeats in JPH3 identified by molecular
genetic testing.
explanation: >-
Direct support for molecular confirmation of HDL2 with JPH3 repeat
testing.
- reference: PMID:26079385
reference_title: "Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Molecular testing in individuals with an HD phenotype and African
ancestry should include testing routinely for JPH3 mutations.
explanation: >-
Supports routine inclusion of JPH3 testing in the diagnostic workup
of relevant HD phenocopies.
treatments:
- name: Genetic counseling
description: >-
Families benefit from formal counseling because HDL2 is autosomal
dominant and predictive testing is possible once the familial JPH3
expansion is known.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
At conception, each child of an individual with HDL2 has a 50%
chance of inheriting the HDL2-causing allele.
explanation: >-
The 50% transmission risk makes genetic counseling a core management
need for affected families.
- name: Supportive symptomatic management
description: >-
No HDL2-specific disease-modifying therapy is established; management is
symptomatic and adapted from HD care with attention to movement
suppression, mobility, speech, swallowing, nutrition, and psychiatric
support.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:20301701
reference_title: "Huntington Disease-Like 2."
supports: PARTIAL
evidence_source: OTHER
snippet: >-
Treatment is symptomatic and is presumably similar to that for HD
and other neurodegenerative disorders – although this must be
considered speculative pending objective data.
explanation: >-
GeneReviews supports symptomatic supportive care for HDL2, but the
statement is necessarily partial because direct disease-specific trial
data remain limited.
references:
- reference: PMID:20301701
title: "Huntington Disease-Like 2."
tags:
- GeneReviews
findings:
- statement: Anderson DG(1), Krause A(2), Margolis RL(3).
supporting_text: Anderson DG(1), Krause A(2), Margolis RL(3).
evidence:
- reference: PMID:20301701
reference_title: Huntington Disease-Like 2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Anderson DG(1), Krause A(2), Margolis RL(3).
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
- reference: DOI:10.1002/ajmg.b.32332
title: Junctophilin 3 (<i>JPH3</i>) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: Junctophilin 3 (<i>JPH3</i>) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype
supporting_text: Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p.
evidence:
- reference: DOI:10.1002/ajmg.b.32332
reference_title: Junctophilin 3 (<i>JPH3</i>) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p.
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
- reference: DOI:10.1002/ana.21081
title: Huntington's disease–like 2 is associated with CUG repeat‐containing RNA foci
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: Huntington's disease–like 2 (HDL2) is caused by a CAG/CTG expansion mutation on chromosome 16q24.3.
supporting_text: Huntington's disease–like 2 (HDL2) is caused by a CAG/CTG expansion mutation on chromosome 16q24.3.
evidence:
- reference: DOI:10.1002/ana.21081
reference_title: Huntington's disease–like 2 is associated with CUG repeat‐containing RNA foci
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Huntington's disease–like 2 (HDL2) is caused by a CAG/CTG expansion mutation on chromosome 16q24.3.
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
- reference: DOI:10.1016/j.neuron.2011.03.021
title: An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice
supporting_text: An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice
- reference: DOI:10.1038/nrdp.2015.5
title: Huntington disease
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: Huntington disease
supporting_text: Huntington disease
- reference: DOI:10.1097/wco.0000000000000386
title: Pathogenic insights from Huntington's disease-like 2 and other Huntington's disease genocopies
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: of review Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease.
supporting_text: of review Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease.
evidence:
- reference: DOI:10.1097/wco.0000000000000386
reference_title: Pathogenic insights from Huntington's disease-like 2 and other Huntington's disease genocopies
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: of review Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease.
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
- reference: DOI:10.1159/000444020
title: The Frequency of Huntington Disease and Huntington Disease-Like 2 in the South African Population
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: Huntington disease (HD) has most recently been estimated to affect between 10.6 and 13.7 per 100,000 individuals in European populations.
supporting_text: Huntington disease (HD) has most recently been estimated to affect between 10.6 and 13.7 per 100,000 individuals in European populations.
evidence:
- reference: DOI:10.1159/000444020
reference_title: The Frequency of Huntington Disease and Huntington Disease-Like 2 in the South African Population
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Huntington disease (HD) has most recently been estimated to affect between 10.6 and 13.7 per 100,000 individuals in European populations.
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
- reference: DOI:10.1177/18796397241300141
title: Comparative analysis of neurofilament light chain in Huntington's disease like 2 and Huntington's disease
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings:
- statement: Huntington's disease-like 2 (HDL2) closely resembles Huntington's disease (HD) in clinical and pathological features.
supporting_text: Huntington's disease-like 2 (HDL2) closely resembles Huntington's disease (HD) in clinical and pathological features.
evidence:
- reference: DOI:10.1177/18796397241300141
reference_title: Comparative analysis of neurofilament light chain in Huntington's disease like 2 and Huntington's disease
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Huntington's disease-like 2 (HDL2) closely resembles Huntington's disease (HD) in clinical and pathological features.
explanation: Deep research cited this publication as relevant literature for Huntington Disease-like 2.
- reference: DOI:10.1002/ana.22598
title: Loss of junctophilin-3 contributes to huntington disease-like 2 pathogenesis
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings: []
- reference: DOI:10.32388/lkfkvq
title: Huntington disease-like 2
found_in:
- Huntington_Disease-like_2-deep-research-falcon.md
findings: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Huntington disease-like 2 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
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For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
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For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
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For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Huntington disease-like 2 (HDL2) is a rare, adult-onset, progressive neurodegenerative disorder that clinically and pathologically closely resembles Huntington disease (HD) (i.e., an “HD phenocopy/genocopy”). It is caused by a pathogenic trinucleotide repeat expansion at the junctophilin-3 locus (JPH3) and is enriched in individuals with African ancestry. (anderson2025huntingtondiseaselike2 pages 1-3, margolis2003huntingtonsdiseaselike2 pages 1-2, margolis2016pathogenicinsightsfrom pages 1-2)
Not available from retrieved full text: MONDO, Orphanet (ORPHA), MeSH, ICD-10/ICD-11 codes.
Most information used here is aggregated from gene- and disease-level resources (GeneReviews-style) and peer-reviewed primary literature (human postmortem, cell models, and mouse models), plus large diagnostic/referral cohorts for epidemiology. (anderson2025huntingtondiseaselike2 pages 1-3, krause2015junctophilin3(jph3) pages 4-6, rudnicki2007huntingtonsdisease–like2 pages 6-8, wilburn2011anantisensecag pages 1-2)
Primary cause (genetic): a germline heterozygous CTG/CAG trinucleotide repeat expansion at the JPH3 locus. (anderson2025huntingtondiseaselike2 pages 1-3, margolis2016pathogenicinsightsfrom pages 1-2)
Repeat characteristics / definitions (current working thresholds): - Normal: typically 6–28 repeats (anderson2025huntingtondiseaselike2 pages 1-3, margolis2016pathogenicinsightsfrom pages 1-2) - Intermediate/uncertain: 29–39 repeats (uncertain clinical significance) (anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 14-16) - Pathogenic: generally ≥40 CTG repeats (“full-penetrance” in GeneReviews-style resource; some ambiguity near the boundary) (anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 14-16) - Reported affected range: commonly ~40–59 triplets (margolis2016pathogenicinsightsfrom pages 1-2, seixas2012lossofjunctophilin‐3 pages 1-2) - Largest reported expansion in humans: 63 CTG repeats (anderson2025huntingtondiseaselike2 pages 3-5)
Genotype–phenotype: increasing repeat size correlates with earlier onset, estimated ~1.2–2.9 years earlier per triplet (reported in GeneReviews-style summary). (anderson2025huntingtondiseaselike2 pages 3-5)
No genetic or environmental protective factors specific to HDL2 were identified in the retrieved sources.
No HDL2-specific gene–environment interaction evidence was identified in the retrieved sources.
HDL2 is typically described as a progressive triad of: - Movement disorder: chorea and/or other hyperkinetic features; parkinsonism can also occur (anderson2025huntingtondiseaselike2 pages 1-3, krause2015junctophilin3(jph3) pages 6-8) - Psychiatric/behavioral features: e.g., irritability, apathy, depression (reported in review) (margolis2016pathogenicinsightsfrom pages 1-2) - Cognitive decline progressing to dementia (anderson2025huntingtondiseaselike2 pages 3-5, anderson2025huntingtondiseaselike2 pages 1-3)
Age of onset and progression: mean age at onset reported as 41 years (SD 11.1; range 12–66), with progressive course and death typically 10–20 years after onset. (anderson2025huntingtondiseaselike2 pages 3-5, anderson2025huntingtondiseaselike2 pages 1-3)
Frequency notes: In a South African clinical-file subset, parkinsonian features were reported in 5/22 (23%) HDL2 vs 1/39 (3%) HD (χ2=6.45, p=0.011), suggesting possible relative enrichment (limited sample size). (krause2015junctophilin3(jph3) pages 6-8)
Direct HDL2-specific quality-of-life instrument results were not identified in the retrieved sources. Functional impairment is inferred from progressive motor disability, cognitive decline/dementia, and need for multidisciplinary supportive care (e.g., PT, speech therapy, nutrition, home safety modifications). (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 1-3)
The retrieved sources treat ≥40 CTG repeats as pathogenic/diagnostic in a clinically compatible case. (anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 14-16)
Population allele frequency in gnomAD/1000 Genomes was not available in the retrieved sources.
HDL2 is described as a germline, inherited autosomal dominant disorder (no somatic-only HDL2 cases in retrieved sources). (anderson2025huntingtondiseaselike2 pages 1-3)
Evidence supports a multimodal model combining: 1) RNA gain-of-function from expanded CUG repeat RNA and RNA-binding protein sequestration; 2) possible antisense/polyQ-mediated toxicity (strong in BAC-HDL2 mouse; unproven/undetectable or low in human brain); 3) loss of JPH3 function (reduced transcript/protein in patient brain; motor deficits in Jph3 mutant mice). (rudnicki2007huntingtonsdisease–like2 pages 6-8, seixas2012lossofjunctophilin‐3 pages 1-2, margolis2016pathogenicinsightsfrom pages 2-4, wilburn2011anantisensecag pages 1-2)
No HDL2-specific modifier genes were identified in the retrieved sources.
No HDL2-specific epigenetic findings were identified in the retrieved sources.
Not applicable based on retrieved sources (repeat expansion at JPH3 locus rather than large structural variant). (anderson2025huntingtondiseaselike2 pages 1-3)
No specific environmental, lifestyle, toxin, or infectious triggers for HDL2 were identified in the retrieved sources.
Trigger: inherited JPH3 CTG repeat expansion (≥40) (anderson2025huntingtondiseaselike2 pages 1-3)
Upstream molecular events (RNA-focused): expanded CUG repeat RNA from JPH3 forms nuclear RNA foci in HDL2 frontal cortex and in cell models. In one study, RNA foci colocalized with MBNL1, were RNase-sensitive, and were associated with reduced nuclear MBNL1 and splicing abnormalities. (rudnicki2007huntingtonsdisease–like2 pages 6-8)
Downstream cellular effects: in neuronal-like cell models, a nontranslatable expanded CUG construct increased apoptosis/toxicity (e.g., caspase activation and TUNEL signal). (rudnicki2007huntingtonsdisease–like2 pages 6-8)
RNA processing dysfunction (splicing): the same study reported MBNL1 depletion (t=8.57, p=0.001) and splicing changes including increased fetal MAPT isoforms lacking exon 2 (t=5.71, p=0.0012) and altered APP exon 7 utilization (t=5.43, p=0.0016). (rudnicki2007huntingtonsdisease–like2 pages 6-8)
Loss-of-function component: JPH3 transcript and full-length protein are decreased in HDL2 frontal cortex, and Jph3 mutant mice show progressive motor phenotypes and impaired motor learning, supporting that reduced JPH3 contributes to disease. (seixas2012lossofjunctophilin‐3 pages 1-2, seixas2012lossofjunctophilin‐3 pages 9-11)
Antisense / polyQ component (model vs human): BAC-HDL2 mice provide evidence for bidirectional transcription and an antisense HDL2-CAG transcript encoding expanded polyglutamine with polyQ-positive nuclear inclusions; however, postmortem human data have been inconsistent in detecting expanded antisense transcripts or expanded polyQ proteins, leaving the extent of this mechanism in human HDL2 unresolved. (margolis2016pathogenicinsightsfrom pages 2-4, wilburn2011anantisensecag pages 1-2)
HDL2 is often discussed within repeat expansion disorder frameworks that can involve RNA gain-of-function, protein gain-of-function, and/or loss of function. The evidence base for HDL2 supports more than one of these. (seixas2012lossofjunctophilin‐3 pages 1-2, margolis2016pathogenicinsightsfrom pages 2-4)
Primary affected system: central nervous system, particularly striatum and cerebral cortex with prominent neuronal loss (anderson2025huntingtondiseaselike2 pages 3-5)
Cell-type emphasis: medium spiny neurons (striatal projection neurons) are highlighted by loss patterns (“loss of medium spiny neurons in a dorsal-to-ventral gradient”). (anderson2025huntingtondiseaselike2 pages 3-5)
A schematic of the BAC-HDL2 construct and bidirectional transcription at the JPH3 locus (including the antisense HDL2-CAG transcript model) is shown in Wilburn et al. (Neuron 2011). (wilburn2011anantisensecag media fdbbbc4c, wilburn2011anantisensecag media aa402816)
No HDL2-specific validated staging system was identified in retrieved sources; clinical monitoring is modeled on HD scales (e.g., UHDRS). (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 11-14)
Referral/diagnostic cohorts (South Africa): - Among black patients referred for an HD phenotype, 20/130 (15%) had JPH3 expansions; among mixed ancestry 3/14 (21%); among white 0/171. (krause2015junctophilin3(jph3) pages 4-6) - In the same dataset, among genetically diagnosed black/mixed-ancestry cases, HDL2 accounted for about 23/76 (~30%) of diagnoses. (krause2015junctophilin3(jph3) pages 4-6) - As of Dec 2013, one service ascertained 41 individuals with JPH3 expansions from 34 families (expansion sizes 40–58). (krause2015junctophilin3(jph3) pages 6-8)
Genetic-ascertainment frequency estimates (South Africa): - A 20-year retrospective review of molecular diagnoses reported combined minimum frequency estimates for HD+HDL2 of 0.25 (black), 2.10 (mixed ancestry), 5.10 (white) per 100,000; these were not HDL2-specific prevalence rates and were noted as minimum estimates with substantial under-ascertainment likely. (baine2016thefrequencyof pages 1-2, baine2016thefrequencyof pages 2-3)
Founder effect / ancestry: haplotype analyses in multiple families are consistent with a founder mutation with African origin, and the literature emphasizes that HDL2 has been described “exclusively” in individuals with confirmed/likely African ancestry in GeneReviews-style summaries. (krause2015junctophilin3(jph3) pages 1-3, anderson2025huntingtondiseaselike2 pages 3-5)
Because HDL2 is clinically indistinguishable from HD, suspicion is highest in individuals with an HD phenotype and African ancestry (or family history consistent with autosomal dominant inheritance) and negative HTT testing. (anderson2025huntingtondiseaselike2 pages 1-3, krause2015junctophilin3(jph3) pages 4-6)
MRI findings include prominent caudate and cortical atrophy with relative sparing of brainstem and cerebellum; semiautomated volumetry suggested greater thalamic atrophy in HDL2 compared with HD despite similar cortical/striatal loss. (anderson2025huntingtondiseaselike2 pages 1-3)
Plasma neurofilament light chain (NfL) is elevated in manifest HDL2 and discriminated HDL2 from controls with AUC 0.926 (95% CI 0.812–1.000) in a small cross-sectional study (HDL2 n=12; controls n=9). (anderson2025comparativeanalysisof pages 9-13)
In the context of “non-HD chorea/HD phenocopies,” HDL2/JPH3 is among the most frequent genetic causes cited in a 2024 practical diagnostic approach preprint, alongside several spinocerebellar ataxia genes and frontotemporal dementia genes. (bates2015huntingtondisease pages 16-19)
Typical survival is described as approximately 10–20 years after onset (and some reviews cite ~15–20 years). (anderson2025huntingtondiseaselike2 pages 1-3, margolis2016pathogenicinsightsfrom pages 1-2)
Progressive motor disability, psychiatric morbidity, and dementia drive increasing care needs; management emphasizes multidisciplinary support, safety evaluation, nutritional support, and psychiatric care. (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 11-14)
Repeat length correlates with age at onset; stronger HDL2-specific prognostic biomarkers beyond repeat size and clinical measures were not identified in the retrieved sources. (anderson2025huntingtondiseaselike2 pages 3-5)
No disease-modifying therapy for HDL2 was identified in retrieved sources; management is symptomatic and largely extrapolated from HD care.
Symptomatic pharmacotherapy examples (from GeneReviews-style guidance): - Chorea/movement suppression: tetrabenazine (and derivatives) and/or low-dose neuroleptics such as fluphenazine or haloperidol (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 1-3) - Psychiatric symptoms: antidepressants (e.g., sertraline, nortriptyline), antipsychotics, mood stabilizers (e.g., lithium, valproate, carbamazepine, lamotrigine), and occasionally ECT (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 1-3)
Supportive/rehabilitative care: - Physical therapy for mobility and fall prevention; home safety modifications (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 11-14) - Speech-language pathology for dysarthria/dysphagia; nutrition/feeding modifications to reduce aspiration risk; communication devices (anderson2025huntingtondiseaselike2 pages 10-11) - Care coordination/social work, legal/financial planning, and palliative care considerations (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 11-14)
No HDL2-specific interventional clinical trials were identified in the retrieved sources or in the clinical trial tool state during this run.
No primary prevention is available for an autosomal dominant repeat expansion disorder, but secondary prevention in the form of genetic counseling and predictive testing for at-risk adults is feasible when a family expansion is known. (anderson2025huntingtondiseaselike2 pages 14-16)
Genetic counseling: recommended to support informed reproductive decision-making (including prenatal and preimplantation genetic testing options) and psychosocial planning. (anderson2025huntingtondiseaselike2 pages 14-16, anderson2025huntingtondiseaselike2 pages 10-11)
No naturally occurring non-human HDL2 analogs were identified in the retrieved sources.
Expanded CUG-repeat transcripts form nuclear foci and cause toxicity (caspase activation/TUNEL) in neuronal-like cells, supporting RNA gain-of-function. (rudnicki2007huntingtonsdisease–like2 pages 6-8)
| Topic | Key facts | Citations |
|---|---|---|
| Identifiers | Disease: Huntington disease-like 2 (HDL2); OMIM disease 606438. Causal gene: JPH3 (junctophilin-3); OMIM gene 605268; locus 16q24.2. HDL2 is an HD phenocopy recognized in aggregated disease-level resources/reviews and molecularly confirmed by repeat testing. | (anderson2025huntingtondiseaselike2 pages 14-16, anderson2025huntingtondiseaselike2 pages 3-5) |
| Gene / variant / threshold | Cause is a germline heterozygous CTG/CAG trinucleotide repeat expansion at the JPH3 locus. Normal alleles are typically 6-28 repeats; 29-39 repeats are of uncertain significance; >=40 CTG repeats is generally considered pathogenic/full-penetrance, with reported affected alleles usually 40-59 and up to 63 repeats reported. Repeat length inversely correlates with age at onset. | (anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 3-5, margolis2016pathogenicinsightsfrom pages 1-2) |
| Inheritance | Autosomal dominant; most affected individuals have an affected parent; each child of an affected individual has a 50% risk of inheriting the expansion. Anticipation is discussed for repeat-length disorders, but penetrance near the lower boundary remains incompletely defined. | (anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 14-16, anderson2025huntingtondiseaselike2 pages 3-5) |
| Populations / epidemiology | HDL2 is reported almost exclusively in people with African ancestry. In a South African referral cohort, 20/130 black patients (15%) and 3/14 mixed-ancestry patients (21%) with an HD phenotype had JPH3 expansions, versus 0/171 white patients; among genetically diagnosed black/mixed-ancestry patients, HDL2 accounted for about 23/76 (~30%). A nationwide South African molecular-ascertainment study found 52 HDL2 and 384 HD diagnoses among 436 genetically confirmed HD/HDL2 cases; combined minimum HD/HDL2 frequencies were 0.25, 2.10, and 5.10 per 100,000 in black, mixed-ancestry, and white groups, respectively (not HDL2-specific prevalence). | (krause2015junctophilin3(jph3) pages 4-6, krause2015junctophilin3(jph3) pages 8-10, baine2016thefrequencyof pages 3-4, baine2016thefrequencyof pages 1-2, baine2016thefrequencyof pages 2-3) |
| Core phenotype / onset / prognosis | Progressive triad of movement, psychiatric/emotional, and cognitive impairment, often clinically indistinguishable from Huntington disease. Mean age at onset about 41 years (SD 11.1; range 12-66). Dementia is described as progressive/universal in advanced disease. Death typically occurs 10-20 years after onset; some reviews cite 15-20 years of progression. Parkinsonian features may be relatively enriched in HDL2 (5/22, 23%) versus matched HD (1/39, 3%) in one South African series. | (anderson2025huntingtondiseaselike2 pages 3-5, anderson2025huntingtondiseaselike2 pages 1-3, margolis2016pathogenicinsightsfrom pages 1-2, krause2015junctophilin3(jph3) pages 6-8) |
| Mechanisms | Evidence supports multimodal pathogenesis: (1) sense-strand expanded CUG RNA forms nuclear RNA foci in HDL2 cortex and cell models; foci colocalize with MBNL1, with nuclear MBNL1 depletion and splicing changes including MAPT exon 2 and APP exon 7 abnormalities; nontranslatable expanded RNA increases caspase-3/7 activity and TUNEL positivity. (2) Antisense CAG/polyQ toxicity is strongly supported in BAC-HDL2 mice, where an antisense transcript produces polyQ-positive nuclear inclusions and CBP-related transcriptional dysfunction, but equivalent expanded antisense/polyQ species are not convincingly detected in human HDL2 brain. (3) JPH3 loss-of-function also contributes: full-length JPH3 transcript/protein is reduced in HDL2 brain, and Jph3 mutant mice show motor impairment, but knockout alone does not recapitulate full human inclusion pathology. | (rudnicki2007huntingtonsdisease–like2 pages 6-8, seixas2012lossofjunctophilin‐3 pages 1-2, margolis2016pathogenicinsightsfrom pages 2-4, seixas2012lossofjunctophilin‐3 pages 9-11, wilburn2011anantisensecag pages 1-2) |
| Neuropathology / imaging | Pathology resembles HD, with prominent striatal and cortical neuronal loss, loss of medium spiny neurons in a dorsal-to-ventral striatal gradient, and cortical intranuclear inclusions staining for polyglutamine, ubiquitin, torsinA, and TBP. MRI shows caudate and cortical atrophy with relative sparing of brainstem/cerebellum; semiautomated volumetry reported greater thalamic atrophy in HDL2 than HD despite similar cortical/striatal volume loss. | (anderson2025huntingtondiseaselike2 pages 3-5, anderson2025huntingtondiseaselike2 pages 1-3, margolis2016pathogenicinsightsfrom pages 1-2) |
| Diagnostics | Diagnosis is established by targeted molecular testing of the JPH3 CTG repeat, typically PCR-based repeat-expansion testing. Assays detect nearly all expanded alleles but can yield false-negative or misleading single-allele results with very long repeats; if suspicion remains high or apparent homozygosity is seen, repeat testing with alternate primers / additional methods and family testing are recommended. Predictive, prenatal, and preimplantation testing are possible once a familial expansion is known. | (anderson2025huntingtondiseaselike2 pages 3-5, anderson2025huntingtondiseaselike2 pages 16-19, anderson2025huntingtondiseaselike2 pages 14-16) |
| Biomarkers | Plasma neurofilament light chain (NfL) is elevated in manifest HDL2. In a cross-sectional study (HDL2 n=12; HD n=9; controls n=9), mean log NfL was 3.1 in HDL2 vs 2.1 in controls and 3.9 in HD; overall group difference p=0.0006. HDL2 vs control ROC AUC was 0.926 (95% CI 0.812-1.000), supporting NfL as a promising research biomarker, though correlations with motor/functional scores were weak. | (anderson2025comparativeanalysisof pages 9-13, anderson2025comparativeanalysisof pages 6-9, anderson2025comparativeanalysisof pages 1-6) |
| Current management | No HDL2-specific disease-modifying therapy or formal HDL2 guideline is available; care is extrapolated from Huntington disease and is symptomatic, multidisciplinary, and real-world supportive. Common measures include tetrabenazine (and derivatives) or low-dose neuroleptics for chorea/movement symptoms; physical therapy, speech-language therapy, nutrition/feeding modifications, aspiration precautions, communication devices, home safety and driving assessment; psychiatric treatment with antidepressants, antipsychotics, mood stabilizers, and occasionally ECT; annual surveillance of motor, cognitive, nutritional, and psychiatric status; social work, palliative care, and genetic counseling. | (anderson2025huntingtondiseaselike2 pages 10-11, anderson2025huntingtondiseaselike2 pages 1-3, anderson2025huntingtondiseaselike2 pages 11-14, anderson2025huntingtondiseaselike2 pages 8-10) |
Table: This table summarizes the highest-yield knowledge-base facts for Huntington disease-like 2, including identifiers, genetics, epidemiology, clinical course, mechanisms, diagnostics, biomarkers, and management. It is designed for rapid curation and includes citation IDs in every row for traceability.
References
(anderson2025huntingtondiseaselike2 pages 1-3): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(margolis2003huntingtonsdiseaselike2 pages 1-2): Russell L Margolis and Susan E Holmes. Huntington's disease-like 2: a clinical, pathological, and molecular comparison to huntington's disease. Clinical Neuroscience Research, 3:187-196, Sep 2003. URL: https://doi.org/10.1016/s1566-2772(03)00061-6, doi:10.1016/s1566-2772(03)00061-6. This article has 14 citations and is from a peer-reviewed journal.
(margolis2016pathogenicinsightsfrom pages 1-2): Russell L. Margolis and Dobrila D. Rudnicki. Pathogenic insights from huntington's disease-like 2 and other huntington's disease genocopies. Current Opinion in Neurology, 29:743-748, Dec 2016. URL: https://doi.org/10.1097/wco.0000000000000386, doi:10.1097/wco.0000000000000386. This article has 13 citations and is from a peer-reviewed journal.
(anderson2025huntingtondiseaselike2 pages 14-16): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(krause2015junctophilin3(jph3) pages 4-6): Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, and Russell Margolis. Junctophilin 3 (jph3) expansion mutations causing huntington disease like 2 (hdl2) are common in south african patients with african ancestry and a huntington disease phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168:573-585, Oct 2015. URL: https://doi.org/10.1002/ajmg.b.32332, doi:10.1002/ajmg.b.32332. This article has 73 citations.
(rudnicki2007huntingtonsdisease–like2 pages 6-8): Dobrila D. Rudnicki, Susan E. Holmes, Mark W. Lin, Charles A. Thornton, Christopher A. Ross, and Russell L. Margolis. Huntington's disease–like 2 is associated with cug repeat‐containing rna foci. Annals of Neurology, 61:272-282, Mar 2007. URL: https://doi.org/10.1002/ana.21081, doi:10.1002/ana.21081. This article has 182 citations and is from a highest quality peer-reviewed journal.
(wilburn2011anantisensecag pages 1-2): Brian Wilburn, Dobrila D. Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L. Sopher, Albert R. La Spada, Alex Osmand, Russell L. Margolis, Yi E. Sun, and X. William Yang. An antisense cag repeat transcript at jph3 locus mediates expanded polyglutamine protein toxicity in huntington's disease-like 2 mice. Neuron, 70:427-440, May 2011. URL: https://doi.org/10.1016/j.neuron.2011.03.021, doi:10.1016/j.neuron.2011.03.021. This article has 168 citations and is from a highest quality peer-reviewed journal.
(seixas2012lossofjunctophilin‐3 pages 1-2): Ana I. Seixas, Susan E. Holmes, Hiroshi Takeshima, Amira Pavlovich, Nancy Sachs, Jennifer L. Pruitt, Isabel Silveira, Christopher A. Ross, Russell L. Margolis, and Dobrila D. Rudnicki. Loss of junctophilin‐3 contributes to huntington disease‐like 2 pathogenesis. Annals of Neurology, 71:245-257, Feb 2012. URL: https://doi.org/10.1002/ana.22598, doi:10.1002/ana.22598. This article has 88 citations and is from a highest quality peer-reviewed journal.
(anderson2025huntingtondiseaselike2 pages 3-5): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(krause2015junctophilin3(jph3) pages 3-4): Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, and Russell Margolis. Junctophilin 3 (jph3) expansion mutations causing huntington disease like 2 (hdl2) are common in south african patients with african ancestry and a huntington disease phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168:573-585, Oct 2015. URL: https://doi.org/10.1002/ajmg.b.32332, doi:10.1002/ajmg.b.32332. This article has 73 citations.
(krause2015junctophilin3(jph3) pages 6-8): Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, and Russell Margolis. Junctophilin 3 (jph3) expansion mutations causing huntington disease like 2 (hdl2) are common in south african patients with african ancestry and a huntington disease phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168:573-585, Oct 2015. URL: https://doi.org/10.1002/ajmg.b.32332, doi:10.1002/ajmg.b.32332. This article has 73 citations.
(anderson2025huntingtondiseaselike2 pages 10-11): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(anderson2025huntingtondiseaselike2 pages 16-19): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(margolis2016pathogenicinsightsfrom pages 2-4): Russell L. Margolis and Dobrila D. Rudnicki. Pathogenic insights from huntington's disease-like 2 and other huntington's disease genocopies. Current Opinion in Neurology, 29:743-748, Dec 2016. URL: https://doi.org/10.1097/wco.0000000000000386, doi:10.1097/wco.0000000000000386. This article has 13 citations and is from a peer-reviewed journal.
(seixas2012lossofjunctophilin‐3 pages 9-11): Ana I. Seixas, Susan E. Holmes, Hiroshi Takeshima, Amira Pavlovich, Nancy Sachs, Jennifer L. Pruitt, Isabel Silveira, Christopher A. Ross, Russell L. Margolis, and Dobrila D. Rudnicki. Loss of junctophilin‐3 contributes to huntington disease‐like 2 pathogenesis. Annals of Neurology, 71:245-257, Feb 2012. URL: https://doi.org/10.1002/ana.22598, doi:10.1002/ana.22598. This article has 88 citations and is from a highest quality peer-reviewed journal.
(wilburn2011anantisensecag media fdbbbc4c): Brian Wilburn, Dobrila D. Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L. Sopher, Albert R. La Spada, Alex Osmand, Russell L. Margolis, Yi E. Sun, and X. William Yang. An antisense cag repeat transcript at jph3 locus mediates expanded polyglutamine protein toxicity in huntington's disease-like 2 mice. Neuron, 70:427-440, May 2011. URL: https://doi.org/10.1016/j.neuron.2011.03.021, doi:10.1016/j.neuron.2011.03.021. This article has 168 citations and is from a highest quality peer-reviewed journal.
(wilburn2011anantisensecag media aa402816): Brian Wilburn, Dobrila D. Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L. Sopher, Albert R. La Spada, Alex Osmand, Russell L. Margolis, Yi E. Sun, and X. William Yang. An antisense cag repeat transcript at jph3 locus mediates expanded polyglutamine protein toxicity in huntington's disease-like 2 mice. Neuron, 70:427-440, May 2011. URL: https://doi.org/10.1016/j.neuron.2011.03.021, doi:10.1016/j.neuron.2011.03.021. This article has 168 citations and is from a highest quality peer-reviewed journal.
(anderson2025huntingtondiseaselike2 pages 11-14): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.
(baine2016thefrequencyof pages 1-2): Fiona K. Baine, Amanda Krause, and L. Jacquie Greenberg. The frequency of huntington disease and huntington disease-like 2 in the south african population. Neuroepidemiology, 46:198-202, Feb 2016. URL: https://doi.org/10.1159/000444020, doi:10.1159/000444020. This article has 43 citations and is from a peer-reviewed journal.
(baine2016thefrequencyof pages 2-3): Fiona K. Baine, Amanda Krause, and L. Jacquie Greenberg. The frequency of huntington disease and huntington disease-like 2 in the south african population. Neuroepidemiology, 46:198-202, Feb 2016. URL: https://doi.org/10.1159/000444020, doi:10.1159/000444020. This article has 43 citations and is from a peer-reviewed journal.
(krause2015junctophilin3(jph3) pages 1-3): Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, and Russell Margolis. Junctophilin 3 (jph3) expansion mutations causing huntington disease like 2 (hdl2) are common in south african patients with african ancestry and a huntington disease phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168:573-585, Oct 2015. URL: https://doi.org/10.1002/ajmg.b.32332, doi:10.1002/ajmg.b.32332. This article has 73 citations.
(anderson2025comparativeanalysisof pages 9-13): David G Anderson, Aline Ferreira-Correia, Filipe B Rodrigues, Lauren M Byrne, Edward J Wild, and Amanda Krause. Comparative analysis of neurofilament light chain in huntington's disease like 2 and huntington's disease. Journal of Huntington's Disease, 14:103-108, Nov 2025. URL: https://doi.org/10.1177/18796397241300141, doi:10.1177/18796397241300141. This article has 0 citations and is from a peer-reviewed journal.
(bates2015huntingtondisease pages 16-19): Gillian P. Bates, Ray Dorsey, James F. Gusella, Michael R. Hayden, Chris Kay, Blair R. Leavitt, Martha Nance, Christopher A. Ross, Rachael I. Scahill, Ronald Wetzel, Edward J. Wild, and Sarah J. Tabrizi. Huntington disease. Nature Reviews Disease Primers, Apr 2026. URL: https://doi.org/10.1038/nrdp.2015.5, doi:10.1038/nrdp.2015.5. This article has 1437 citations.
(krause2015junctophilin3(jph3) pages 8-10): Amanda Krause, Claire Mitchell, Fahmida Essop, Susan Tager, James Temlett, Giovanni Stevanin, Christopher Ross, Dobrila Rudnicki, and Russell Margolis. Junctophilin 3 (jph3) expansion mutations causing huntington disease like 2 (hdl2) are common in south african patients with african ancestry and a huntington disease phenotype. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 168:573-585, Oct 2015. URL: https://doi.org/10.1002/ajmg.b.32332, doi:10.1002/ajmg.b.32332. This article has 73 citations.
(baine2016thefrequencyof pages 3-4): Fiona K. Baine, Amanda Krause, and L. Jacquie Greenberg. The frequency of huntington disease and huntington disease-like 2 in the south african population. Neuroepidemiology, 46:198-202, Feb 2016. URL: https://doi.org/10.1159/000444020, doi:10.1159/000444020. This article has 43 citations and is from a peer-reviewed journal.
(anderson2025comparativeanalysisof pages 6-9): David G Anderson, Aline Ferreira-Correia, Filipe B Rodrigues, Lauren M Byrne, Edward J Wild, and Amanda Krause. Comparative analysis of neurofilament light chain in huntington's disease like 2 and huntington's disease. Journal of Huntington's Disease, 14:103-108, Nov 2025. URL: https://doi.org/10.1177/18796397241300141, doi:10.1177/18796397241300141. This article has 0 citations and is from a peer-reviewed journal.
(anderson2025comparativeanalysisof pages 1-6): David G Anderson, Aline Ferreira-Correia, Filipe B Rodrigues, Lauren M Byrne, Edward J Wild, and Amanda Krause. Comparative analysis of neurofilament light chain in huntington's disease like 2 and huntington's disease. Journal of Huntington's Disease, 14:103-108, Nov 2025. URL: https://doi.org/10.1177/18796397241300141, doi:10.1177/18796397241300141. This article has 0 citations and is from a peer-reviewed journal.
(anderson2025huntingtondiseaselike2 pages 8-10): DD Rudnicki and RL Margolis. Huntington disease-like 2. Definitions, Feb 2020. URL: https://doi.org/10.32388/lkfkvq, doi:10.32388/lkfkvq. This article has 11 citations.