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. HDL2 is caused by a CGG repeat expansion in the JPH3 (junctophilin-3) gene on chromosome 16q24.3.
¶ Genetics and Pathophysiology
- 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
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 throughout the brain, particularly in the striatum and cortex, which are the primary regions affected in HDL2.
HDL2 presents with clinical features almost identical to Huntington's disease:
- 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
- Dysarthria (slurred speech)
- Dysphagia (difficulty swallowing)
- Gait disturbance and falls
- Dystonia in later stages
- Parkinsonism in some patients
- Depression (most common)
- Anxiety disorders
- Apathy
- Impulse control problems
- Less commonly, hallucinations and delusions
- 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.
- Adult-onset progressive chorea
- Cognitive/behavioral decline
- Family history consistent with autosomal dominant inheritance
- Negative Huntington's disease testing (normal HTT CAG repeat)
- Positive JPH3 CGG repeat expansion
- Molecular testing: PCR and fragment analysis to detect CGG repeat expansion in JPH3
- Southern blotting: To confirm large expansions (>100 repeats)
- MRI: Caudate nucleus and putamen atrophy, cortical atrophy in advanced cases
- CT: May show striatal atrophy in moderate to advanced disease
- Huntington's disease (HTT CAG expansion)
- HDL1 (PRNP octapeptide insertions)
- Spinocerebellar ataxias
- Neuroacanthocytosis syndromes
- Benign hereditary chorea
- Drug-induced movement disorders
Currently, there is no cure or disease-modifying therapy for HDL2. Treatment is supportive and symptomatic.
- Tetrabenazine: First-line for chorea control
- Deutetrabenazine: Alternative with potentially better tolerability
- Antipsychotics: Haloperidol, olanzapine, or risperidone
- Depression: SSRIs (sertraline, citalopram)
- Anxiety: Benzodiazepines or SSRIs
- Psychosis: Atypical antipsychotics
- No effective pharmacologic treatments
- Supportive care and cognitive rehabilitation
- Physical therapy: Exercise and fall prevention
- Occupational therapy: Adaptive equipment and home modifications
- Speech therapy: For dysarthria and dysphagia
- Nutritional support: Diet modification and feeding assistance
- Prevalence: Very rare; estimated at <1 per million
- Geographic distribution: Described in families from South Africa, the United States, and other countries
- Ethnicity: Initially described in families of African descent, but now reported in multiple ethnic groups
- Pathogenesis studies: Understanding RNA toxicity and RAN translation
- Biomarker development: Identifying fluid and imaging biomarkers
- Therapeutic development:
- Antisense oligonucleotides (ASOs) targeting JPH3
- Small molecules to reduce toxic RAN translation
- Gene therapy approaches
- Mouse models with expanded CGG repeats in JPH3 are being developed
- These models will be crucial for testing therapeutic interventions