Huntington's disease-like 2 (HDL2) is a rare autosomal dominant neurodegenerative disorder that phenotypically resembles Huntington's disease but is caused by a different genetic mutation. It was first described in 2004 in a large family from South Africa and is now recognized as an important cause of Huntington's disease-like syndrome worldwide[@walker2007]. HDL2 is caused by a CGG repeat expansion in the JPH3 (junctophilin-3) gene on chromosome 16q24.3[@margolis2004].
Pathway / Mechanism Diagram
graph TD
A["HTT Gene: CAG Repeat Expansion"] --> B["Mutant Huntingtin (mHTT)"]
B --> C["Polyglutamine Aggregation"]
C --> D["Nuclear Inclusions"]
B --> E["Transcriptional Dysregulation"]
E --> F["BDNF Downregulation"]
F --> G["Striatal Neuron Vulnerability"]
B --> H["Mitochondrial Dysfunction"]
H --> I["Energy Deficit"]
B --> J["Impaired Autophagy"]
J --> K["Toxic Protein Accumulation"]
G --> L["Medium Spiny Neuron Death"]
I --> L
K --> L
L --> M["Chorea and Motor Symptoms"]
L --> N["Cognitive Decline"]
L --> O["Psychiatric Symptoms"]
style A fill:#ef5350,color:#e0e0e0
style L fill:#ef5350,color:#e0e0e0
style B fill:#5d4400,color:#e0e0e0
Genetics and Pathophysiology
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Huntington's Disease-Like 2 (HDL2)
Overview
Huntington's disease-like 2 (HDL2) is a rare autosomal dominant neurodegenerative disorder that phenotypically resembles Huntington's disease but is caused by a different genetic mutation. It was first described in 2004 in a large family from South Africa and is now recognized as an important cause of Huntington's disease-like syndrome worldwide[@walker2007]. HDL2 is caused by a CGG repeat expansion in the JPH3 (junctophilin-3) gene on chromosome 16q24.3[@margolis2004].
Pathway / Mechanism Diagram
Mermaid diagram (expand to render)
Genetics and Pathophysiology
Genetic Basis
Inheritance: Autosomal dominant
Gene: JPH3 (junctophilin-3)
Mutation Type: CGG trinucleotide repeat expansion in the 5' UTR
Chromosomal Location: 16q24.3
Normal Repeat: 6-27 CGG repeats
Pathogenic Repeat: 41-58+ CGG repeats
Pathophysiology
The exact mechanism by which the JPH3 mutation leads to neurodegeneration remains incompletely understood. Several hypotheses have been proposed:
RNA-mediated toxicity: Expanded CGG repeats may form toxic RNA structures that sequester essential RNA-binding proteins
Repeat-associated non-AUG (RAN) translation: Production of toxic polyglycine-containing proteins
Loss of JPH3 function: Junctophilin-3 is involved in calcium homeostasis at the endoplasmic reticulum-mitochondria contact sites
JPH3 is expressed in [neurons](/entities/neurons) throughout the brain, particularly in the striatum and [cortex](/brain-regions/cortex), which are the primary regions affected in HDL2[@storey2015].
Clinical Presentation
HDL2 presents with clinical features almost identical to Huntington's disease:
Core Symptoms
Chorea: Involuntary, dance-like movements typically starting in the face and progressing to limbs
Cognitive decline: Executive dysfunction, memory impairment, and eventual dementia
Psychiatric disturbances: Depression, anxiety, irritability, and sometimes psychosis
Motor Features
Dysarthria (slurred speech)
Dysphagia (difficulty swallowing)
Gait disturbance and falls
Dystonia in later stages
Parkinsonism in some patients
Psychiatric Features
Depression (most common)
Anxiety disorders
Apathy
Impulse control problems
Less commonly, hallucinations and delusions
Disease Course
Age of onset: Typically 30-50 years, but can range from early 20s to late 60s
Disease duration: 10-20 years from symptom onset to death
Progression: Gradual decline in motor and cognitive function
A similar phenomenon to Huntington's disease is observed where larger repeat expansions are associated with earlier onset[@krause2007].
Diagnosis
Diagnostic Criteria
Adult-onset progressive chorea
Cognitive/behavioral decline
Family history consistent with autosomal dominant inheritance